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Mobaraki S, Nissen PH, Donskov F, Wozniak A, Van Herck Y, Coosemans L, van Nieuwenhuyse T, Lambrechts D, Bechter O, Baldewijns M, Roussel E, Laenen A, Beuselinck B. Cabozantinib Induces Isolated Hyperbilirubinemia in Renal Cell Carcinoma Patients carrying the UGT1A1*28 Polymorphism. Clin Genitourin Cancer 2024; 22:102180. [PMID: 39155162 DOI: 10.1016/j.clgc.2024.102180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Accepted: 07/24/2024] [Indexed: 08/20/2024]
Abstract
BACKGROUND Genetic variants of UGT1A1, involved in glucuronidation and clearance of bilirubin, are associated with reduced bilirubin metabolization and drug-induced isolated hyperbilirubinemia. We studied the impact of the UGT1A1*28 polymorphism on drug-induced isolated hyperbilirubinemia in metastatic renal cell carcinoma patients treated with pazopanib, cabozantinib, and axitinib. METHODS We genotyped the UGT1A1*28 TA6/TA6-TA6/TA7-TA7/TA7 polymorphism and correlated with median baseline, on-treatment and peak bilirubin levels during therapy, incidence of grade-1- or -2 (G1/2)-hyperbilirubinemia and time-to-G1-hyperbilirubinemia. RESULTS Of the 66 patients treated with pazopanib, 29 received axitinib and 28 cabozantinib upon progression. Median baseline bilirubin was higher in TA7/TA7-carriers versus TA6/TA6+TA6/TA7-carriers at start of pazopanib (P < .0001), cabozantinib (P < .0001), and axitinib (P = .007). During pazopanib therapy, median bilirubin increased 1.4-fold in TA7/TA7+TA6/TA7-carriers but not in TA6/TA6-carriers. On cabozantinib, bilirubin increased 1.5-fold in TA7/TA7-carriers but not in TA6/TA6+TA6/TA7-carriers. Axitinib did not increase bilirubin in any genotype. Peak bilirubin in TA7/TA7- versus TA6/TA6+TA6/TA7-carriers was higher on pazopanib (P < .0001) or cabozantinib (P < .0001). With pazopanib, G1-hyperbilirubinemia occurred in 57% of TA7/TA7- and 12% of TA6/TA6+TA6/TA7-carriers (P = .0009) and G2-hyperbilirubinemia in 36% and 6% of the patients, respectively (P = .004). On cabozantinib, G1-hyperbilirubinemia occurred in 100% of TA7/TA7- and 5% of TA6/TA6+TA6/TA7-carriers (P < .0001) and G2-hyperbilirubinemia in 33% and 0% of the patients, respectively (P = .04). On axitinib, no correlation between the genotypes and G1/2-hyperbilirubinemia was observed. CONCLUSION We validate the previously described impact of the UGT1A1*28 polymorphism on isolated bilirubin increase on pazopanib. We report for the first time that cabozantinib also interferes with UGT1A1 and causes isolated bilirubin increase.
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Affiliation(s)
- Sajedeh Mobaraki
- Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium
| | - Peter Henrik Nissen
- Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Frede Donskov
- Department of Oncology, University Hospital of Southern Denmark, Esbjerg, Denmark
| | | | - Yannick Van Herck
- Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium
| | - Lina Coosemans
- Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium
| | | | - Diether Lambrechts
- Laboratory for Translational Genetics, Department of Human Genetics, VIB Center for Cancer Biology, KU Leuven, Leuven, Belgium
| | - Oliver Bechter
- Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium
| | | | - Eduard Roussel
- Department of Urology, University Hospitals Leuven, Leuven, Belgium
| | | | - Benoit Beuselinck
- Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium.
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Elgarhy FM, Borham A, Alziny N, AbdElaal KR, Shuaib M, Musaibah AS, Hussein MA, Abdelnaser A. From Drug Discovery to Drug Approval: A Comprehensive Review of the Pharmacogenomics Status Quo with a Special Focus on Egypt. Pharmaceuticals (Basel) 2024; 17:881. [PMID: 39065732 PMCID: PMC11279872 DOI: 10.3390/ph17070881] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 06/19/2024] [Accepted: 06/29/2024] [Indexed: 07/28/2024] Open
Abstract
Pharmacogenomics (PGx) is the hope for the full optimization of drug therapy while minimizing the accompanying adverse drug events that cost billions of dollars annually. Since years before the century, it has been known that inter-individual variations contribute to differences in specific drug responses. It is the bridge to what is well-known today as "personalized medicine". Addressing the drug's pharmacokinetics and pharmacodynamics is one of the features of this science, owing to patient characteristics that vary on so many occasions. Mainly in the liver parenchymal cells, intricate interactions between the drug molecules and enzymes family of so-called "Cytochrome P450" occur which hugely affects how the body will react to the drug in terms of metabolism, efficacy, and safety. Single nucleotide polymorphisms, once validated for a transparent and credible clinical utility, can be used to guide and ensure the succession of the pharmacotherapy plan. Novel tools of pharmacoeconomics science are utilized extensively to assess cost-effective pharmacogenes preceding the translation to the bedside. Drug development and discovery incorporate a drug-gene perspective and save more resources. Regulations and laws shaping the clinical PGx practice can be misconceived; however, these pre-/post approval processes ensure the product's safety and efficacy. National and international regulatory agencies seek guidance on maintaining conduct in PGx practice. In this patient-centric era, social and legal considerations manifest in a way that makes them unavoidable, involving patients and other stakeholders in a deliberate journey toward utmost patient well-being. In this comprehensive review, we contemporarily addressed the scientific leaps in PGx, along with various challenges that face the proper implementation of personalized medicine in Egypt. These informative insights were drawn to serve what the Egyptian population, in particular, would benefit from in terms of knowledge and know-how while maintaining the latest global trends. Moreover, this review is the first to discuss various modalities and challenges faced in Egypt regarding PGx, which we believe could be used as a pilot piece of literature for future studies locally, regionally, and internationally.
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Affiliation(s)
- Fadya M. Elgarhy
- Institute of Global Health and Human Ecology, School of Sciences and Engineering, The American University, Cairo 11835, Egypt; (F.M.E.); (A.B.); (N.A.); (M.S.); (A.S.M.); (M.A.H.)
- Egypt Center for Research and Regenerative Medicine (ECRRM), Cairo 4435121, Egypt
| | - Abdallah Borham
- Institute of Global Health and Human Ecology, School of Sciences and Engineering, The American University, Cairo 11835, Egypt; (F.M.E.); (A.B.); (N.A.); (M.S.); (A.S.M.); (M.A.H.)
| | - Noha Alziny
- Institute of Global Health and Human Ecology, School of Sciences and Engineering, The American University, Cairo 11835, Egypt; (F.M.E.); (A.B.); (N.A.); (M.S.); (A.S.M.); (M.A.H.)
| | - Khlood R. AbdElaal
- Graduate Program of Biotechnology, School of Sciences and Engineering, The American University, Cairo 11835, Egypt;
| | - Mahmoud Shuaib
- Institute of Global Health and Human Ecology, School of Sciences and Engineering, The American University, Cairo 11835, Egypt; (F.M.E.); (A.B.); (N.A.); (M.S.); (A.S.M.); (M.A.H.)
| | - Abobaker Salem Musaibah
- Institute of Global Health and Human Ecology, School of Sciences and Engineering, The American University, Cairo 11835, Egypt; (F.M.E.); (A.B.); (N.A.); (M.S.); (A.S.M.); (M.A.H.)
| | - Mohamed Ali Hussein
- Institute of Global Health and Human Ecology, School of Sciences and Engineering, The American University, Cairo 11835, Egypt; (F.M.E.); (A.B.); (N.A.); (M.S.); (A.S.M.); (M.A.H.)
| | - Anwar Abdelnaser
- Institute of Global Health and Human Ecology, School of Sciences and Engineering, The American University, Cairo 11835, Egypt; (F.M.E.); (A.B.); (N.A.); (M.S.); (A.S.M.); (M.A.H.)
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Lingaratnam S, Shah M, Nicolazzo J, Michael M, Seymour JF, James P, Lazarakis S, Loi S, Kirkpatrick CMJ. A systematic review and meta-analysis of the impacts of germline pharmacogenomics on severe toxicity and symptom burden in adult patients with cancer. Clin Transl Sci 2024; 17:e13781. [PMID: 38700261 PMCID: PMC11067509 DOI: 10.1111/cts.13781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 02/12/2024] [Accepted: 03/14/2024] [Indexed: 05/05/2024] Open
Abstract
The clinical application of Pharmacogenomics (PGx) has improved patient safety. However, comprehensive PGx testing has not been widely adopted in clinical practice, and significant opportunities exist to further optimize PGx in cancer care. This systematic review and meta-analysis aim to evaluate the safety outcomes of reported PGx-guided strategies (Analysis 1) and identify well-studied emerging pharmacogenomic variants that predict severe toxicity and symptom burden (Analysis 2) in patients with cancer. We searched MEDLINE, EMBASE, CENTRAL, clinicaltrials.gov, and International Clinical Trials Registry Platform from inception to January 2023 for clinical trials or comparative studies evaluating PGx strategies or unconfirmed pharmacogenomic variants. The primary outcomes were severe adverse events (SAE; ≥ grade 3) or symptom burden with pain and vomiting as defined by trial protocols and assessed by trial investigators. We calculated pooled overall relative risk (RR) and 95% confidence interval (95%CI) using random effects models. PROSPERO, registration number CRD42023421277. Of 6811 records screened, six studies were included for Analysis 1, 55 studies for Analysis 2. Meta-analysis 1 (five trials, 1892 participants) showed a lower absolute incidence of SAEs with PGx-guided strategies compared to usual therapy, 16.1% versus 34.0% (RR = 0.72, 95%CI 0.57-0.91, p = 0.006, I2 = 34%). Meta-analyses 2 identified nine medicine(class)-variant pairs of interest across the TYMS, ABCB1, UGT1A1, HLA-DRB1, and OPRM1 genes. Application of PGx significantly reduced rates of SAEs in patients with cancer. Emergent medicine-variant pairs herald further research into the expansion and optimization of PGx to improve systemic anti-cancer and supportive care medicine safety and efficacy.
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Affiliation(s)
- Senthil Lingaratnam
- Pharmacy DepartmentPeter MacCallum Cancer CentreMelbourneVictoriaAustralia
- Sir Peter MacCallum Department of OncologyUniversity of MelbourneMelbourneVictoriaAustralia
- Monash Institute of Pharmaceutical Sciences, Monash UniversityMelbourneVictoriaAustralia
| | - Mahek Shah
- Faculty of Pharmacy and Pharmaceutical SciencesMonash UniversityMelbourneVictoriaAustralia
| | - Joseph Nicolazzo
- Monash Institute of Pharmaceutical Sciences, Monash UniversityMelbourneVictoriaAustralia
| | - Michael Michael
- Sir Peter MacCallum Department of OncologyUniversity of MelbourneMelbourneVictoriaAustralia
- Department of Medical OncologyPeter MacCallum Cancer CentreMelbourneVictoriaAustralia
| | - John F. Seymour
- Sir Peter MacCallum Department of OncologyUniversity of MelbourneMelbourneVictoriaAustralia
- Department of Clinical HaematologyPeter MacCallum Cancer Centre and Royal Melbourne HospitalMelbourneVictoriaAustralia
| | - Paul James
- Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre and Royal Melbourne HospitalMelbourneVictoriaAustralia
| | - Smaro Lazarakis
- Health Sciences LibraryRoyal Melbourne HospitalMelbourneVictoriaAustralia
| | - Sherene Loi
- Sir Peter MacCallum Department of OncologyUniversity of MelbourneMelbourneVictoriaAustralia
- Division of Cancer ResearchPeter MacCallum Cancer CentreMelbourneVictoriaAustralia
| | - Carl M. J. Kirkpatrick
- Monash Institute of Pharmaceutical Sciences, Monash UniversityMelbourneVictoriaAustralia
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Özmen D, Alpaydın DD, Saldoğan MA, Eşkazan AE. A safety review of tyrosine kinase inhibitors for chronic myeloid leukemia. Expert Opin Drug Saf 2024; 23:411-423. [PMID: 38484148 DOI: 10.1080/14740338.2024.2331190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 03/07/2024] [Indexed: 04/04/2024]
Abstract
INTRODUCTION Since the introduction of first tyrosine kinase inhibitor (TKI) imatinib, the treatment of chronic myeloid leukemia (CML) has reached excellent survival expectancies. Long survival rates bring about issues regarding TKI safety. AREAS COVERED The aim of this review is to compare the side effects of current TKIs both in the first and later lines and outline a safety andprofile of CML treatment. Seminal studies on TKIs and other newer drugs and extended follow-up of these studies; real-life data of each drug were usedduring the course of this. PubMed was used as a search database and onlyarticles in English were included. EXPERT OPINION With longer follow-up CML patients, resistant slowgrade adverse events seem to be the major obstacle in the way of treatmentefficacy. If efficacy is the priority, vigorous treatment of side effect and administration of full dose TKI are reasonable. But when treatment goals are reached, dose modifications or alternative treatment regimens may be acceptedpossible. More studies are needed on dose modification protocols and potential benefits and safety of treatment-free remission.
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Affiliation(s)
- Deniz Özmen
- Division of Hematology, Department of Internal Medicine, Cerrahpaşa Faculty of Medicine, Istanbul University-Cerrahpaşa, Istanbul, Turkey
| | - Duygu Demet Alpaydın
- Cerrahpaşa Faculty of Medicine, Istanbul University-Cerrahpaşa, Istanbul, Turkey
| | | | - Ahmet Emre Eşkazan
- Division of Hematology, Department of Internal Medicine, Cerrahpaşa Faculty of Medicine, Istanbul University-Cerrahpaşa, Istanbul, Turkey
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Wei S, Li X, Wu H, Zhang Q, Wu Y, Zhao Z, Mei S, Feng W. UGT1A polymorphism rs4148324 associated with topiramate plasma concentration to dose ratio in children with epilepsy. Seizure 2024; 116:107-112. [PMID: 37858371 DOI: 10.1016/j.seizure.2023.10.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 09/23/2023] [Accepted: 10/06/2023] [Indexed: 10/21/2023] Open
Abstract
PURPOSE The objective of this study is to evaluate the association between genetic polymorphisms and the concentration to dose ratio of topiramate in children with epilepsy. METHODS A cohort of 163 pediatric patients with epilepsy receiving topiramate therapy were enrolled. The ultra-performance liquid chromatography-tandem mass spectrometry method was employed to measure the trough plasma concentration of topiramate at steady-state. These concentrations were normalized by dividing them by the ratio of total daily dose to body weight, yielding the concentration to dose ratio (CDR) of topiramate. MassArray system identified 30 single nucleotide polymorphisms associated with the pharmacokinetics and pharmacodynamics of topiramate. The CDR values were logarithmic transformed (lnCDR) for normal distribution. The association between the identified genetic polymorphisms and lnCDR was assessed using the PLINK software, employing linear regression analysis with adjustments by epilepsy types, estimated glomerular filtration rate, alanine aminotransferase, valproic acid, phenobarbital, and oxcarbazepine. RESULTS Variant rs4148324 (UGT1A1/3/4/5/6/7/8/9/10, BETA = 0.182, P = 0.010) was significantly associated with lnCDR of topiramate. Patients carrying the G allele exhibited higher normalized topiramate plasma concentrations. No other significant associations were found. CONCLUSIONS In pediatric patients receiving topiramate therapy, rs4148324 was associated with normalized topiramate plasma concentration. Further studies are warranted to validate and confirm the findings.
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Affiliation(s)
- Shifeng Wei
- Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, 119 Nansihuan West Road, Fengtai District, Beijing 100070, China; Department of Clinical Pharmacology, College of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China
| | - Xingmeng Li
- Department of Neurology, Beijing Children's Hospital, Capital Medical University, Beijing 100045, China
| | - Han Wu
- Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, 119 Nansihuan West Road, Fengtai District, Beijing 100070, China; Department of Clinical Pharmacology, College of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China
| | - Qiang Zhang
- Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, 119 Nansihuan West Road, Fengtai District, Beijing 100070, China; Department of Clinical Pharmacology, College of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China
| | - Yun Wu
- Department of Neurology, Beijing Children's Hospital, Capital Medical University, Beijing 100045, China
| | - Zhigang Zhao
- Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, 119 Nansihuan West Road, Fengtai District, Beijing 100070, China; Department of Clinical Pharmacology, College of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China.
| | - Shenghui Mei
- Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, 119 Nansihuan West Road, Fengtai District, Beijing 100070, China; Department of Clinical Pharmacology, College of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China.
| | - Weixing Feng
- Department of Neurology, Beijing Children's Hospital, Capital Medical University, Beijing 100045, China.
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Cheng F, Wang H, Li W, Zhang Y. Clinical pharmacokinetics and drug-drug interactions of tyrosine-kinase inhibitors in chronic myeloid leukemia: A clinical perspective. Crit Rev Oncol Hematol 2024; 195:104258. [PMID: 38307392 DOI: 10.1016/j.critrevonc.2024.104258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 12/22/2023] [Accepted: 01/02/2024] [Indexed: 02/04/2024] Open
Abstract
In the past decade, numerous tyrosine kinase inhibitors (TKIs) have been introduced in the treatment of chronic myeloid leukemia. Given the significant interpatient variability in TKIs pharmacokinetics, potential drug-drug interactions (DDIs) can greatly impact patient therapy. This review aims to discuss the pharmacokinetic characteristics of TKIs, specifically focusing on their absorption, distribution, metabolism, and excretion profiles. Additionally, it provides a comprehensive overview of the utilization of TKIs in special populations such as the elderly, children, and patients with liver or kidney dysfunction. We also highlight known or suspected DDIs between TKIs and other drugs, highlighting various clinically relevant interactions. Moreover, specific recommendations are provided to guide haemato-oncologists, oncologists, and clinical pharmacists in managing DDIs during TKI treatment in daily clinical practice.
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Affiliation(s)
- Fang Cheng
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan 430022, China
| | - Hongxiang Wang
- Department of Hematology, the Central Hospital of Wuhan, 430014, China
| | - Weiming Li
- Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| | - Yu Zhang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan 430022, China.
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Kostrubsky V, Liu Y, Muste C, Gu C, Kirkland M, Nishimura N, Hasegawa K, Hasumi K, Yuan L. Preclinical safety, toxicokinetics and metabolism of BIIB131, a novel prothrombolytic agent for acute stroke. Regul Toxicol Pharmacol 2023; 145:105498. [PMID: 37778433 DOI: 10.1016/j.yrtph.2023.105498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Revised: 08/23/2023] [Accepted: 09/28/2023] [Indexed: 10/03/2023]
Abstract
BIIB131, a small molecule, is currently in Phase 2 for the treatment of acute ischemic stroke. Safety and metabolism of BIIB131 were evaluated following intravenous administration to rats and monkeys. Exposure increased dose-proportionally in rats up to 60 mg/kg and more than dose-proportionally in monkeys at greater than 10 mg/kg accompanied by prolonged half-life and safety findings. The BIIB131 was poorly metabolized in microsomes with no inhibition of CYPs. BIIB131-glucuronide, formed by UGT1A1, accounted for 21.5% metabolism in human hepatocytes and 28-40% in rat bile. In rats, excretion was primarily via the bile. BIIB131 inhibited the hERG and Nav1.5 cardiac channels by 39% but showed no effect on cardiovascular parameters in monkeys. Toxicology findings were limited to reversable hematuria, changes in urinary parameters and local effects. A MTD of 30 mg/kg was established in monkeys, the most sensitive species, at total plasma Cmax and AUC of 6- and 14-fold, respectively, greater than the NOAEL. The Phase 1 study started with intravenous 0.05 mg/kg and ascended to 6.0 mg/kg which corresponded to safety margins of 147- to 0.9-fold (for Cmax) within the linear drug exposure. Thus, the preclinical profile of BIIB131 has been appropriately characterized and supports its further clinical development.
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Affiliation(s)
- Vick Kostrubsky
- Nonclinical Safety Science, Biogen, Inc., 225 Binney Street, Cambridge, MA, 02142, USA.
| | - Ying Liu
- Drug Metabolism and Pharmacokinetics, Biogen, Inc., 225 Binney Street, Cambridge, MA, 02142, USA
| | - Cathy Muste
- Drug Metabolism and Pharmacokinetics, Biogen, Inc., 225 Binney Street, Cambridge, MA, 02142, USA
| | - Chungang Gu
- Drug Metabolism and Pharmacokinetics, Biogen, Inc., 225 Binney Street, Cambridge, MA, 02142, USA
| | - Melissa Kirkland
- Nonclinical Safety Science, Biogen, Inc., 225 Binney Street, Cambridge, MA, 02142, USA
| | - Naoko Nishimura
- Division of Research and Development, TMS Co., Ltd., Tokyo, Japan
| | - Keiko Hasegawa
- Division of Research and Development, TMS Co., Ltd., Tokyo, Japan
| | - Keiji Hasumi
- Division of Research and Development, TMS Co., Ltd., Tokyo, Japan; Department of Applied Biological Science, Tokyo University of Agriculture and Technology, Tokyo, 183-8509, Japan
| | - Long Yuan
- Drug Metabolism and Pharmacokinetics, Biogen, Inc., 225 Binney Street, Cambridge, MA, 02142, USA
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Principi N, Petropulacos K, Esposito S. Impact of Pharmacogenomics in Clinical Practice. Pharmaceuticals (Basel) 2023; 16:1596. [PMID: 38004461 PMCID: PMC10675377 DOI: 10.3390/ph16111596] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 11/03/2023] [Accepted: 11/06/2023] [Indexed: 11/26/2023] Open
Abstract
Polymorphisms of genes encoding drug metabolizing enzymes and transporters can significantly modify pharmacokinetics, and this can be associated with significant differences in drug efficacy, safety, and tolerability. Moreover, genetic variants of some components of the immune system can explain clinically relevant drug-related adverse events. However, the implementation of drug dose individualization based on pharmacogenomics remains scarce. In this narrative review, the impact of genetic variations on the disposition, safety, and tolerability of the most commonly prescribed drugs is reported. Moreover, reasons for poor implementation of pharmacogenomics in everyday clinical settings are discussed. The literature analysis showed that knowledge of how genetic variations can modify the effectiveness, safety, and tolerability of a drug can lead to the adjustment of usually recommended drug dosages, improve effectiveness, and reduce drug-related adverse events. Despite some efforts to introduce pharmacogenomics in clinical practice, presently very few centers routinely use genetic tests as a guide for drug prescription. The education of health care professionals seems critical to keep pace with the rapidly evolving field of pharmacogenomics. Moreover, multimodal algorithms that incorporate both clinical and genetic factors in drug prescribing could significantly help in this regard. Obviously, further studies which definitively establish which genetic variations play a role in conditioning drug effectiveness and safety are needed. Many problems must be solved, but the advantages for human health fully justify all the efforts.
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Affiliation(s)
| | | | - Susanna Esposito
- Pediatric Clinic, Department of Medicine and Surgery, University Hospital of Parma, 43126 Parma, Italy
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Reizine N, O’Donnell PH. Modern developments in germline pharmacogenomics for oncology prescribing. CA Cancer J Clin 2022; 72:315-332. [PMID: 35302652 PMCID: PMC9262778 DOI: 10.3322/caac.21722] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 01/15/2022] [Accepted: 01/21/2022] [Indexed: 02/06/2023] Open
Abstract
The integration of genomic data into personalized treatment planning has revolutionized oncology care. Despite this, patients with cancer remain vulnerable to high rates of adverse drug events and medication inefficacy, affecting prognosis and quality of life. Pharmacogenomics is a field seeking to identify germline genetic variants that contribute to an individual's unique drug response. Although there is widespread integration of genomic information in oncology, somatic platforms, rather than germline biomarkers, have dominated the attention of cancer providers. Patients with cancer potentially stand to benefit from improved integration of both somatic and germline genomic information, especially because the latter may complement treatment planning by informing toxicity risk for drugs with treatment-limiting tolerabilities and narrow therapeutic indices. Although certain germline pharmacogenes, such as TPMT, UGT1A1, and DPYD, have been recognized for decades, recent attention has illuminated modern potential dosing implications for a whole new set of anticancer agents, including targeted therapies and antibody-drug conjugates, as well as the discovery of additional genetic variants and newly relevant pharmacogenes. Some of this information has risen to the level of directing clinical action, with US Food and Drug Administration label guidance and recommendations by international societies and governing bodies. This review is focused on key new pharmacogenomic evidence and oncology-specific dosing recommendations. Personalized oncology care through integrated pharmacogenomics represents a unique multidisciplinary collaboration between oncologists, laboratory science, bioinformatics, pharmacists, clinical pharmacologists, and genetic counselors, among others. The authors posit that expanded consideration of germline genetic information can further transform the safe and effective practice of oncology in 2022 and beyond.
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Affiliation(s)
- Natalie Reizine
- Division of Hematology and Oncology, Department of Medicine, The University of Illinois at Chicago
| | - Peter H. O’Donnell
- Section of Hematology/Oncology, Department of Medicine, Center for Personalized Therapeutics, and Committee on Clinical Pharmacology and Pharmacogenomics, The University of Chicago
- Correspondence to: Dr. Peter H. O’Donnell, Section of Hematology/Oncology, Department of Medicine, The University of Chicago, 5841 S. Maryland Avenue, MC2115, Chicago, IL 60637, USA. ()
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Fukuda N, Akamine Y, Abumiya M, Takahashi S, Yoshioka T, Kameoka Y, Takahashi N, Miura M. Relationship between achievement of major molecular response or deep molecular response and nilotinib plasma concentration in patients with chronic myeloid leukemia receiving first-line nilotinib therapy. Cancer Chemother Pharmacol 2022; 89:609-616. [PMID: 35316401 DOI: 10.1007/s00280-022-04419-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 03/08/2022] [Indexed: 11/02/2022]
Abstract
PURPOSE We evaluated the plasma exposure and response relationships of nilotinib for patients with newly diagnosed chronic myeloid leukemia (CML) in real-world practice. METHODS For the 26 patients enrolled in this study, at 3, 6, 12, and 24 months after nilotinib administration, the trough plasma concentrations (Ctrough) of nilotinib were analyzed. The relationships between nilotinib Ctrough and the molecular response to nilotinib treatment at each point (each n = 26) were evaluated. RESULTS Median nilotinib Ctrough values were significantly higher in patients with a major molecular response (MMR) at 3 months than in patients without an MMR (809 and 420 ng/mL, respectively; P = 0.046). Based on the area under the receiver-operating characteristic curve, the threshold value of the nilotinib Ctrough at 3 months for predicting MMR achievement was 619 ng/mL at the best sensitivity (71.4%) and specificity (77.8%). Patients with a nilotinib Ctrough of above 619 ng/mL had a significantly shorter time to achievement of a deep molecular response (DMR; 9.0 and 18.0 months, respectively; P = 0.020) and higher rates of DMR by 2 years in Kaplan-Meier plots (P = 0.025) compared with that in patients with a nilotinib Ctrough of less than 619 ng/mL. CONCLUSION For patients with newly diagnosed CML, the nilotinib dose may be adjusted using a Ctrough of above 619 ng/mL as the minimum effective concentration, i.e., the lowest concentration required for MMR or DMR achievement within a shorter time, during early stages after beginning therapy to obtain faster and deeper clinical responses.
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Affiliation(s)
- Natsuki Fukuda
- Department of Pharmacy, Akita University Hospital, 1-1-1 Hondo, Akita, Japan
| | - Yumiko Akamine
- Department of Pharmacy, Akita University Hospital, 1-1-1 Hondo, Akita, Japan
| | - Maiko Abumiya
- Department of Pharmacy, Akita University Hospital, 1-1-1 Hondo, Akita, Japan
| | - Saori Takahashi
- Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.,Clinical Research Promotion and Support Center, Akita University Hospital, Akita, Japan
| | - Tomoko Yoshioka
- Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan
| | - Yoshihiro Kameoka
- Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan.,Clinical Research Promotion and Support Center, Akita University Hospital, Akita, Japan
| | - Naoto Takahashi
- Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan
| | - Masatomo Miura
- Department of Pharmacy, Akita University Hospital, 1-1-1 Hondo, Akita, Japan. .,Department of Pharmacokinetics, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.
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11
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Pang HL, Zhu GH, Zhou QH, Ai CZ, Zhu YD, Wang P, Dou TY, Xia YL, Ma H, Ge GB. Discovery and Characterization of the Key Constituents in Ginkgo biloba Leaf Extract With Potent Inhibitory Effects on Human UDP-Glucuronosyltransferase 1A1. Front Pharmacol 2022; 13:815235. [PMID: 35264954 PMCID: PMC8899474 DOI: 10.3389/fphar.2022.815235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 01/24/2022] [Indexed: 12/04/2022] Open
Abstract
Human UDP-glucuronosyltransferase 1A1 (hUGT1A1) is one of the most essential phase II enzymes in humans. Dysfunction or strong inhibition of hUGT1A1 may result in hyperbilirubinaemia and clinically relevant drug/herb-drug interactions (DDIs/HDIs). Recently, a high-throughput fluorescence-based assay was constructed by us to find the compounds/herbal extracts with strong inhibition against intracellular hUGT1A1. Following screening of over one hundred of herbal products, the extract of Ginkgo biloba leaves (GBL) displayed the most potent hUGT1A1 inhibition in HeLa-UGT1A1 cells (Hela cells overexpressed hUGT1A1). Further investigations demonstrated that four biflavones including bilobetin, isoginkgetin, sciadopitysin and ginkgetin, are key constituents responsible for hUGT1A1 inhibition in living cells. These biflavones potently inhibit hUGT1A1 in both human liver microsomes (HLM) and living cells, with the IC50 values ranging from 0.075 to 0.41 μM in living cells. Inhibition kinetic analyses and docking simulations suggested that four tested biflavones potently inhibit hUGT1A1-catalyzed NHPN-O-glucuronidation in HLM via a mixed inhibition manner, showing the Ki values ranging from 0.07 to 0.74 μM. Collectively, our findings uncover the key constituents in GBL responsible for hUGT1A1 inhibition and decipher their inhibitory mechanisms against hUGT1A1, which will be very helpful for guiding the rational use of GBL-related herbal products in clinical settings.
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Affiliation(s)
- Hui-Lin Pang
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China
| | - Guang-Hao Zhu
- Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shangha, China
| | - Qi-Hang Zhou
- Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shangha, China
| | - Chun-Zhi Ai
- State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, Guilin, China
| | - Ya-Di Zhu
- Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shangha, China
| | - Ping Wang
- Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shangha, China
| | - Tong-Yi Dou
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China
| | - Yang-Liu Xia
- School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, China
| | - Hong Ma
- Shanghai Research Institute of Acupuncture and Meridian, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guang-Bo Ge
- Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shangha, China
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12
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Sissung TM, Figg WD. Pharmacogenomics Testing in Phase I Oncology Clinical Trials: Constructive Criticism Is Warranted. Cancers (Basel) 2022; 14:cancers14051131. [PMID: 35267440 PMCID: PMC8909728 DOI: 10.3390/cancers14051131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 02/08/2022] [Accepted: 02/19/2022] [Indexed: 12/04/2022] Open
Abstract
Simple Summary Phase I clinical trials are a cornerstone of pharmaceutical development in oncology. Many studies have now attempted to incorporate pharmacogenomics into phase I studies; however, many of these studies have fundamental flaws that that preclude interpretation and application of their findings. Study populations are often small and heterogeneous with multiple disease states, multiple dose levels, and prior therapies. Genetic testing typically includes few variants in candidate genes that do no encapsulate the full range of phenotypic variability in protein function. Moreover, a plurality of these studies do not present scientifically robust clinical or preclinical justification for undertaking pharmacogenomics studies. A significant amount of progress in understanding pharmacogenomic variability has occurred since pharmacogenomics approaches first began appearing in the literature. This progress can be immediately leveraged for the vast majority of Phase I studies. The purpose of this review is to summarize the current literature pertaining to Phase I incorporation of pharmacogenomics studies, analyze potential flaws in study design, and suggest approaches that can improve design of future scientific efforts. Abstract While over ten-thousand phase I studies are published in oncology, fewer than 1% of these studies stratify patients based on genetic variants that influence pharmacology. Pharmacogenetics-based patient stratification can improve the success of clinical trials by identifying responsive patients who have less potential to develop toxicity; however, the scientific limits imposed by phase I study designs reduce the potential for these studies to make conclusions. We compiled all phase I studies in oncology with pharmacogenetics endpoints (n = 84), evaluating toxicity (n = 42), response or PFS (n = 32), and pharmacokinetics (n = 40). Most of these studies focus on a limited number of agent classes: Topoisomerase inhibitors, antimetabolites, and anti-angiogenesis agents. Eight genotype-directed phase I studies were identified. Phase I studies consist of homogeneous populations with a variety of comorbidities, prior therapies, racial backgrounds, and other factors that confound statistical analysis of pharmacogenetics. Taken together, phase I studies analyzed herein treated small numbers of patients (median, 95% CI = 28, 24–31), evaluated few variants that are known to change phenotype, and provided little justification of pharmacogenetics hypotheses. Future studies should account for these factors during study design to optimize the success of phase I studies and to answer important scientific questions.
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Affiliation(s)
| | - William D. Figg
- Correspondence: ; Tel.: +1-240-760-6179; Fax: +1-240-541-4536
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13
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Fahmy A, Hopkins AM, Sorich MJ, Rowland A. Evaluating the utility of therapeutic drug monitoring in the clinical use of small molecule kinase inhibitors: a review of the literature. Expert Opin Drug Metab Toxicol 2021; 17:803-821. [PMID: 34278936 DOI: 10.1080/17425255.2021.1943357] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Introduction: Orally administered small molecule kinase inhibitors (KI) are a key class of targeted anti-cancer medicines that have contributed substantially to improved survival outcomes in patients with advanced disease. Since the introduction of KIs in 2001, there has been a building body of evidence that the benefit derived from these drugs may be further enhanced by individualizing dosing on the basis of concentration.Areas covered: This review considers the rationale for individualized KI dosing and the requirements for robust therapeutic drug monitoring (TDM). Current evidence supporting TDM-guided KI dosing is presented and critically evaluated, and finally potential approaches to address translational challenges for TDM-guided KI dosing and alternate approaches to support individualization of KI dosing are discussed.Expert opinion: Intuitively, the individualization of KI dosing through an approach such as TDM-guided dosing has great potential to enhance the effectiveness and tolerability of these drugs. However, based on current literature evidence it is unrealistic to propose that TDM-guided KI dosing should be routinely implemented into clinical practice.
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Affiliation(s)
- Alia Fahmy
- College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
| | - Ashley M Hopkins
- College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
| | - Michael J Sorich
- College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
| | - Andrew Rowland
- College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
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14
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Nelson RS, Seligson ND, Bottiglieri S, Carballido E, Cueto AD, Imanirad I, Levine R, Parker AS, Swain SM, Tillman EM, Hicks JK. UGT1A1 Guided Cancer Therapy: Review of the Evidence and Considerations for Clinical Implementation. Cancers (Basel) 2021; 13:1566. [PMID: 33805415 PMCID: PMC8036652 DOI: 10.3390/cancers13071566] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/18/2021] [Accepted: 03/19/2021] [Indexed: 02/07/2023] Open
Abstract
Multi-gene assays often include UGT1A1 and, in certain instances, may report associated toxicity risks for irinotecan, belinostat, pazopanib, and nilotinib. However, guidance for incorporating UGT1A1 results into therapeutic decision-making is mostly lacking for these anticancer drugs. We summarized meta-analyses, genome-wide association studies, clinical trials, drug labels, and guidelines relating to the impact of UGT1A1 polymorphisms on irinotecan, belinostat, pazopanib, or nilotinib toxicities. For irinotecan, UGT1A1*28 was significantly associated with neutropenia and diarrhea, particularly with doses ≥ 180 mg/m2, supporting the use of UGT1A1 to guide irinotecan prescribing. The drug label for belinostat recommends a reduced starting dose of 750 mg/m2 for UGT1A1*28 homozygotes, though published studies supporting this recommendation are sparse. There was a correlation between UGT1A1 polymorphisms and pazopanib-induced hepatotoxicity, though further studies are needed to elucidate the role of UGT1A1-guided pazopanib dose adjustments. Limited studies have investigated the association between UGT1A1 polymorphisms and nilotinib-induced hepatotoxicity, with data currently insufficient for UGT1A1-guided nilotinib dose adjustments.
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Affiliation(s)
- Ryan S. Nelson
- Department of Consultative Services, ARUP Laboratories, Salt Lake City, UT 84108, USA;
- Department of Individualized Cancer Management, Moffitt Cancer Center, Tampa, FL 33612, USA;
| | - Nathan D. Seligson
- Department of Pharmacotherapy and Translational Research, The University of Florida, Jacksonville, FL 32610, USA;
- Department of Hematology and Oncology, Nemours Children’s Specialty Care, Jacksonville, FL 32207, USA
| | - Sal Bottiglieri
- Department of Pharmacy, Moffitt Cancer Center, Tampa, FL 33612, USA;
| | - Estrella Carballido
- Department of Oncological Sciences, University of South Florida, Tampa, FL 33612, USA; (E.C.); (I.I.); (R.L.)
- Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Alex Del Cueto
- Department of Individualized Cancer Management, Moffitt Cancer Center, Tampa, FL 33612, USA;
| | - Iman Imanirad
- Department of Oncological Sciences, University of South Florida, Tampa, FL 33612, USA; (E.C.); (I.I.); (R.L.)
- Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Richard Levine
- Department of Oncological Sciences, University of South Florida, Tampa, FL 33612, USA; (E.C.); (I.I.); (R.L.)
- Department of Satellite and Community Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA
| | | | - Sandra M. Swain
- Georgetown University Medical Center, MedStar Health, Washington, DC 20007, USA;
| | - Emma M. Tillman
- Indiana University School of Medicine, Indianapolis, IN 46202, USA;
| | - J. Kevin Hicks
- Department of Individualized Cancer Management, Moffitt Cancer Center, Tampa, FL 33612, USA;
- Department of Oncological Sciences, University of South Florida, Tampa, FL 33612, USA; (E.C.); (I.I.); (R.L.)
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15
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[Consensus of Chinese experts on prevention and standardized treatment of drug-induced liver injury in patients with blood diseases (2021)]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2021; 42:185-192. [PMID: 33910302 PMCID: PMC8081943 DOI: 10.3760/cma.j.issn.0253-2727.2021.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Indexed: 11/05/2022]
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16
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Wang Z, Jiang L, Yan H, Xu Z, Luo P. Adverse events associated with nilotinib in chronic myeloid leukemia: mechanisms and management strategies. Expert Rev Clin Pharmacol 2021; 14:445-456. [PMID: 33618586 DOI: 10.1080/17512433.2021.1894129] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Introduction: Nilotinib is a second-generation tyrosine kinase inhibitor (TKI) targeting BCR/ABL, which is used for the first-line treatment of newly diagnosed chronic myeloid leukemia (CML) patients and the second-line treatment of most CML patients who are resistant or intolerant to prior therapy that includes imatinib. In addition to common adverse reactions, long-term use of nilotinib shows some toxicities that are different from those of occurring during other BCR/ABL TKI treatments, such as cardiovascular toxicity. It is life-threatening, which would affect not only the choice of initial treatment of CML patients but also the safety of long-term medication.Areas covered: Through searching literature and reports from PubMed and clinical trials, here we review a profile of the adverse effects induced by nilotinib. We also discuss the potential molecular toxicological mechanisms and clinical management, which may provide strategies to prevent or intervene the toxicity associated with nilotinib.Expert opinion: Severe adverse effects associated with nilotinib limit its long-term clinical application. However, the exact mechanisms underlying these toxicities remain unclear. Future research should focus on the developing strategies to reduce the toxicities of nilotinib as well as to avoid similar toxicity in the development of new drugs.
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Affiliation(s)
- Zeng Wang
- Department of Colorectal Pharmacy, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Cancer and Basic Medicine (ICBM), Chinese Academy of Sciences, Hangzhou, China
| | - Liyu Jiang
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Hao Yan
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Zhifei Xu
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
| | - Peihua Luo
- Center for Drug Safety Evaluation and Research of Zhejiang University, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China
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17
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Lin YS, Thummel KE, Thompson BD, Totah RA, Cho CW. Sources of Interindividual Variability. Methods Mol Biol 2021; 2342:481-550. [PMID: 34272705 DOI: 10.1007/978-1-0716-1554-6_17] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
The efficacy, safety, and tolerability of drugs are dependent on numerous factors that influence their disposition. A dose that is efficacious and safe for one individual may result in sub-therapeutic or toxic blood concentrations in others. A significant source of this variability in drug response is drug metabolism, where differences in presystemic and systemic biotransformation efficiency result in variable degrees of systemic exposure (e.g., AUC, Cmax, and/or Cmin) following administration of a fixed dose.Interindividual differences in drug biotransformation have been studied extensively. It is recognized that both intrinsic factors (e.g., genetics, age, sex, and disease states) and extrinsic factors (e.g., diet , chemical exposures from the environment, and the microbiome) play a significant role. For drug-metabolizing enzymes, genetic variation can result in the complete absence or enhanced expression of a functional enzyme. In addition, upregulation and downregulation of gene expression, in response to an altered cellular environment, can achieve the same range of metabolic function (phenotype), but often in a less predictable and time-dependent manner. Understanding the mechanistic basis for variability in drug disposition and response is essential if we are to move beyond the era of empirical, trial-and-error dose selection and into an age of personalized medicine that will improve outcomes in maintaining health and treating disease.
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Affiliation(s)
- Yvonne S Lin
- Department of Pharmaceutics, University of Washington, Seattle, WA, USA.
| | - Kenneth E Thummel
- Department of Pharmaceutics, University of Washington, Seattle, WA, USA
| | - Brice D Thompson
- Department of Pharmaceutics, University of Washington, Seattle, WA, USA
| | - Rheem A Totah
- Department of Medicinal Chemistry, University of Washington, Seattle, WA, USA
| | - Christi W Cho
- Department of Medicinal Chemistry, University of Washington, Seattle, WA, USA
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18
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Abstract
INTRODUCTION Nilotinib is a selective inhibitor of the BCR-ABL tyrosine kinase receptor and is used in the management of chronic myelogenous leukemia (CML). Nilotinib therapy at high doses is associated with elevated serum bilirubin levels. If the serum bilirubin level exceeds 3 times the upper limit of normal, the recommendation is to either adjust nilotinib dosage or temporarily discontinue the treatment. However, it is unclear whether hyperbilirubinemia indicates obvious liver histology damage. PATIENT CONCERNS A 24-year-old man with confirmed CML was treated with nilotinib therapy and developed hyperbilirubinemia after the treatment. Although the first remission of the hyperbilirubinemia was achieved after dose adjustment, the hematological parameters deteriorated. Thus, we initiated an antineoplastic therapy (at the standard dose) until complete remission of the CML was achieved. The pathogenic mechanism of hyperbilirubinemia may be related to the inhibition of uridine diphosphate-glucuronosyltransferase (UGT1A1) activity. Liver histological analysis revealed no significant liver damage. In addition, the patient had no family history of hyperbilirubinemia and liver disease. DIAGNOSIS The patient was admitted to our hospital under the diagnosis of hyperbilirubinemia, and histopathology by liver biopsy showed no obvious damage. We also detected a UGT1A1 mutation [ex1 c.686C > A (p.Pro229Gln)] in the patient and his mother. INTERVENTIONS When the nilotinib dose was decreased to 300 mg daily, the total bilirubin (TBIL) level decreased to 30 to 50 μmol/L for 1 month. However, because the Bcr-Abl/Abl ratio did not correspond to the major molecular response (MMR; <0.1%), the nilotinib dose was readjusted to 400 mg daily. One week later, the TBIL and indirect bilirubin levels increased to 89 and 79 μmol/L, respectively. The levels of alanine transaminase and other liver functional indicators were normal. OUTCOMES A Naranjo Adverse Drug Reaction (ADR) Probability Scale score of 13 indicates that hyperbilirubinemia is attributed to ADR caused by nilotinib rather than by drug-induced liver injury. CONCLUSION Although reducing the nilotinib dose can alleviate the occurrence of hyperbilirubinemia, the effect of MMR is also reduced. Treatment of CML without dose adjustment or discontinuation of nilotinib therapy may be more advantageous.
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19
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Vairy S, Le Teuff G, Bautista F, De Carli E, Bertozzi AI, Pagnier A, Fouyssac F, Nysom K, Aerts I, Leblond P, Millot F, Berger C, Canale S, Paci A, Poinsignon V, Chevance A, Ezzalfani M, Vidaud D, Di Giannatale A, Hladun-Alvaro R, Petit FM, Vassal G, Geoerger B, Le Deley MC, Grill J. Phase I study of vinblastine in combination with nilotinib in children, adolescents, and young adults with refractory or recurrent low-grade glioma. Neurooncol Adv 2020; 2:vdaa075. [PMID: 32666050 PMCID: PMC7344116 DOI: 10.1093/noajnl/vdaa075] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Background New rescue regimens are needed for pediatric refractory/recurrent low-grade glioma. Nilotinib is a tyrosine kinase inhibitor that has potential synergistic effects with vinblastine on angiogenesis, tumor cell growth, and immunomodulation. Methods This phase I trial aimed to determine the recommended doses of this combination for phase II trials (RP2D) using the dual-agent Bayesian continual reassessment method. Nilotinib was given orally twice daily (BID) in combination with once-weekly vinblastine injections for a maximum of 12 cycles of 28 days (clinicaltrials.gov, NCT01884922). Results Thirty-five pediatric patients were enrolled across 4 dose levels. The median age was 7 years and 10 had neurofibromatosis type 1. Patients had received a median of 3 prior treatment lines and 25% had received more than 4 previous treatment lines. Dose-limiting toxicity (DLT) during cycle 1 was hematologic, dermatologic, and cardiovascular. The RP2D was identified at 3 mg/m2 weekly for vinblastine with 230 mg/m2 BID for nilotinib (estimated probability of DLT = 18%; 95% credibility interval, 7-29%). Fifteen patients completed the 12 cycles; 2 stopped therapy prematurely due to toxicity and 18 due to disease progression. Three patients achieved a partial response leading to an objective response rate of 8.8% (95% confidence interval [CI], 1.9-23.7), and the disease control rate was 85.3% (95% CI, 68.9-95.1). The 12-month progression-free survival was 37.1% (95% CI, 23.2-53.67). Conclusions Vinblastine and nilotinib combination was mostly limited by myelosuppression and dermatologic toxicity. The efficacy of the combination at the RP2D is currently evaluated in a randomized phase II trial comparing this regimen to vinblastine alone.
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Affiliation(s)
- Stephanie Vairy
- Department of Pediatric and Adolescent Oncology, Gustave Roussy, Villejuif, France
| | - Gwénaël Le Teuff
- Université Paris-Saclay, Université Paris-Sud, UVSQ, CESP, INSERM, Villejuif, France.,Service de Biostatistique et d'Epidémiologie, Gustave Roussy, Villejuif, France
| | - Francisco Bautista
- Department of Pediatric and Adolescent Oncology, Gustave Roussy, Villejuif, France
| | - Emilie De Carli
- Département d'Hematologie et d'Oncologie Pediatrique, Centre Hospitalier Universitaire d'Angers, Angers, France
| | - Anne-Isabelle Bertozzi
- Département d'Hematologie et d'Oncologie Pediatrique, Hopital Purpan, Centre Hospitalier Universitaire de Toulouse, Toulouse, France
| | - Anne Pagnier
- Département d'Hematologie et d'Oncologie Pediatrique, Centre Hospitalier Universitaire de Grenoble, La Tronche, France
| | - Fanny Fouyssac
- Département d'Hematologie et d'Oncologie Pediatrique, Centre Hospitalier Universitaire de Nancy, Nancy, France
| | - Karsten Nysom
- Department of Pediatric Hematology and Oncology, Rigshospitalet, Copenhagen, Denmark
| | | | - Pierre Leblond
- Unité d'oncologie pédiatrique, Centre Oscar Lambret, Lille, France
| | - Frederic Millot
- Département d'Hematologie et d'Oncologie Pediatrique, Centre Hospitalier Universitaire de Poitiers, Poitiers, France
| | - Claire Berger
- Département d'Hematologie et d'Oncologie Pediatrique, Centre Hospitalier Universitaire de Saint-Etienne, Saint-Priest-en-Jarez, France.,University Research Team EA, SNA-EPIS, Saint-Etienne, France
| | - Sandra Canale
- Department of Radiology, Gustave Roussy, Villejuif, France
| | - Angelo Paci
- Department of Pharmacology and Pharmacokinetics Unit School of Pharmacy, Université Paris-Saclay, Université Paris-Sud, Gustave Roussy, Villejuif, France
| | - Vianney Poinsignon
- Department of Pharmacology and Pharmacokinetics Unit School of Pharmacy, Université Paris-Saclay, Université Paris-Sud, Gustave Roussy, Villejuif, France
| | - Aurelie Chevance
- Université Paris-Saclay, Université Paris-Sud, UVSQ, CESP, INSERM, Villejuif, France.,Service de Biostatistique et d'Epidémiologie, Gustave Roussy, Villejuif, France
| | - Monia Ezzalfani
- Université Paris-Saclay, Université Paris-Sud, UVSQ, CESP, INSERM, Villejuif, France.,Service de Biostatistique et d'Epidémiologie, Gustave Roussy, Villejuif, France
| | - Dominique Vidaud
- Service de Génétique et Biologie Moléculaires, Hopital Cochin, Hopitaux Universitaires de Paris Centre, Assistance Publique-Hôpitaux de Paris, and EA7331, Faculte de Pharmacie de Paris, Universite Paris Descartes, Paris, France
| | - Angela Di Giannatale
- Department of Pediatric and Adolescent Oncology, Gustave Roussy, Villejuif, France
| | - Raquel Hladun-Alvaro
- Department of Pediatric and Adolescent Oncology, Gustave Roussy, Villejuif, France
| | - Francois M Petit
- Département de Génétique Moléculaire, Hopital Antoine Beclere, Clamart, France
| | - Gilles Vassal
- Department of Pediatric and Adolescent Oncology, Gustave Roussy, Villejuif, France
| | - Birgit Geoerger
- Department of Pediatric and Adolescent Oncology, Gustave Roussy, Villejuif, France
| | - Marie-Cécile Le Deley
- Université Paris-Saclay, Université Paris-Sud, UVSQ, CESP, INSERM, Villejuif, France.,Service de Biostatistique et d'Epidémiologie, Gustave Roussy, Villejuif, France
| | - Jacques Grill
- Department of Pediatric and Adolescent Oncology, Gustave Roussy, Villejuif, France
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Ravegnini G, Valori G, Zhang Q, Ricci R, Hrelia P, Angelini S. Pharmacogenetics in the treatment of gastrointestinal stromal tumors - an updated review. Expert Opin Drug Metab Toxicol 2020; 16:797-808. [PMID: 32597248 DOI: 10.1080/17425255.2020.1789589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
INTRODUCTION Gastrointestinal stromal tumors (GIST) are the best example of a targeted therapy in solid tumors. The introduction of tyrosine kinase inhibitors (TKIs) deeply improved the prognosis of this tumor. However, a degree of inter-patient variability is still reported in response rates and pharmacogenetics may play an important role in the final clinical outcome. AREAS COVERED In this review, the authors provide an updated overview of the pharmacogenetic literature analyzing the role of polymorphisms in both GIST treatment efficacy and toxicity. EXPERT OPINION Besides the primary role of somatic DNA in dictating the clinical response to TKIs, several polymorphisms influencing their pharmacokinetics and pharmacodynamics have been identified as being potentially involved. In the last 10 years, many potential biomarkers have been proposed to predict clinical response and toxicity after TKI administration. However, the evidence is still too limited to promote a clinical translation. To date, the somatic mutational status represents the main player in clinical response to TKIs in GIST treatment; however, pharmacogenetics could still explain the degree of inter-patient variability observed in GIST patients. A combination of different theoretical approaches, experimental model systems, and statistical methods is clearly needed, in order to translate pharmacogenetics to clinical practice in the near future.
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Affiliation(s)
- Gloria Ravegnini
- Department of Pharmacy and Biotechnology, University of Bologna , Bologna, Italy
| | - Giorgia Valori
- Department of Pharmacy and Biotechnology, University of Bologna , Bologna, Italy
| | - Qianqian Zhang
- UOC di Anatomia Patologica, Fondazione Policlinico Universitario 'A. Gemelli' IRCCS , Rome, Italy
| | - Riccardo Ricci
- UOC di Anatomia Patologica, Fondazione Policlinico Universitario 'A. Gemelli' IRCCS , Rome, Italy.,Department of Pathology, Universita Cattolica del Sacro Cuore , Rome, Italy
| | - Patrizia Hrelia
- Department of Pharmacy and Biotechnology, University of Bologna , Bologna, Italy
| | - Sabrina Angelini
- Department of Pharmacy and Biotechnology, University of Bologna , Bologna, Italy
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21
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Carr DF, Turner RM, Pirmohamed M. Pharmacogenomics of anticancer drugs: Personalising the choice and dose to manage drug response. Br J Clin Pharmacol 2020; 87:237-255. [PMID: 32501544 DOI: 10.1111/bcp.14407] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 05/11/2020] [Accepted: 05/22/2020] [Indexed: 12/13/2022] Open
Abstract
The field of pharmacogenomics has made great strides in oncology over the last 20 years and indeed a significant number of pre-emptive genetic tests are now routinely undertaken prior to anticancer drug administration. Many of these gene-drug interactions are the fruits of candidate gene and genome-wide association studies, which have largely focused on common genetic variants (allele frequency>1%). Examples where there is clinical utility include genotyping or phenotyping for G6PD to prevent rasburicase-induced RBC haemolysis, and TPMT to prevent thiopurine-induced bone marrow suppression. Other associations such as CYP2D6 status in determining the efficacy of tamoxifen are more controversial because of contradictory evidence from different sources, which has led to variability in the implementation of testing. As genomic technology becomes ever cheaper and more accessible, we must look to the additional data our genome can provide to explain interindividual variability in anticancer drug response. Clearly genes do not act on their own and it is therefore important to investigate genetic factors in conjunction with clinical factors, interacting concomitant drug therapies and other factors such as the microbiome, which can all affect drug disposition. Taking account of all of these factors, in conjunction with the somatic genome, is more likely to provide better predictive accuracy in determining anticancer drug response, both efficacy and safety. This review summarises the existing knowledge related to the pharmacogenomics of anticancer drugs and discusses areas of opportunity for further advances in personalisation of therapy in order to improve both drug safety and efficacy.
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Affiliation(s)
- Daniel F Carr
- Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK
| | - Richard M Turner
- Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK
| | - Munir Pirmohamed
- Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK
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22
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Iurlo A, Bucelli C, Cattaneo D, Levati GV, Viani B, Tavazzi D, Consonni D, Baldini L, Cappellini MD. UGT1A1 genotype does not affect tyrosine kinase inhibitors efficacy and safety in chronic myeloid leukemia. Am J Hematol 2019; 94:E283-E285. [PMID: 31364196 DOI: 10.1002/ajh.25596] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Revised: 07/23/2019] [Accepted: 07/24/2019] [Indexed: 12/23/2022]
Affiliation(s)
- Alessandra Iurlo
- Hematology DivisionFoundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan Milan Italy
| | - Cristina Bucelli
- Hematology DivisionFoundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan Milan Italy
| | - Daniele Cattaneo
- Hematology DivisionFoundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan Milan Italy
| | - Giorgia Virginia Levati
- Hematology DivisionFoundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan Milan Italy
| | - Benedetta Viani
- Hematology DivisionFoundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan Milan Italy
| | - Dario Tavazzi
- Department of Clinical Sciences and Community HealthUniversity of Milan, and Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico Milan Italy
| | - Dario Consonni
- Epidemiology UnitFoundation IRCCS Ca' Granda Ospedale Maggiore Policlinico Milan Italy
| | - Luca Baldini
- Hematology DivisionFoundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan Milan Italy
| | - Maria Domenica Cappellini
- Department of Clinical Sciences and Community HealthUniversity of Milan, and Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico Milan Italy
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23
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Carretero-González A, Salamanca Santamaría J, Castellano D, de Velasco G. Three case reports: Temporal association between tyrosine-kinase inhibitor-induced hepatitis and immune checkpoint inhibitors in renal cell carcinoma. Medicine (Baltimore) 2019; 98:e18098. [PMID: 31764847 PMCID: PMC6882583 DOI: 10.1097/md.0000000000018098] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
RATIONALE Hepatotoxicity is a well-known adverse effect of vascular endothelial growth factor receptor (VEGFR) tyrosine-kinase inhibitors (TKIs), usually employed for the treatment of metastatic renal cell carcinoma (mRCC). Immune checkpoint inhibitors (ICIs) have been shown to improve survival in specific patients with mRCC, but concerns have arisen over their safety profile, particularly as regards the risk of liver damage in those patients receiving TKIs sequentially or concurrently with these new drugs. Here, we report three cases of hepatitis presentation in patients receiving TKIs after ICIs that should potentially be considered in current clinical practice, where a combination of these hepatotoxic drugs is becoming increasingly used. PATIENTS CONCERNS All three patients were receiving TKIs therapy and presented with nonspecific clinical deterioration and liver enzyme elevation in different time frames according to the start of treatment. All were previously treated with ICIs. DIAGNOSES After performing imaging techniques and complementary laboratory tests for the differential diagnosis of hepatic injury, the diagnosis of potentially TKI-induced hepatitis was assumed in all these cases. Hepatic biopsy was performed only in the first case in order to confirm the diagnosis. INTERVENTIONS Potential toxic drugs were interrupted and steroids course with slow reduction regimen was administered in all these cases because of the previous use of ICIs. OUTCOMES The patients described improved with this conservative treatment without complications during the following weeks. Only one case presented a new episode of mild hepatic alteration while on treatment with following treatment. LESSONS Taking into account this new therapeutic context, stricter monitoring for potentially increased/altered adverse events should be indicated. Adequate patient selection and consideration of the safety profile of the different drugs used could help to optimize treatment in the near future.
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Affiliation(s)
- Glyn Steventon
- Consultant in ADMET, England, United Kingdom of Great Britain and Northern Ireland
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25
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Lv X, Xia Y, Finel M, Wu J, Ge G, Yang L. Recent progress and challenges in screening and characterization of UGT1A1 inhibitors. Acta Pharm Sin B 2019; 9:258-278. [PMID: 30972276 PMCID: PMC6437557 DOI: 10.1016/j.apsb.2018.09.005] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Revised: 08/16/2018] [Accepted: 08/27/2018] [Indexed: 02/07/2023] Open
Abstract
Uridine-diphosphate glucuronosyltransferase 1A1 (UGT1A1) is an important conjugative enzyme in mammals that is responsible for the conjugation and detoxification of both endogenous and xenobiotic compounds. Strong inhibition of UGT1A1 may trigger adverse drug/herb-drug interactions, or result in metabolic disorders of endobiotic metabolism. Therefore, both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have recommended assaying the inhibitory potential of drugs under development on the human UGT1A1 prior to approval. This review focuses on the significance, progress and challenges in discovery and characterization of UGT1A1 inhibitors. Recent advances in the development of UGT1A1 probes and their application for screening UGT1A1 inhibitors are summarized and discussed in this review for the first time. Furthermore, a long list of UGT1A1 inhibitors, including information on their inhibition potency, inhibition mode, and affinity, has been prepared and analyzed. Challenges and future directions in this field are highlighted in the final section. The information and knowledge that are presented in this review provide guidance for rational use of drugs/herbs in order to avoid the occurrence of adverse effects via UGT1A1 inhibition, as well as presenting methods for rapid screening and characterization of UGT1A1 inhibitors and for facilitating investigations on UGT1A1-ligand interactions.
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Abstract
Idiosyncratic hepatotoxicity is a leading reason for the discontinuation or dose modification of Food and Drug Administration (FDA)-approved medications in the United States. We report the case of a 53-year-old woman with chronic myeloid leukemia who developed acute cholestatic hepatitis in response to the tyrosine kinase inhibitor nilotinib. Nilotinib was discontinued, and the patient's liver function tests normalized over the next 3 months. We conclude that nilotinib may cause life-threatening hepatotoxicity and recommend that patients on the medication undergo regular monitoring of their liver tests.
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27
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Qosa H, Avaritt BR, Hartman NR, Volpe DA. In vitro UGT1A1 inhibition by tyrosine kinase inhibitors and association with drug-induced hyperbilirubinemia. Cancer Chemother Pharmacol 2018; 82:795-802. [PMID: 30105461 DOI: 10.1007/s00280-018-3665-x] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Accepted: 08/03/2018] [Indexed: 12/20/2022]
Abstract
PURPOSE Hyperbilirubinemia has been observed in patients treated with tyrosine kinase inhibitor (TKI) drugs. Therefore, it would be beneficial to understand whether there is a relationship between inhibition of uridine-5'-diphosphate glucuronosyltransferase (UGT) 1A1 activity and observed bilirubin elevations in TKI drug-treated patients. UGT1A1 is responsible for the glucuronidation of bilirubin which leads to its elimination in the bile. METHODS To examine this question, an in vitro glucuronidation assay was developed to determine the inhibitory effect of TKI drugs employing human liver microsomes (HLM) with varying UGT1A1 activity. Utilizing β-estradiol as the UGT1A1 probe substrate, 20 TKI drugs were evaluated at concentrations that represent clinical plasma levels. Adverse event reports were searched to generate an empirical Bayes geometric mean (EGBM) score for clinical hyperbilirubinemia with the TKI drugs. RESULTS Erlotinib, nilotinib, regorafenib, pazopanib, sorafenib and vemurafenib had IC50 values that were lower than their clinical steady-state Cmax concentrations. These TKI drugs had high incidences of hyperbilirubinemia and higher EBGM scores. The IC50 values and Cmax/IC50 ratios correlated well with EBGM scores for hyperbilirubinemia (P < 0.005). For the TKI drugs with higher incidence of hyperbilirubinemia in Gilbert syndrome patients, who have reduced UGT1A1 activity, six of eight had smaller ratios in the low UGT1A1 activity microsomes than the wild-type microsomes for drugs, indicating greater sensitivity to the drugs in this phenotype. CONCLUSIONS These results suggest that in vitro UGT1A1 inhibition assays have the potential to predict clinical hyperbilirubinemia.
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Affiliation(s)
- Hisham Qosa
- Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD, 20993, USA
| | - Brittany R Avaritt
- Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD, 20993, USA
- Office of Generic Drugs, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD, 20993, USA
| | - Neil R Hartman
- Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD, 20993, USA
| | - Donna A Volpe
- Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food and Drug Administration, 10903 New Hampshire Ave., Silver Spring, MD, 20993, USA.
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28
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Nath A, Wang J, Stephanie Huang R. Pharmacogenetics and Pharmacogenomics of Targeted Therapeutics in Chronic Myeloid Leukemia. Mol Diagn Ther 2018; 21:621-631. [PMID: 28698977 DOI: 10.1007/s40291-017-0292-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
The advent of targeted therapeutics has greatly improved outcomes of chronic myeloid leukemia (CML) patients. Despite increased efficacy and better clinical responses over cytotoxic chemotherapies, many patients receiving targeted drugs exhibit a poor initial response, develop drug resistance, or undergo relapse after initial success. This inter-individual variation in response has heightened the interest in studying pharmacogenetics and pharmacogenomics (PGx) of cancer drugs. In this review, we discuss the influence of various germline and somatic factors on targeted drug response in CML. Specifically, we examine the role of genetic variants in drug metabolism genes, i.e. CYP3A family genes, and drug transporters, i.e. ABC and SLC family genes. Additionally, we focus on acquired somatic variations in BCR-ABL1, and the potential role played by additional downstream signaling pathways, in conferring resistance to targeted drugs in CML. This review highlights the importance of PGx of targeted therapeutics and its potential application to improving treatment decisions and patient outcomes.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily B/genetics
- Antineoplastic Agents/pharmacology
- Antineoplastic Agents/therapeutic use
- Cytochrome P-450 CYP3A/genetics
- Drug Resistance, Neoplasm/drug effects
- Drug Resistance, Neoplasm/genetics
- Fusion Proteins, bcr-abl/genetics
- Glucuronosyltransferase/genetics
- Humans
- Inactivation, Metabolic/genetics
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
- Organic Cation Transporter 1/genetics
- Pharmacogenetics
- Protein Kinase Inhibitors/therapeutic use
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Affiliation(s)
- Aritro Nath
- Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL, USA
| | - Jacqueline Wang
- Biological Sciences Collegiate Division, The University of Chicago, Chicago, IL, USA
| | - R Stephanie Huang
- Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL, USA.
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29
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Yamamoto K, Yano I. Genetic polymorphisms associated with adverse reactions of molecular-targeted therapies in renal cell carcinoma. Med Oncol 2018; 35:16. [PMID: 29302760 DOI: 10.1007/s12032-017-1077-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Accepted: 12/27/2017] [Indexed: 12/28/2022]
Abstract
The prognosis of patients with metastatic renal cell carcinoma has drastically improved due to the development of molecular-targeted drugs and their use in clinical practice. However, these drugs cause some diverse adverse reactions in patients and sometimes affect clinical outcomes of cancer therapy. Therefore, predictive markers are necessary to avoid severe adverse reactions, to establish novel and effective prevention methods, and to improve treatment outcomes. Some genetic factors involved in these adverse reactions have been reported; however, perspectives on each adverse response have not been integrated yet. In this review, genetic polymorphisms relating to molecular-targeted therapy-induced adverse reactions in patients with renal cell carcinoma are summarized in the points of pharmacokinetic and pharmacodynamic mechanisms. We also discuss about the relationship between systemic drug exposure and adverse drug reactions.
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Affiliation(s)
- Kazuhiro Yamamoto
- Department of Pharmacy, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
| | - Ikuko Yano
- Department of Pharmacy, Kobe University Hospital, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
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30
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Kim GJ, Lee SY, Park JH, Ryu BY, Kim JH. Role of Preemptive Genotyping in Preventing Serious Adverse Drug Events in South Korean Patients. Drug Saf 2017; 40:65-80. [PMID: 27638658 DOI: 10.1007/s40264-016-0454-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
INTRODUCTION Preemptive and multi-variant genotyping is suggested to improve the safety of patient drug therapy. The number of South Koreans who would benefit from this approach is unknown. OBJECTIVE We aimed to quantify the number of patients who may experience serious adverse drug events (ADEs) due to high-risk pharmacogenetic variants and who may benefit from preemptive genotyping. METHODS The health claims dataset of the Korean Health Insurance Review and Assessment service for 3 % of the South Korean population for year 2011 was used to calculate the number of patients exposed to 84 drugs covered by National Health Insurance with pharmacogenomic biomarkers. The product of ADE risk-conferring genotype prevalence, ADE prevalence rates, and genotype effect sizes in South Koreans or East Asians derived from published literature and the 1000 Genomes Project, and the drug exposure data were solved to estimate the number of South Koreans in whom preemptive genotyping may prevent serious ADEs. RESULTS Among 1,341,077 patients in the dataset with prescriptions, 47.4 % were prescribed a drug whose response was affected by genetic variants and 31.9 % were prescribed at least one drug with serious ADEs modulated by these variants. Without genetic testing, the number of South Korean patients predicted to experience serious ADEs due to their higher ADE risk genotypes was estimated at 729. Extrapolating this to the total South Korean population indicated that approximately 24,300 patients in 2011 might have benefitted from preemptive genotyping. CONCLUSIONS This study quantified the number of South Korean patients predicted to have serious ADEs and demonstrated the need for preemptive genotyping to assist safer drug therapy in South Korea.
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Affiliation(s)
- Grace Juyun Kim
- Seoul National University Biomedical Informatics (SNUBI), 28 Yongon-dong, Chongno-gu, Seoul, 110799, South Korea
| | - Soo Youn Lee
- Interdisciplinary Program in Bioinformatics, Seoul National University College of Natural Sciences, 28 Yongon-dong, Chongno-gu, Seoul, 110799, South Korea
| | - Ji Hye Park
- Interdisciplinary Program in Bioinformatics, Seoul National University College of Natural Sciences, 28 Yongon-dong, Chongno-gu, Seoul, 110799, South Korea
| | - Brian Y Ryu
- Interdisciplinary Program in Bioinformatics, Seoul National University College of Natural Sciences, 28 Yongon-dong, Chongno-gu, Seoul, 110799, South Korea
| | - Ju Han Kim
- Seoul National University Biomedical Informatics (SNUBI), 28 Yongon-dong, Chongno-gu, Seoul, 110799, South Korea. .,Division of Biomedical Informatics, Systems Biomedical Informatics National Core Research Center (SBI-NCRC), Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul, 110799, South Korea.
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31
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Abstract
Idiosyncratic hepatotoxicity is one of the most common reasons for an approved drug being restricted. This article focuses on hepatotoxicity of selected and recently introduced agents, such as, tyrosine kinase inhibitors, monoclonal antibodies, novel oral anticoagulants, newer antiplatelets, antibiotics, anti-diabetics, anti-epileptics, anti-depressants, anti-psychotics and anti-retrovirals. Overall, the incidence of clinically relevant hepatotoxicity from newer agents seems to be lower than that of the older agents. Nevertheless, cases of severe hepatotoxicity have been reported due to some of these newer agents, including, trastuzumab, ipilimumab, infliximab, imatinib, bosutinib, dasatinib, gefitinib, erlotinib, sunitinib, ponatinib, lapatinib, vemurafenib, dabigatran, rivaroxaban, felbamate, lamotrigine, levetiracetam, venlafaxine, duloxetine, darunavir, and maraviroc.
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Affiliation(s)
- Chalermrat Bunchorntavakul
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, 2 Dulles, 3400 Spruce Street, HUP, Philadelphia, PA 19104, USA; Division of Gastroenterology and Hepatology, Department of Medicine, Rajavithi Hospital, College of Medicine, Rangsit University, Rajavithi Road, Ratchathewi, Bangkok 10400, Thailand
| | - K Rajender Reddy
- Liver Transplantation, Viral Hepatitis Center, University of Pennsylvania, 2 Dulles, 3400 Spruce Street, HUP, Liver Transplant Office, Philadelphia, PA 19104, USA.
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32
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Yao Z, Li S, Qin Z, Hong X, Dai Y, Wu B, Ye W, Gonzalez FJ, Yao X. Characterization of human UDP-glucuronosyltransferases responsible for glucuronidation and inhibition of norbakuchinic acid, a primary metabolite of hepatotoxicity and nephrotoxicity component bakuchiol inPsoralea corylifolia L. RSC Adv 2017. [DOI: 10.1039/c7ra10376j] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Norbakuchinic acid (NBKA) is the most abundant metabolite of bakuchiol (a hepatotoxicity and nephrotoxicity component inPsoralea corylifoliaL.) in plasma and urine.
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Affiliation(s)
- Zhihong Yao
- College of Pharmacy
- Jinan University
- Guangzhou 510632
- P. R. China
- Guangdong Provincial Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research
| | - Shishi Li
- College of Pharmacy
- Jinan University
- Guangzhou 510632
- P. R. China
| | - Zifei Qin
- College of Pharmacy
- Jinan University
- Guangzhou 510632
- P. R. China
- Guangdong Provincial Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research
| | - Xiaodan Hong
- College of Pharmacy
- Jinan University
- Guangzhou 510632
- P. R. China
- Guangzhou Research and Creativity Biotechnology Co. Ltd
| | - Yi Dai
- College of Pharmacy
- Jinan University
- Guangzhou 510632
- P. R. China
- Guangdong Provincial Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research
| | - Baojian Wu
- College of Pharmacy
- Jinan University
- Guangzhou 510632
- P. R. China
- Guangdong Provincial Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research
| | - Wencai Ye
- College of Pharmacy
- Jinan University
- Guangzhou 510632
- P. R. China
- Guangdong Provincial Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research
| | - Frank J. Gonzalez
- Laboratory of Metabolism
- Center for Cancer Research
- National Cancer Institute
- National Institutes of Health
- Bethesda
| | - Xinsheng Yao
- College of Pharmacy
- Jinan University
- Guangzhou 510632
- P. R. China
- Guangdong Provincial Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research
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Saif MW, Smith MH, Maloney A, Diasio RB. Imatinib-induced hyperbilirubinemia with UGT1A1 (*28) promoter polymorphism: first case series in patients with gastrointestinal stromal tumor. Ann Gastroenterol 2016; 29:551-556. [PMID: 27708529 PMCID: PMC5049570 DOI: 10.20524/aog.2016.0053] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Accepted: 05/12/2016] [Indexed: 12/12/2022] Open
Abstract
Imatinib, an orally administered protein-tyrosine kinase inhibitor (TKI) is indicated for the treatment of chronic myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST). Severe hepatotoxicity associated with imatinib is rare, and relationship to polymorphism of uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) expression and related frequency of hyperbilirubinemia or toxicity are not well known. We present a case series patients who developed hyperbilirubinemia while on oral administration imatinib for treatment of GIST. Genetic testing for polymorphism of UGT1A1 showed the first patient to be homozygous for the UGT1A1 TA7 (*28) polymorphism and the second patient heterozygous for the UGT1A1 TA1 (*28) polymorphism. The first patient had to stop imatinib due to severe and persistent hyperbilirubenemia peaking >3 despite reducing imatininb to only 100 mg every other day while the second patient improved at this dose. Our case series represent the first data associating UGT1A1 polymorphism and imatinib in patients being treated for GIST. Given the prevalence of Gilbert's syndrome and the increasing use of imatinib, we encourage physicians to be aware of this possible toxicity as hepatotoxicity can be fatal if not managed in a timely fashion. This association is also timely due to recent FDA requirement for testing UGT1A1 polymorphism for nilotinib, another TKI.
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Affiliation(s)
- Muhammad Wasif Saif
- Division of Hematology/Oncology and Experimental Therapeutics, Tufts Cancer Center- Tufts Medical Center, Boston, MA, USA (Muhammad Wasif Saif, Melissa Hennessey Smith, Antonia Maloney), USA
| | - Melissa Hennessey Smith
- Division of Hematology/Oncology and Experimental Therapeutics, Tufts Cancer Center- Tufts Medical Center, Boston, MA, USA (Muhammad Wasif Saif, Melissa Hennessey Smith, Antonia Maloney), USA
| | - Antonia Maloney
- Division of Hematology/Oncology and Experimental Therapeutics, Tufts Cancer Center- Tufts Medical Center, Boston, MA, USA (Muhammad Wasif Saif, Melissa Hennessey Smith, Antonia Maloney), USA
| | - Robert B. Diasio
- Mayo Clinic Cancer Center, Rochester, MN (Robert B. Diasio), USA
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34
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Steegmann JL, Baccarani M, Breccia M, Casado LF, García-Gutiérrez V, Hochhaus A, Kim DW, Kim TD, Khoury HJ, Le Coutre P, Mayer J, Milojkovic D, Porkka K, Rea D, Rosti G, Saussele S, Hehlmann R, Clark RE. European LeukemiaNet recommendations for the management and avoidance of adverse events of treatment in chronic myeloid leukaemia. Leukemia 2016; 30:1648-71. [PMID: 27121688 PMCID: PMC4991363 DOI: 10.1038/leu.2016.104] [Citation(s) in RCA: 335] [Impact Index Per Article: 37.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2016] [Accepted: 04/18/2016] [Indexed: 12/20/2022]
Abstract
Most reports on chronic myeloid leukaemia (CML) treatment with tyrosine kinase inhibitors (TKIs) focus on efficacy, particularly on molecular response and outcome. In contrast, adverse events (AEs) are often reported as infrequent, minor, tolerable and manageable, but they are increasingly important as therapy is potentially lifelong and multiple TKIs are available. For this reason, the European LeukemiaNet panel for CML management recommendations presents an exhaustive and critical summary of AEs emerging during CML treatment, to assist their understanding, management and prevention. There are five major conclusions. First, the main purpose of CML treatment is the antileukemic effect. Suboptimal management of AEs must not compromise this first objective. Second, most patients will have AEs, usually early, mostly mild to moderate, and which will resolve spontaneously or are easily controlled by simple means. Third, reduction or interruption of treatment must only be done if optimal management of the AE cannot be accomplished in other ways, and frequent monitoring is needed to detect resolution of the AE as early as possible. Fourth, attention must be given to comorbidities and drug interactions, and to new events unrelated to TKIs that are inevitable during such a prolonged treatment. Fifth, some TKI-related AEs have emerged which were not predicted or detected in earlier studies, maybe because of suboptimal attention to or absence from the preclinical data. Overall, imatinib has demonstrated a good long-term safety profile, though recent findings suggest underestimation of symptom severity by physicians. Second and third generation TKIs have shown higher response rates, but have been associated with unexpected problems, some of which could be irreversible. We hope these recommendations will help to minimise adverse events, and we believe that an optimal management of them will be rewarded by better TKI compliance and thus better CML outcomes, together with better quality of life.
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Affiliation(s)
- J L Steegmann
- Servicio de Hematologia y Grupo 44
IIS-IP, Hospital Universitario de la Princesa, Madrid,
Spain
| | - M Baccarani
- Department of Hematology and Oncology
‘L. and A. Seràgnoli', St Orsola University Hospital,
Bologna, Italy
| | - M Breccia
- Department of Cellular Biotechnologies
and Hematology, Sapienza University, Rome, Italy
| | - L F Casado
- Servicio de Hematologia, Hospital Virgen
de la Salud, Toledo, Spain
| | - V García-Gutiérrez
- Servicio Hematología y
Hemoterapia, Hospital Universitario Ramón y Cajal,
Madrid, Spain
| | - A Hochhaus
- Hematology/Oncology,
Universitätsklinikum Jena, Jena, Germany
| | - D-W Kim
- Seoul St Mary's Hospital, Leukemia
Research Institute, The Catholic University of Korea, Seoul,
South Korea
| | - T D Kim
- Medizinische Klinik mit Schwerpunkt
Onkologie und Hämatologie, Campus Charité Mitte,
Charité—Universitätsmedizin Berlin, Berlin,
Germany
| | - H J Khoury
- Department of Hematology and Medical
Oncology, Winship Cancer Institute of Emory University,
Atlanta, GA, USA
| | - P Le Coutre
- Medizinische Klinik mit Schwerpunkt
Onkologie und Hämatologie, Campus Charité Mitte,
Charité—Universitätsmedizin Berlin, Berlin,
Germany
| | - J Mayer
- Department of Internal Medicine,
Hematology and Oncology, Masaryk University Hospital Brno,
Brno, Czech Republic
| | - D Milojkovic
- Department of Haematology Imperial
College, Hammersmith Hospital, London, UK
| | - K Porkka
- Department of Hematology, Helsinki
University Hospital Comprehensive Cancer Center, Helsinki,
Finland
- Hematology Research Unit, University of
Helsinki, Helsinki, Finland
| | - D Rea
- Service d'Hématologie
Adulte, Hôpital Saint-Louis, APHP, Paris,
France
| | - G Rosti
- Department of Hematology and Oncology
‘L. and A. Seràgnoli', St Orsola University Hospital,
Bologna, Italy
| | - S Saussele
- III. Med. Klinik Medizinische
Fakultät Mannheim der Universität Heidelberg,
Mannheim, Germany
| | - R Hehlmann
- Medizinische Fakultät Mannheim der
Universität Heidelberg, Mannheim, Germany
| | - R E Clark
- Department of Molecular and Clinical
Cancer Medicine, University of Liverpool, Liverpool,
UK
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Wen F, Li Q. Treatment dilemmas of cetuximab combined with chemotherapy for metastatic colorectal cancer. World J Gastroenterol 2016; 22:5332-5341. [PMID: 27340349 PMCID: PMC4910654 DOI: 10.3748/wjg.v22.i23.5332] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Revised: 05/02/2016] [Accepted: 05/23/2016] [Indexed: 02/06/2023] Open
Abstract
Although monoclonal antibodies (mAbs) against epidermal growth factor receptor (EGFR) have largely enriched the available therapeutic choices for colorectal cancer (CRC), the understanding and management of their associated clinical toxicities are limited. In addition, the combined strategies of administering EGFR mAbs and traditional cytotoxic agents, such as 5-fluorouracil, oxaliplatin and irinotecan, have resulted in a more complicated management of CRC treatment-related side effects compared with EGFR mAb monotherapy. We believe that a thorough recognition of the toxicities of EGFR mAb drugs is essential for physicians to increase the therapeutic index in the treatment of CRC. This review aims to summarize the existing information regarding the treatment dilemmas of cetuximab combined with chemotherapy in the management of metastatic CRC.
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[Expert panel consensus statement on prevention and standardized treatment of drug-induced liver injury in patients with blood diseases (2016)]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2016; 37:441-52. [PMID: 27431065 PMCID: PMC7348330 DOI: 10.3760/cma.j.issn.0253-2727.2016.06.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Indexed: 01/08/2023]
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Miura M. Therapeutic drug monitoring of imatinib, nilotinib, and dasatinib for patients with chronic myeloid leukemia. Biol Pharm Bull 2016; 38:645-54. [PMID: 25947908 DOI: 10.1248/bpb.b15-00103] [Citation(s) in RCA: 109] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Imatinib, nilotinib, and dasatinib are tyrosine kinase inhibitors (TKIs) that have become first-line treatments for Philadelphia chromosome-positive chronic myeloid leukemia (CML). According to European LeukemiaNet recommendations, the clinical response of CML patients receiving TKI therapy should be evaluated after 3, 6, and 12 months. For patients not achieving a satisfactory response within 3 months, the mean plasma concentration for the three months of TKI administration must be considered. In TKI therapy for CML patients, therapeutic drug monitoring is a new strategy for dosage optimization to obtain a faster and more effective clinical response. The imatinib plasma trough concentration (C₀) should be set above 1000 ng/mL to obtain a response and below 3000 ng/mL to avoid serious adverse events such as neutropenia. For patients with a UGT1A1*6/*6, *6/*28, or *28/*28 genotype initially administered 300-400 mg/d, a target nilotinib C₀ of 500 ng/mL is recommended to prevent elevation of bilirubin levels, whereas for patients with the UGT1A1*1 allele initially administered 600 mg/d, a target nilotinib C₀ of 800 ng/mL is recommended. For dasatinib, it is recommended that a higher Cmax or C₂ (above 50 ng/mL) to obtain a clinical response and a lower C₀ (less than 2.5 ng/mL) to avoid pleural effusion be maintained by once daily administration of dasatinib. Although at present clinicians consider the next pharmacotherapy from clinical responses (efficacy/toxicity) obtained by a fixed dosage of TKI, the TKI dosage should be adjusted based on target plasma concentrations to maximize the efficacy and to minimize the incidence of adverse events.
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Lv X, Wang XX, Hou J, Fang ZZ, Wu JJ, Cao YF, Liu SW, Ge GB, Yang L. Comparison of the inhibitory effects of tolcapone and entacapone against human UDP-glucuronosyltransferases. Toxicol Appl Pharmacol 2016; 301:42-9. [PMID: 27089846 DOI: 10.1016/j.taap.2016.04.009] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2016] [Revised: 04/12/2016] [Accepted: 04/14/2016] [Indexed: 01/15/2023]
Abstract
Tolcapone and entacapone are two potent catechol-O-methyltransferase (COMT) inhibitors with a similar skeleton and displaying similar pharmacological activities. However, entacapone is a very safe drug used widely in the treatment of Parkinson's disease, while tolcapone is only in limited use for Parkinson's patients and needs careful monitoring of hepatic functions due to hepatotoxicity. This study aims to investigate and compare the inhibitory effects of entacapone and tolcapone on human UDP-glucosyltransferases (UGTs), as well as to evaluate the potential risks from the view of drug-drug interactions (DDI). The results demonstrated that both tolcapone and entacapone exhibited inhibitory effects on UGT1A1, UGT1A7, UGT1A9 and UGT1A10. In contrast to entacapone, tolcapone exhibited more potent inhibitory effects on UGT1A1, UGT1A7, and UGT1A10, while their inhibitory potentials against UGT1A9 were comparable. It is noteworthy that the inhibition constants (Ki) of tolcapone and entacapone against bilirubin-O-glucuronidation in human liver microsomes (HLM) are determined as 0.68μM and 30.82μM, respectively, which means that the inhibition potency of tolcapone on UGT1A1 mediated bilirubin-O-glucuronidation in HLM is much higher than that of entacapone. Furthermore, the potential risks of tolcapone or entacapone via inhibition of human UGT1A1 were quantitatively predicted by the ratio of the areas under the plasma drug concentration-time curve (AUC). The results indicate that tolcapone may result in significant increase in AUC of bilirubin or the drugs primarily metabolized by UGT1A1, while entacapone is unlikely to cause a significant DDI through inhibition of UGT1A1.
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Affiliation(s)
- Xia Lv
- Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Southern Medical University, Guangzhou 510515, China
| | | | - Jie Hou
- Dalian Medical University, Dalian 116044, China
| | | | - Jing-Jing Wu
- Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Southern Medical University, Guangzhou 510515, China
| | | | - Shu-Wen Liu
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Southern Medical University, Guangzhou 510515, China
| | - Guang-Bo Ge
- Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; State Key Laboratory of Organ Failure Research, Guangdong Provincial Institute of Nephrology, Southern Medical University, Guangzhou 510515, China.
| | - Ling Yang
- Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, China.
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Gammal RS, Court MH, Haidar CE, Iwuchukwu OF, Gaur AH, Alvarellos M, Guillemette C, Lennox JL, Whirl‐Carrillo M, Brummel SS, Ratain MJ, Klein TE, Schackman BR, Caudle KE, Haas DW. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for UGT1A1 and Atazanavir Prescribing. Clin Pharmacol Ther 2016; 99:363-9. [PMID: 26417955 PMCID: PMC4785051 DOI: 10.1002/cpt.269] [Citation(s) in RCA: 137] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Accepted: 09/24/2015] [Indexed: 01/09/2023]
Abstract
The antiretroviral protease inhibitor atazanavir inhibits hepatic uridine diphosphate glucuronosyltransferase (UGT) 1A1, thereby preventing the glucuronidation and elimination of bilirubin. Resultant indirect hyperbilirubinemia with jaundice can cause premature discontinuation of atazanavir. Risk for bilirubin-related discontinuation is highest among individuals who carry two UGT1A1 decreased function alleles (UGT1A1*28 or *37). We summarize published literature that supports this association and provide recommendations for atazanavir prescribing when UGT1A1 genotype is known (updates at www.pharmgkb.org).
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Affiliation(s)
- RS Gammal
- Department of Pharmaceutical SciencesSt. Jude Children's Research HospitalMemphisTennesseeUSA
| | - MH Court
- Individualized Medicine Program, Department of Veterinary Clinical SciencesWashington State University College of Veterinary MedicinePullmanWashingtonUSA
| | - CE Haidar
- Department of Pharmaceutical SciencesSt. Jude Children's Research HospitalMemphisTennesseeUSA
| | - OF Iwuchukwu
- Division of Pharmaceutical SciencesFairleigh Dickinson University School of PharmacyFlorham ParkNew JerseyUSA
- Division of Clinical Pharmacology, Department of MedicineVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - AH Gaur
- Department of Infectious DiseasesSt. Jude Children's Research HospitalMemphisTennesseeUSA
| | - M Alvarellos
- Department of GeneticsStanford UniversityStanfordCaliforniaUSA
| | - C Guillemette
- Laval University CHU de Québec Research CenterQuebecQuebecCanada
| | - JL Lennox
- Division of Infectious DiseaseEmory University School of MedicineAtlantaGeorgiaUSA
| | | | - SS Brummel
- Center for Biostatistics in AIDS ResearchHarvard T.H. Chan School of Public HealthBostonMassachusettsUSA
| | - MJ Ratain
- Center for Personalized Therapeutics, Comprehensive Cancer CenterThe University of ChicagoChicagoIllinoisUSA
| | - TE Klein
- Department of GeneticsStanford UniversityStanfordCaliforniaUSA
| | - BR Schackman
- Department of Healthcare Policy and ResearchWeill Cornell Medical CollegeNew YorkNew YorkUSA
| | - KE Caudle
- Department of Pharmaceutical SciencesSt. Jude Children's Research HospitalMemphisTennesseeUSA
| | - DW Haas
- Departments of Medicine, Pharmacology, Pathology, Microbiology & ImmunologyVanderbilt University School of MedicineNashvilleTennesseeUSA
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Abstract
Certain genetic polymorphisms of UDP glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) can reduce gene expression (*28, *60, *93) or activity (*6), thereby altering the pharmacokinetics, pharmacodynamics, and the risk of toxicities of UGT1A1 substrates, of which irinotecan is a widely-described example. This review presents an overview of the clinical effects of UGT1A1 polymorphisms on the pharmacology of UGT1A1 substrates, with a special focus on the novel histone deacetylase inhibitor belinostat. Belinostat, approved for the treatment of peripheral T-cell lymphoma, is primarily glucuronidated by UGT1A1. Recent preclinical and clinical data showed that UGT1A1*28 was associated with reduced glucuronidation in human liver microsomes, while in a retrospective analysis of a Phase I trial with patients receiving belinostat UGT1A1*60 was predominantly associated with increased belinostat plasma concentrations. Furthermore, both UGT1A1*28 and *60 variants were associated with increased incidence of thrombocytopenia and neutropenia. Using population pharmacokinetic analysis a 33% dose reduction has been proposed for patients carrying UGT1A1 variant alleles. Clinical effects of this genotype-based dosing recommendation is currently prospectively being investigated. Overall, the data suggest that UGT1A1 genotyping is useful for improving belinostat therapy.
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Affiliation(s)
- Andrew K L Goey
- Clinical Pharmacology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
| | - William D Figg
- Clinical Pharmacology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
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Identification and characterization of naturally occurring inhibitors against UDP-glucuronosyltransferase 1A1 in Fructus Psoraleae (Bu-gu-zhi). Toxicol Appl Pharmacol 2015; 289:70-8. [DOI: 10.1016/j.taap.2015.09.003] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2015] [Revised: 08/19/2015] [Accepted: 09/01/2015] [Indexed: 01/18/2023]
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Gambacorti‐Passerini C, Kantarjian HM, Kim D, Khoury HJ, Turkina AG, Brümmendorf TH, Matczak E, Bardy‐Bouxin N, Shapiro M, Turnbull K, Leip E, Cortes JE. Long-term efficacy and safety of bosutinib in patients with advanced leukemia following resistance/intolerance to imatinib and other tyrosine kinase inhibitors. Am J Hematol 2015; 90:755-68. [PMID: 26040495 PMCID: PMC5132035 DOI: 10.1002/ajh.24034] [Citation(s) in RCA: 64] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2015] [Accepted: 04/04/2015] [Indexed: 01/24/2023]
Abstract
Long-term efficacy and safety of bosutinib (≥4 years follow-up from last enrolled patient) were evaluated in an ongoing phase 1/2 study in the advanced leukemia cohort with prior treatment failure (accelerated-phase [AP, n = 79] chronic myeloid leukemia [CML], blast-phase [BP, n = 64] CML, acute lymphoblastic leukemia [ALL, n = 24]). Fourteen AP, 2 BP, and 1 ALL patient remained on bosutinib at 4 years (vs. 38, 8, 1 at 1 year); median (range) treatment durations: 10.2 (0.1-88.6), 2.8 (0.03-55.9), 0.97 (0.3-89.2) months. Among AP and BP patients, 57% and 28% newly attained or maintained baseline overall hematologic response (OHR); 40% and 37% attained/maintained major cytogenetic response (MCyR) by 4 years (most by 12 months). In responders at 1 versus 4 years, Kaplan-Meier (KM) probabilities of maintaining OHR were 78% versus 49% (AP) and 28% versus 19% (BP); KM probabilities of maintaining MCyR were 65% versus 49% (AP) and 21% versus 21% (BP). Most common AEs (AP, BP) were gastrointestinal (96%; 83%), primarily diarrhea (85%; 64%), which was typically low grade (maximum grade 1/2: 81%; 59%) and transient; no patient discontinued due to diarrhea. Serious AEs occurred in 44 (56%) AP and 37 (58%) BP patients, most commonly pneumonia (n = 9) for AP and pyrexia (n = 6) for BP; 11 and 13 died within 30 days of last dose (2 considered bosutinib-related [AP] per investigator). Responses were durable in ∼50% AP responders at 4 years (∼25% BP patients responded at year 1, suggesting possible bridge-to-transplant role in BP patients); toxicity was manageable.
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Affiliation(s)
| | - Hagop M. Kantarjian
- Department of LeukemiaDivision of Cancer MedicineUniversity of Texas MD Anderson Cancer CenterHoustonTexas
| | - Dong‐Wook Kim
- Department of HematologySeoul St. Mary's HospitalSeoulSouth Korea
| | - Hanna J. Khoury
- Division of HematologyWinship Cancer Institute of Emory UniversityAtlantaGeorgia
| | | | - Tim H. Brümmendorf
- Clinic for OncologyHematologyand Stem Cell TransplantationUniversitätsklinikum Aachen, RWTH AachenGermany
- OncologyHematologyand Stem Cell TransplantationUniversitätsklinikum Hamburg‐EppendorfHamburgGermany
| | | | | | | | | | | | - Jorge E. Cortes
- Department of LeukemiaDivision of Cancer MedicineUniversity of Texas MD Anderson Cancer CenterHoustonTexas
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Khurana V, Minocha M, Pal D, Mitra AK. Inhibition of OATP-1B1 and OATP-1B3 by tyrosine kinase inhibitors. ACTA ACUST UNITED AC 2015; 29:249-59. [PMID: 24807167 DOI: 10.1515/dmdi-2014-0014] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2014] [Accepted: 04/01/2014] [Indexed: 11/15/2022]
Abstract
BACKGROUND The potential of tyrosine kinase inhibitors (TKIs) interacting with other therapeutics through hepatic uptake transporter inhibition has not been fully delineated in drug-drug interactions (DDIs). This study was designed to estimate the half-maximal inhibitory concentration (IC50) values of five small-molecule TKIs (pazopanib, nilotinib, vandetanib, canertinib and erlotinib) interacting with organic anion-transporting polypeptides (OATPs): OATP-1B1 and -1B3. METHODS The IC50 values of TKIs and rifampicin (positive control) were determined by concentration-dependent inhibition of TKIs on cellular accumulation of radiolabeled probe substrates [3H]estrone sulfate and [3H]cholecystokinin octapeptide. Chinese hamster ovary cells transfected with humanized OATP-1B1 and OATP-1B3 transporter proteins, respectively, were utilized to carry out these studies. RESULTS Pazopanib and nilotinib show inhibitory activity on OATP-1B1 transporter protein. IC50 values for rifampicin, pazopanib and nilotinib were 10.46±1.15, 3.89±1.21 and 2.78±1.13 μM, respectively, for OATP-1B1 transporter. Vandetanib, canertinib and erlotinib did not exhibit any inhibitory potency toward OATP-1B1 transporter protein. Only vandetanib expressed inhibitory potential toward OATP-1B3 transporter protein out of the five selected TKIs. IC50 values for rifampicin and vandetanib for OATP-1B3 transporter inhibition were 3.67±1.20 and 18.13±1.21 μM, respectively. No significant inhibition in the presence of increasing concentrations of pazopanib, nilotinib, canertinib and erlotinib were observed for OATP-1B3 transporter. CONCLUSIONS Because selected TKIs are inhibitors of OATP-1B1 and -1B3 expressed in hepatic tissue, these compounds can be regarded as molecular targets for transporter-mediated DDIs. These findings provide the basis for further preclinical and clinical studies investigating the transporter-based DDI potential of TKIs.
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Lv X, Ge GB, Feng L, Troberg J, Hu LH, Hou J, Cheng HL, Wang P, Liu ZM, Finel M, Cui JN, Yang L. An optimized ratiometric fluorescent probe for sensing human UDP-glucuronosyltransferase 1A1 and its biological applications. Biosens Bioelectron 2015; 72:261-7. [PMID: 25988789 DOI: 10.1016/j.bios.2015.05.003] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2015] [Revised: 04/15/2015] [Accepted: 05/04/2015] [Indexed: 01/10/2023]
Abstract
This study aimed to develop a practical ratiometric fluorescent probe for highly selective and sensitive detection of human UDP-glucuronosyltransferase 1A1 (UGT1A1), one of the most important phase II enzymes. 4-Hydroxy-1,8-naphthalimide (HN) was selected as the fluorophore for this study because it possesses intramolecular charge transfer (ICT) feature and displays outstanding optical properties. A series of N-substituted derivatives with various hydrophobic, acidic and basic groups were designed and synthesized to evaluate the selectivity of HN derivatives toward UGT1A1. Our results demonstrated that the introduction of an acidic group to HN could significantly improve the selectivity of UGT1A1. Among the synthesized fluorescent probes, NCHN (N-3-carboxy propyl-4-hydroxy-1,8-naphthalimide) displayed the best combination of selectivity, sensitivity and ratiometric fluorescence response following UGT1A1-catalyzed glucuronidation. UGT1A1-catalyzed NCHN-4-O-glucuronidation generated a single fluorescent product with a high quantum yield (Φ=0.688) and brought remarkable changes in both color and fluorescence in comparison with the parental substrate. The newly developed probe has been successfully applied for sensitive measurements of UGT1A1 activities in human liver preparations, as well as for rapid screening of UGT1A1 modulators, using variable enzyme sources. Furthermore, its potential applications for live imaging of endogenous UGT1A1in cells have also been demonstrated.
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Affiliation(s)
- Xia Lv
- Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
| | - Guang-Bo Ge
- Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116012, China
| | - Lei Feng
- State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116012, China
| | - Johanna Troberg
- Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | - Liang-Hai Hu
- College of Life Science, Jilin University, Changchun, China
| | - Jie Hou
- Dalian Medical University, Dalian 116044, China
| | | | - Ping Wang
- Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
| | - Zhao-Ming Liu
- Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
| | - Moshe Finel
- Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | - Jing-Nan Cui
- State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116012, China.
| | - Ling Yang
- Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
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Management of adverse events associated with tyrosine kinase inhibitors in chronic myeloid leukemia. Ann Hematol 2015; 94 Suppl 2:S149-58. [PMID: 25814081 DOI: 10.1007/s00277-015-2318-y] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Accepted: 10/07/2014] [Indexed: 12/11/2022]
Abstract
Tyrosine kinase inhibitors (TKIs) targeting the breakpoint cluster region-Abelson 1 (BCR-ABL1) oncoprotein represent an outstanding progress in chronic myeloid leukemia (CML), and long-term survival has become a reality. However, the majority of patients need to be treated during their entire life span; thus, outcome does not solely depend on treatment efficacy but also on how well therapy is tolerated. TKIs have an overall favorable safety profile in clinical practice. Although many patients may encounter adverse events, these usually occur early after treatment initiation, are mild to moderate in intensity and resolve spontaneously, or are easily controlled with adequate supportive care. Whenever treatment interruption is necessary, re-exposition to the same TKI or switch to an alternative TKI is successful in the majority of the cases. However, long-term safety issues have not been fully elucidated at present, especially for new-generation TKIs. Recent evidence has emerged that these new agents may sometimes impinge on vital organs such as the heart and lung in an irreversible fashion especially when comorbidities are present; thus, decision regarding of which TKI should be used must take into account disease-related, TKI-related, and patient-related variables. The purpose of this article is to provide an up-to-date review of common adverse events associated with TKIs and how these events may be optimally managed.
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Abstract
The variability in treatment outcomes among patients receiving the same therapy for seemingly similar tumors can be attributed in part to genetics. The tumor's (somatic) genome largely dictates the effectiveness of the therapy, and the patient's (germline) genome influences drug exposure and the patient's sensitivity to toxicity. Many potentially clinically useful associations have been discovered between common germline genetic polymorphisms and outcomes of cancer treatment. This review highlights the germline pharmacogenetic associations that are currently being used to guide cancer treatment decisions, those that are most likely to someday be clinically useful, and associations that are well known but their roles in clinical management are not yet certain. In the future, germline genetic information will likely be available from tumor genetic analyses, creating an efficient opportunity to integrate the two genomes to optimize treatment outcomes for each individual cancer patient.
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Affiliation(s)
- Daniel L Hertz
- Department of Clinical, Social, and Administrative Sciences, University of Michigan College of Pharmacy, Ann Arbor, Michigan 48109;
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Abumiya M, Takahashi N, Niioka T, Kameoka Y, Fujishima N, Tagawa H, Sawada K, Miura M. Influence of UGT1A1 6, 27, and 28 polymorphisms on nilotinib-induced hyperbilirubinemia in Japanese patients with chronic myeloid leukemia. Drug Metab Pharmacokinet 2014; 29:449-54. [PMID: 24898899 DOI: 10.2133/dmpk.dmpk-14-rg-031] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Nilotinib potently inhibits human uridine diphosphate-glucuronosyltransferase (UGT1A1) activity, causing hyperbilirubinemia. We investigated the influence of UGT1A1 polymorphisms and nilotinib plasma trough concentrations (C0) on nilotinib-induced hyperbilirubinemia in 34 Japanese patients with chronic myeloid leukemia (CML). The proportion of patients with hyperbilirubinemia was significantly higher among patients with the UGT1A1*6/*6 and *6/*28 genotypes (poor metabolizers) than among those with other genotypes (p = 0.004). The median time to elevation of bilirubin levels in UGT1A1 poor metabolizers was 2.0 weeks (hazard ratio, 6.11). The median time to reduction in nilotinib dose in UGT1A1 poor metabolizers was 4.0 weeks (hazard ratio, 7.52; p = 0.002). Consequently, in the maintenance phase 3 months following the initiation of nilotinib therapy, the median daily dose and C0 of nilotinib were 350 mg/day and 372 ng/mL, respectively, in UGT1A1 poor metabolizers, and 600 mg/day and 804 ng/mL, respectively, in the other patients. Patients at increased hyperbilirubinemia risk could be identified by prospective UGT1A1 genotyping prior to nilotinib therapy. To avoid an interruption of CML treatment due to nilotinib-induced hyperbilirubinemia, it may be beneficial to reduce the initial nilotinib dose to 300-400 mg/day for UGT1A1 poor metabolizers.
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Takahashi N, Miura M, Kuroki J, Mitani K, Kitabayashi A, Sasaki O, Kimura H, Imai K, Tsukamoto N, Noji H, Kondo T, Motegi M, Kato Y, Mita M, Saito H, Yoshida C, Torimoto Y, Kimura T, Wano Y, Nomura J, Yamamoto S, Mayama K, Honma R, Sugawara T, Sato S, Shinagawa A, Abumiya M, Niioka T, Harigae H, Sawada K. Multicenter phase II clinical trial of nilotinib for patients with imatinib-resistant or -intolerant chronic myeloid leukemia from the East Japan CML study group evaluation of molecular response and the efficacy and safety of nilotinib. Biomark Res 2014; 2:6. [PMID: 24650752 PMCID: PMC3994575 DOI: 10.1186/2050-7771-2-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2014] [Accepted: 02/27/2014] [Indexed: 12/31/2022] Open
Abstract
Background Nilotinib is a second-generation tyrosine kinase inhibitor that exhibits significant efficacy as first- or second-line treatment in patients with chronic myeloid leukemia (CML). We conducted a multicenter Phase II Clinical Trial to evaluate the safety and efficacy of nilotinib among Japanese patients with imatinib-resistant or -intolerant CML-chronic phase (CP) or accelerated phase (AP). Results We analyzed 49 patients (33 imatinib-resistant and 16 imatinib-intolerant) treated with nilotinib 400 mg twice daily. The major molecular response (MMR) rate was 47.8% at 12 months among 35 patients who did not demonstrate an MMR at study entry. Somatic BCR-ABL1 mutations (Y253H, I418V, and exon 8/9 35-bp insertion [35INS]) were detected in 3 patients at 12 months or upon discontinuation of nilotinib. Although 75.5% of patients were still being treated at 12 months, nilotinib treatment was discontinued because of progressing disease in 1 patient, insufficient effect in 2, and adverse events in 9. There was no statistically significant correlation between MMR and trough concentrations of nilotinib. Similarly, no correlation was observed between trough concentrations and adverse events, except for pruritus and hypokalemia. Hyperbilirubinemia was frequently observed (all grades, 51.0%; grades 2–4, 29%; grades 3–4, 4.1%). Hyperbilirubinemia higher than grade 2 was significantly associated with the uridine diphosphate glucuronosyltransferase (UGT)1A9 I399C/C genotype (P = 0.0086; Odds Ratio, 21.2; 95% Confidence Interval 2.2–208.0). Conclusions Nilotinib was efficacious and well tolerated by patients with imatinib-resistant or -intolerant CML-CP/AP. Hyperbilirubinemia may be predicted before nilotinib treatment, and may be controlled by reducing the daily dose of nilotinib in patients with UGT1A9 polymorphisms. Trial registration clinicaltrials.gov: UMIN000002201
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Affiliation(s)
- Naoto Takahashi
- Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, 1-1-1 Hondo, 010-8543 Akita, Japan.
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Giles FJ, Rosti G, Beris P, Clark RE, le Coutre P, Mahon FX, Steegmann JL, Valent P, Saglio G. Nilotinib is superior to imatinib as first-line therapy of chronic myeloid leukemia: the ENESTnd study. Expert Rev Hematol 2014; 3:665-73. [DOI: 10.1586/ehm.10.61] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Dy GK, Adjei AA. Understanding, recognizing, and managing toxicities of targeted anticancer therapies. CA Cancer J Clin 2013; 63:249-79. [PMID: 23716430 DOI: 10.3322/caac.21184] [Citation(s) in RCA: 232] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2012] [Revised: 02/21/2013] [Accepted: 02/25/2013] [Indexed: 12/11/2022] Open
Abstract
Answer questions and earn CME/CNE Advances in genomics and molecular biology have identified aberrant proteins in cancer cells that are attractive targets for cancer therapy. Because these proteins are overexpressed or dysregulated in cancer cells compared with normal cells, it was assumed that their inhibitors will be narrowly targeted and relatively nontoxic. However, this hope has not been achieved. Current targeted agents exhibit the same frequency and severity of toxicities as traditional cytotoxic agents, with the main difference being the nature of the toxic effects. Thus, the classical chemotherapy toxicities of alopecia, myelosuppression, mucositis, nausea, and vomiting have been generally replaced by vascular, dermatologic, endocrine, coagulation, immunologic, ocular, and pulmonary toxicities. These toxicities need to be recognized, prevented, and optimally managed.
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Affiliation(s)
- Grace K Dy
- Department of Medicine, Roswell Park Cancer Institute, Buffalo, New York, USA
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