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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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Lin C, Zhang S, Yang P, Zhang B, Guo W, Wu R, Liu Y, Wang J, Wu H, Cai H. Combination of UGT1A1 polymorphism and baseline plasma bilirubin levels in predicting the risk of antipsychotic-induced dyslipidemia in schizophrenia patients. SCHIZOPHRENIA (HEIDELBERG, GERMANY) 2024; 10:52. [PMID: 38760414 PMCID: PMC11101411 DOI: 10.1038/s41537-024-00473-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Accepted: 05/04/2024] [Indexed: 05/19/2024]
Abstract
The prolonged usage of atypical antipsychotic drugs (AAPD) among individuals with schizophrenia often leads to metabolic side effects such as dyslipidemia. These effects not only limit one's selection of AAPD but also significantly reduce compliance and quality of life of patients. Recent studies suggest that bilirubin plays a crucial role in maintaining lipid homeostasis and may be a potential pre-treatment biomarker for individuals with dyslipidemia. The present study included 644 schizophrenia patients from two centers. Demographic and clinical characteristics were collected at baseline and 4 weeks after admission to investigate the correlation between metabolites, episodes, usage of AAPDs, and occurrence of dyslipidemia. Besides, we explored the combined predictive value of genotypes and baseline bilirubin for dyslipidemia by employing multiple PCR targeted capture techniques to sequence two pathways: bilirubin metabolism-related genes and lipid metabolism-related genes. Our results indicated that there existed a negative correlation between the changes in bilirubin levels and triglyceride (TG) levels in patients with schizophrenia. Among three types of bilirubin, direct bilirubin in the baseline (DBIL-bl) proved to be the most effective in predicting dyslipidemia in the ROC analysis (AUC = 0.627, p < 0.001). Furthermore, the odds ratio from multinomial logistic regression analysis showed that UGT1A1*6 was a protective factor for dyslipidemia (ß = -12.868, p < 0.001). The combination of baseline DBIL and UGT1A1*6 significantly improved the performance in predicting dyslipidemia (AUC = 0.939, p < 0.001). Schizophrenia patients with UGT1A1*6 mutation and a certain level of baseline bilirubin may be more resistant to dyslipidemia and have more selections for AAPD than other patients.
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Affiliation(s)
- Chenquan Lin
- Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Shuangyang Zhang
- Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Ping Yang
- Department of Psychiatry, Hunan Brain Hospital, Changsha, China
| | - Bikui Zhang
- Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Hunan, China
| | - Wenbin Guo
- Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha, China
- National Clinical Research Center on Mental Disorders, Changsha, China
| | - Renrong Wu
- Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha, China
- National Clinical Research Center on Mental Disorders, Changsha, China
| | - Yong Liu
- Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha, China
- National Clinical Research Center on Mental Disorders, Changsha, China
| | - Jianjian Wang
- Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha, China
- National Clinical Research Center on Mental Disorders, Changsha, China
| | - Haishan Wu
- Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha, China
- National Clinical Research Center on Mental Disorders, Changsha, China
| | - Hualin Cai
- Department of Pharmacy, The Second Xiangya Hospital of Central South University, Changsha, China.
- Institute of Clinical Pharmacy, Central South University, Changsha, China.
- International Research Center for Precision Medicine, Transformative Technology and Software Services, Hunan, China.
- National Clinical Research Center on Mental Disorders, Changsha, China.
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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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Prakash TC, Enkemann S. Current Progress on the Influence Human Genetics Has on the Efficacy of Tyrosine Kinase Inhibitors Used to Treat Chronic Myeloid Leukemia. Cureus 2024; 16:e56545. [PMID: 38646295 PMCID: PMC11027790 DOI: 10.7759/cureus.56545] [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: 01/25/2024] [Accepted: 03/19/2024] [Indexed: 04/23/2024] Open
Abstract
The use of tyrosine kinase inhibitors (TKIs) has become the mainstay of treatment in patients suffering from chronic myeloid leukemia (CML), an adult leukemia caused by a reciprocal translocation between chromosomes 9 and 22, which creates an oncogene resulting in a myeloproliferative neoplasm. These drugs function by inhibiting the ATP-binding site on the fusion oncoprotein and subsequently halting proliferative activity. The goal of this work is to investigate the current state of research into genetic factors that influence the efficacy of four FDA-approved TKIs used to treat CML. This overview attempts to identify genetic criteria that could be considered when choosing one drug over the others and to identify where more research is needed. Our results suggest that the usual liver enzymes impacting patient response may not be a major factor affecting the efficacy of imatinib, nilotinib, and bosutinib, and yet, that is where most of the past research has focused. More research is warranted on the impact that human polymorphisms of the CYP enzymes have on dasatinib. The impact of polymorphisms in UGT1A1 should be investigated thoroughly in other TKIs, not only nilotinib. The role of influx and efflux transporters has been inconsistent thus far, possibly due to failures to account for the multiple proteins that can transport TKIs and the impact that tumors have on transporter expression. Because physicians cannot currently use a patient's genetic profile to better target their treatment with TKIs, it is critical that more research be conducted on auxiliary pathways or off-target binding effects to generate new leads for further study. Hopefully, new avenues of research will help explain treatment failures and improve patient outcomes.
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Affiliation(s)
- Tara C Prakash
- Department of Cell Biology and Physiology, Edward Via College of Osteopathic Medicine, Spartanburg, USA
| | - Steven Enkemann
- Department of Cell Biology and Physiology, Edward Via College of Osteopathic Medicine, Spartanburg, USA
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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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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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Yang X, Zhu G, Zhang Y, Wu X, Liu B, Liu Y, Yang Q, Du W, Liang J, Hu J, Yang P, Ge G, Cai W, Ma G. Inhibition of Human UDP-Glucuronosyltransferases1A1-Mediated Bilirubin Glucuronidation by the Popular Flavonoids Baicalein, Baicalin, and Hyperoside Is Responsible for Herb (Shuang-Huang-Lian)-Induced Jaundice. Drug Metab Dispos 2022; 50:552-565. [PMID: 35241486 DOI: 10.1124/dmd.121.000714] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 02/11/2022] [Indexed: 11/22/2022] Open
Abstract
Bilirubin-related adverse drug reactions (ADRs) or malady (e.g., jaundice) induced by some herbs rich in certain flavonoids have been widely reported. However, the causes and mechanisms of the ADRs are not well understood. The aim of this paper was to explore the mechanism of Shuang-huang-lian (SHL) injections and its major constituents-induced jaundice via inhibiting human UDP-glucuronosyltransferases1A1 (hUGT1A1)-mediated bilirubin glucuronidation. The inhibitory effects of SHL and its major constituents in the herbal medicine, including baicalein (BAI), baicalin (BA), and hyperoside (HYP), on bilirubin glucuroBBREVInidation were investigated. This study indicated that the average formation rates of bilirubin glucuronides [i.e., mono-glucuronide 1 (BMG1), BMG2, and bilirubin diglucuronide] displayed significant differences (P < 0.05). Specifically, the formation of BMGs was favored regardless of whether an inhibitor was absent or present. SHL, BAI, BA, and HYP dose-dependently inhibit bilirubin glucuronidation, showing the IC50 values against total bilirubin glucuronidation were in the range of (7.69 ± 0.94)-(37.09 ± 2.03) μg/ml, (4.51 ± 0.27)-(20.84 ± 1.99) μM, (22.36 ± 5.74)-(41.35 ± 2.40) μM, and (15.16 ± 1.12)-(42.80 ± 2.63) μM for SHL, BAI, BA, and HYP, respectively. Both inhibition kinetics assays and molecular docking simulations suggested that SHL, BAI, BA, and HYP significantly inhibited hUGT1A1-mediated bilirubin glucuronidation via a mixed-type inhibition. Collectively, some naturally occurring flavonoids (BAI, BA, and HYP) in SHL have been identified as the inhibitors against hUGT1A1-mediated bilirubin glucuronidation, which well explains the bilirubin-related ADRs or malady triggered by SHL in clinical settings. SIGNIFICANCE STATEMENT: Herbal products and their components (e.g., flavonoids), which been widely used across the entire world, may cause liver injury. As a commonly used herbal products rich in flavonoids, SHL injections easily lead to symptoms of liver injury (e.g., jaundice) owing to significant inhibition of hUGT1A1-mediated bilirubin glucuronidation by its flavonoid components (i.e., baicalein, baicalin, and hyperoside). Herb-induced bilirubin-related ADRs and the associated clinical significance should be seriously considered.
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Affiliation(s)
- Xiaolei Yang
- School of Pharmacy, Fudan University, Shanghai, China (X.Y., Y.Z., B.L., Y.L., Q.Y., W.D., J.L., J.H., P.Y., W.C., G.M.); Shanghai Frontiers Science Center of Chinese Medicine Chemical Biology (G.Z., G.G.) and Institute of Interdisciplinary Integrative Medicine Research (G.Z., G.G.), Shanghai University of Traditional Chinese Medicine, Shanghai, China; Department of Hepatobiliary and Pancreatic Surgery (X.W.) and Institute of Fudan Minhang Academic Health System (X.W.), Minhang Hospital, Fudan University, Shanghai, China; and Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (B.L.)
| | - Guanghao Zhu
- School of Pharmacy, Fudan University, Shanghai, China (X.Y., Y.Z., B.L., Y.L., Q.Y., W.D., J.L., J.H., P.Y., W.C., G.M.); Shanghai Frontiers Science Center of Chinese Medicine Chemical Biology (G.Z., G.G.) and Institute of Interdisciplinary Integrative Medicine Research (G.Z., G.G.), Shanghai University of Traditional Chinese Medicine, Shanghai, China; Department of Hepatobiliary and Pancreatic Surgery (X.W.) and Institute of Fudan Minhang Academic Health System (X.W.), Minhang Hospital, Fudan University, Shanghai, China; and Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (B.L.)
| | - Ying Zhang
- School of Pharmacy, Fudan University, Shanghai, China (X.Y., Y.Z., B.L., Y.L., Q.Y., W.D., J.L., J.H., P.Y., W.C., G.M.); Shanghai Frontiers Science Center of Chinese Medicine Chemical Biology (G.Z., G.G.) and Institute of Interdisciplinary Integrative Medicine Research (G.Z., G.G.), Shanghai University of Traditional Chinese Medicine, Shanghai, China; Department of Hepatobiliary and Pancreatic Surgery (X.W.) and Institute of Fudan Minhang Academic Health System (X.W.), Minhang Hospital, Fudan University, Shanghai, China; and Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (B.L.)
| | - Xubo Wu
- School of Pharmacy, Fudan University, Shanghai, China (X.Y., Y.Z., B.L., Y.L., Q.Y., W.D., J.L., J.H., P.Y., W.C., G.M.); Shanghai Frontiers Science Center of Chinese Medicine Chemical Biology (G.Z., G.G.) and Institute of Interdisciplinary Integrative Medicine Research (G.Z., G.G.), Shanghai University of Traditional Chinese Medicine, Shanghai, China; Department of Hepatobiliary and Pancreatic Surgery (X.W.) and Institute of Fudan Minhang Academic Health System (X.W.), Minhang Hospital, Fudan University, Shanghai, China; and Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (B.L.)
| | - Bei Liu
- School of Pharmacy, Fudan University, Shanghai, China (X.Y., Y.Z., B.L., Y.L., Q.Y., W.D., J.L., J.H., P.Y., W.C., G.M.); Shanghai Frontiers Science Center of Chinese Medicine Chemical Biology (G.Z., G.G.) and Institute of Interdisciplinary Integrative Medicine Research (G.Z., G.G.), Shanghai University of Traditional Chinese Medicine, Shanghai, China; Department of Hepatobiliary and Pancreatic Surgery (X.W.) and Institute of Fudan Minhang Academic Health System (X.W.), Minhang Hospital, Fudan University, Shanghai, China; and Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (B.L.)
| | - Ye Liu
- School of Pharmacy, Fudan University, Shanghai, China (X.Y., Y.Z., B.L., Y.L., Q.Y., W.D., J.L., J.H., P.Y., W.C., G.M.); Shanghai Frontiers Science Center of Chinese Medicine Chemical Biology (G.Z., G.G.) and Institute of Interdisciplinary Integrative Medicine Research (G.Z., G.G.), Shanghai University of Traditional Chinese Medicine, Shanghai, China; Department of Hepatobiliary and Pancreatic Surgery (X.W.) and Institute of Fudan Minhang Academic Health System (X.W.), Minhang Hospital, Fudan University, Shanghai, China; and Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (B.L.)
| | - Qing Yang
- School of Pharmacy, Fudan University, Shanghai, China (X.Y., Y.Z., B.L., Y.L., Q.Y., W.D., J.L., J.H., P.Y., W.C., G.M.); Shanghai Frontiers Science Center of Chinese Medicine Chemical Biology (G.Z., G.G.) and Institute of Interdisciplinary Integrative Medicine Research (G.Z., G.G.), Shanghai University of Traditional Chinese Medicine, Shanghai, China; Department of Hepatobiliary and Pancreatic Surgery (X.W.) and Institute of Fudan Minhang Academic Health System (X.W.), Minhang Hospital, Fudan University, Shanghai, China; and Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (B.L.)
| | - Wandi Du
- School of Pharmacy, Fudan University, Shanghai, China (X.Y., Y.Z., B.L., Y.L., Q.Y., W.D., J.L., J.H., P.Y., W.C., G.M.); Shanghai Frontiers Science Center of Chinese Medicine Chemical Biology (G.Z., G.G.) and Institute of Interdisciplinary Integrative Medicine Research (G.Z., G.G.), Shanghai University of Traditional Chinese Medicine, Shanghai, China; Department of Hepatobiliary and Pancreatic Surgery (X.W.) and Institute of Fudan Minhang Academic Health System (X.W.), Minhang Hospital, Fudan University, Shanghai, China; and Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (B.L.)
| | - Jingru Liang
- School of Pharmacy, Fudan University, Shanghai, China (X.Y., Y.Z., B.L., Y.L., Q.Y., W.D., J.L., J.H., P.Y., W.C., G.M.); Shanghai Frontiers Science Center of Chinese Medicine Chemical Biology (G.Z., G.G.) and Institute of Interdisciplinary Integrative Medicine Research (G.Z., G.G.), Shanghai University of Traditional Chinese Medicine, Shanghai, China; Department of Hepatobiliary and Pancreatic Surgery (X.W.) and Institute of Fudan Minhang Academic Health System (X.W.), Minhang Hospital, Fudan University, Shanghai, China; and Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (B.L.)
| | - Jiarong Hu
- School of Pharmacy, Fudan University, Shanghai, China (X.Y., Y.Z., B.L., Y.L., Q.Y., W.D., J.L., J.H., P.Y., W.C., G.M.); Shanghai Frontiers Science Center of Chinese Medicine Chemical Biology (G.Z., G.G.) and Institute of Interdisciplinary Integrative Medicine Research (G.Z., G.G.), Shanghai University of Traditional Chinese Medicine, Shanghai, China; Department of Hepatobiliary and Pancreatic Surgery (X.W.) and Institute of Fudan Minhang Academic Health System (X.W.), Minhang Hospital, Fudan University, Shanghai, China; and Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (B.L.)
| | - Ping Yang
- School of Pharmacy, Fudan University, Shanghai, China (X.Y., Y.Z., B.L., Y.L., Q.Y., W.D., J.L., J.H., P.Y., W.C., G.M.); Shanghai Frontiers Science Center of Chinese Medicine Chemical Biology (G.Z., G.G.) and Institute of Interdisciplinary Integrative Medicine Research (G.Z., G.G.), Shanghai University of Traditional Chinese Medicine, Shanghai, China; Department of Hepatobiliary and Pancreatic Surgery (X.W.) and Institute of Fudan Minhang Academic Health System (X.W.), Minhang Hospital, Fudan University, Shanghai, China; and Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (B.L.)
| | - Guangbo Ge
- School of Pharmacy, Fudan University, Shanghai, China (X.Y., Y.Z., B.L., Y.L., Q.Y., W.D., J.L., J.H., P.Y., W.C., G.M.); Shanghai Frontiers Science Center of Chinese Medicine Chemical Biology (G.Z., G.G.) and Institute of Interdisciplinary Integrative Medicine Research (G.Z., G.G.), Shanghai University of Traditional Chinese Medicine, Shanghai, China; Department of Hepatobiliary and Pancreatic Surgery (X.W.) and Institute of Fudan Minhang Academic Health System (X.W.), Minhang Hospital, Fudan University, Shanghai, China; and Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (B.L.)
| | - Weimin Cai
- School of Pharmacy, Fudan University, Shanghai, China (X.Y., Y.Z., B.L., Y.L., Q.Y., W.D., J.L., J.H., P.Y., W.C., G.M.); Shanghai Frontiers Science Center of Chinese Medicine Chemical Biology (G.Z., G.G.) and Institute of Interdisciplinary Integrative Medicine Research (G.Z., G.G.), Shanghai University of Traditional Chinese Medicine, Shanghai, China; Department of Hepatobiliary and Pancreatic Surgery (X.W.) and Institute of Fudan Minhang Academic Health System (X.W.), Minhang Hospital, Fudan University, Shanghai, China; and Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (B.L.)
| | - Guo Ma
- School of Pharmacy, Fudan University, Shanghai, China (X.Y., Y.Z., B.L., Y.L., Q.Y., W.D., J.L., J.H., P.Y., W.C., G.M.); Shanghai Frontiers Science Center of Chinese Medicine Chemical Biology (G.Z., G.G.) and Institute of Interdisciplinary Integrative Medicine Research (G.Z., G.G.), Shanghai University of Traditional Chinese Medicine, Shanghai, China; Department of Hepatobiliary and Pancreatic Surgery (X.W.) and Institute of Fudan Minhang Academic Health System (X.W.), Minhang Hospital, Fudan University, Shanghai, China; and Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (B.L.)
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8
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Chen Y, Guan S, Guan Y, Tang S, Zhou Y, Wang X, Bi H, Huang M. Novel Clinical Biomarkers for Drug-Induced Liver Injury. Drug Metab Dispos 2022; 50:671-684. [PMID: 34903588 DOI: 10.1124/dmd.121.000732] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 12/07/2021] [Indexed: 11/22/2022] Open
Abstract
Drug-induced liver injury (DILI) remains a critical clinical issue and has been a treatment challenge today as it was in the past. However, the traditional biomarkers or indicators are insufficient to predict the risks and outcome of patients with DILI due to its poor specificity and sensitivity. Recently, the development of high-throughput technologies, especially omics and multiomics has sparked growing interests in identification of novel clinical DILI biomarkers, many of which also provide a mechanistic insight. Accordingly, in this minireview, we summarize recent advances in novel clinical biomarkers for DILI prediction, diagnosis, and prognosis and highlight the limitations or challenges involved in biomarker discovery or its clinical translation. Although huge work has been done, most reported biomarkers lack comprehensive information and more specific DILI biomarkers are still needed to complement the traditional biomarkers such as alanine aminotransferase (ALT) or aspartate transaminase (AST) in clinical decision-making. SIGNIFICANCE STATEMENT: This current review outlines an overview of novel clinical biomarkers for drug-induced liver injury (DILI) identified in clinical retrospective or prospective clinical analysis. Many of these biomarkers provide a mechanistic insight and are promising to complement the traditional DILI biomarkers. This work also highlights the limitations or challenges involved in biomarker discovery or its clinical translation.
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Affiliation(s)
- Youhao Chen
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou 510006, China (Y.C., S.G., Y.G., S.T., Y.Z., X.W., H.B., M.H.)., School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China (H.B.); and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangzhou, Guangdong Provincial Key Laboratory of New Drug Screening; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China (H.B.), Beijing, China (H.B.)
| | - Shaoxing Guan
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou 510006, China (Y.C., S.G., Y.G., S.T., Y.Z., X.W., H.B., M.H.)., School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China (H.B.); and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangzhou, Guangdong Provincial Key Laboratory of New Drug Screening; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China (H.B.), Beijing, China (H.B.)
| | - Yanping Guan
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou 510006, China (Y.C., S.G., Y.G., S.T., Y.Z., X.W., H.B., M.H.)., School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China (H.B.); and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangzhou, Guangdong Provincial Key Laboratory of New Drug Screening; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China (H.B.), Beijing, China (H.B.)
| | - Siyuan Tang
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou 510006, China (Y.C., S.G., Y.G., S.T., Y.Z., X.W., H.B., M.H.)., School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China (H.B.); and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangzhou, Guangdong Provincial Key Laboratory of New Drug Screening; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China (H.B.), Beijing, China (H.B.)
| | - Yanying Zhou
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou 510006, China (Y.C., S.G., Y.G., S.T., Y.Z., X.W., H.B., M.H.)., School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China (H.B.); and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangzhou, Guangdong Provincial Key Laboratory of New Drug Screening; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China (H.B.), Beijing, China (H.B.)
| | - Xueding Wang
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou 510006, China (Y.C., S.G., Y.G., S.T., Y.Z., X.W., H.B., M.H.)., School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China (H.B.); and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangzhou, Guangdong Provincial Key Laboratory of New Drug Screening; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China (H.B.), Beijing, China (H.B.)
| | - Huichang Bi
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou 510006, China (Y.C., S.G., Y.G., S.T., Y.Z., X.W., H.B., M.H.)., School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China (H.B.); and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangzhou, Guangdong Provincial Key Laboratory of New Drug Screening; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China (H.B.), Beijing, China (H.B.)
| | - Min Huang
- School of Pharmaceutical Sciences, Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University, Guangzhou 510006, China (Y.C., S.G., Y.G., S.T., Y.Z., X.W., H.B., M.H.)., School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China (H.B.); and NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Guangzhou, Guangdong Provincial Key Laboratory of New Drug Screening; School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China (H.B.), Beijing, China (H.B.)
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9
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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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10
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Hwang WL, Chen TC, Lin HY, Chang MC, Hsiao PC, Bai LY, Kuo CY, Chen YC, Liu TC, Gau JP, Wang PN, Hwang WS, Kuo MC, Liu CY, Liu YC, Ma MC, Su NW, Wang CC, Wu YY, Yao M, Yeh SP, Cheng HW, Lee YM, Ku FC, Tang JL. NOVEL-1st: an observational study to assess the safety and efficacy of nilotinib in newly diagnosed patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase in Taiwan. Int J Hematol 2022; 115:704-712. [PMID: 35212915 DOI: 10.1007/s12185-022-03311-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 02/09/2022] [Accepted: 02/09/2022] [Indexed: 11/28/2022]
Abstract
Nilotinib has been approved for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP). However, the real-world evidence of nilotinib in newly diagnosed untreated Ph+ CML-CP is limited in Taiwan. The NOVEL-1st study was a non-interventional, multi-center study collecting long-term safety and effectiveness data in patients with newly diagnosed and untreated Ph+ CML-CP receiving nilotinib. We enrolled 129 patients from 11 hospitals. Overall, 1,466 adverse events (AEs) were reported; among these, 151 were serious and 524 were nilotinib-related. Common hematological AEs were thrombocytopenia (31.0%), anemia (20.9%), and leukopenia (14.0%); common nilotinib-related AEs were thrombocytopenia (29.5%), anemia (14.7%), and leukopenia (12.4%). Early molecular response, defined as BCR-ABL ≤ 10% at Month 3, was seen in 87.6% of patients. By 36 months, the cumulative rates of complete hematologic response, complete cytogenetic response, major molecular response, molecular response 4.0-log reduction, and molecular response 4.5-log reduction were 98.5, 92.5, 85.8, 65.0, and 45.0%, respectively. Nilotinib is effective and well-tolerated in patients with newly diagnosed Ph+ CML-CP in the real-world setting. Long-term holistic care and a highly tolerable AE profile may contribute to good treatment outcomes in Ph+ CML-CP under first-line treatment with nilotinib.
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Affiliation(s)
- Wen-Li Hwang
- Taichung Veterans General Hospital, Taichung, Taiwan.,Asia University Hospital, Taichung, Taiwan
| | | | | | | | | | - Li-Yuan Bai
- China Medical University Hospital, Taichung, Taiwan
| | - Ching-Yuan Kuo
- Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | | | - Ta-Chih Liu
- Kaohsiung Medical University Chung-Ho Memorial Hospital, Kaohsiung, Taiwan.,Chang Bing Show Chwan Memorial Hospital, Changhua, Taiwan
| | - Jyh-Pyng Gau
- Taipei Veterans General Hospital, Taipei, Taiwan
| | - Po-Nan Wang
- Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Wei-Shou Hwang
- Chung Shan Medical University Hospital, Taichung, Taiwan
| | | | - Chun-Yu Liu
- Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yi-Chang Liu
- Kaohsiung Medical University Chung-Ho Memorial Hospital, Kaohsiung, Taiwan
| | - Ming-Chun Ma
- Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan
| | - Nai-Wen Su
- Mackay Memorial Hospital, Taipei, Taiwan
| | | | - Yi-Ying Wu
- Tri-Service General Hospital, Taipei, Taiwan
| | - Ming Yao
- National Taiwan University Hospital, Taipei, Taiwan
| | - Su-Peng Yeh
- China Medical University Hospital, Taichung, Taiwan
| | | | | | | | - Jih-Luh Tang
- National Taiwan University Hospital, Taipei, Taiwan.
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11
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Tan YW. Is dose modification or discontinuation of nilotinib necessary in nilotinib-induced hyperbilirubinemia? World J Meta-Anal 2021; 9:488-495. [DOI: 10.13105/wjma.v9.i6.488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 10/14/2021] [Accepted: 12/24/2021] [Indexed: 02/06/2023] Open
Abstract
Nilotinib is a specific breakpoint cluster region-Abelson leukemia virus-tyrosine kinase inhibitor that is used as an effective first- or second-line treatment in imatinib-resistant chronic myelogenous leukemia (CML) patients. Hepatotoxicity due to nilotinib is a commonly reported side effect; however, abnormal liver function test (LFT) results have been reported in asymptomatic cases. When alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels are more than five-fold the upper limit of the normal (ULN) or when the serum total bilirubin level is more than three-fold the ULN, dose modification or discontinuation of nilotinib is recommended, resulting in decreased levels of hematological indicators in certain patients with CML. Nilotinib-induced hyperbilirubinemia typically manifests as indirect bilirubinemia without elevated ALT or AST levels. Such abnormal liver functioning is thus not attributed to the presence of a true histologic lesion of the liver. The underlying mechanism may be related to the inhibition of uridine diphosphate glucuronosyltransferase activity. Therefore, nilotinib dose adjustment is not recommended for this type of hyperbilirubinemia, and in the absence of elevated liver enzyme levels or presence of abnormal LFT findings, physicians should consider maintaining nilotinib dose intensity without modifications.
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Affiliation(s)
- You-Wen Tan
- Department of Hepatology, The Third Hospital of Zhenjiang Affiliated Jiangsu University, Zhenjiang 212003, Jiangsu Province, China
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12
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Maillard M, Louveau B, Vilquin P, Goldwirt L, Thomas F, Mourah S. Pharmacogenomics in solid cancers and hematologic malignancies: Improving personalized drug prescription. Therapie 2021; 77:171-183. [PMID: 34922740 DOI: 10.1016/j.therap.2021.11.003] [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: 09/11/2021] [Accepted: 09/29/2021] [Indexed: 11/30/2022]
Abstract
The discovery of molecular alterations involved in oncogenesis is evolving rapidly and has led to the development of new innovative targeted therapies in oncology. High-throughput sequencing techniques help to identify genomic targets and to provide predictive molecular biomarkers of response to guide alternative therapeutic strategies. Besides the emergence of these theranostic markers for the new targeted treatments, pharmacogenetic markers (corresponding to genetic variants existing in the constitutional DNA, i.e., the host genome) can help to optimize the use of chemotherapy. In this review, we present the current clinical applications of constitutional PG and the recent concepts and advances in pharmacogenomics, a rapidly evolving field that focuses on various molecular alterations identified on constitutional or somatic (tumor) genome.
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Affiliation(s)
- Maud Maillard
- Institut Claudius-Regaud, Institut universitaire du cancer de Toulouse, IUCT-Oncopole, 31059 Toulouse, France; Centre de recherches en cancérologie de Toulouse CRCT, 31037 Toulouse, France; Université Paul-Sabatier Toulouse III, 31062 Toulouse, France
| | - Baptiste Louveau
- Inserm, UMR_S976, 75475 Paris, France; Université de Paris, 75010 Paris, France; Pharmacogenomics department, Hôpital Saint-Louis, AP-HP, 75010 Paris, France
| | - Paul Vilquin
- Inserm, UMR_S976, 75475 Paris, France; Université de Paris, 75010 Paris, France; Pharmacogenomics department, Hôpital Saint-Louis, AP-HP, 75010 Paris, France
| | - Lauriane Goldwirt
- Inserm, UMR_S976, 75475 Paris, France; Université de Paris, 75010 Paris, France; Pharmacogenomics department, Hôpital Saint-Louis, AP-HP, 75010 Paris, France
| | - Fabienne Thomas
- Institut Claudius-Regaud, Institut universitaire du cancer de Toulouse, IUCT-Oncopole, 31059 Toulouse, France; Centre de recherches en cancérologie de Toulouse CRCT, 31037 Toulouse, France; Université Paul-Sabatier Toulouse III, 31062 Toulouse, France
| | - Samia Mourah
- Inserm, UMR_S976, 75475 Paris, France; Université de Paris, 75010 Paris, France; Pharmacogenomics department, Hôpital Saint-Louis, AP-HP, 75010 Paris, France.
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13
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Liu D, Yu Q, Ning Q, Liu Z, Song J. The relationship between UGT1A1 gene & various diseases and prevention strategies. Drug Metab Rev 2021; 54:1-21. [PMID: 34807779 DOI: 10.1080/03602532.2021.2001493] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
UDP-glucuronyltransferase 1A1 (UGT1A1) is a member of the Phase II metabolic enzyme family and the only enzyme that can metabolize detoxified bilirubin. Inactivation and very low activity of UGT1A1 in the liver can be fatal or lead to lifelong Gilbert's syndrome (GS) and Crigler-Najjar syndrome (CN). To date, more than one hundred UGT1A1 polymorphisms have been discovered. Although most UGT1A1 polymorphisms are not fatal, which diseases might be associated with low activity UGT1A1 or UGT1A1 polymorphisms? This scientific topic has been studied for more than a hundred years, there are still many uncertainties. Herein, this article will summarize all the possibilities of UGT1A1 gene-related diseases, including GS and CN, neurological disease, hepatobiliary disease, metabolic difficulties, gallstone, cardiovascular disease, Crohn's disease (CD) obesity, diabetes, myelosuppression, leukemia, tumorigenesis, etc., and provide guidance for researchers to conduct in-depth study on UGT1A1 gene-related diseases. In addition, this article not only summarizes the prevention strategies of UGT1A1 gene-related diseases, but also puts forward some insights for sharing.
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Affiliation(s)
- Dan Liu
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, PR China.,Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, PR China.,Guangdong Key Laboratory for Translational Cancer Research of Chinese Medicine, Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, PR China
| | - Qi Yu
- Guangdong Key Laboratory for Translational Cancer Research of Chinese Medicine, Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, PR China
| | - Qing Ning
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, PR China.,Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, PR China
| | - Zhongqiu Liu
- Guangdong Key Laboratory for Translational Cancer Research of Chinese Medicine, Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, PR China
| | - Jie Song
- Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, PR China.,Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, PR China
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14
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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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15
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Mueller-Schoell A, Groenland SL, Scherf-Clavel O, van Dyk M, Huisinga W, Michelet R, Jaehde U, Steeghs N, Huitema ADR, Kloft C. Therapeutic drug monitoring of oral targeted antineoplastic drugs. Eur J Clin Pharmacol 2021; 77:441-464. [PMID: 33165648 PMCID: PMC7935845 DOI: 10.1007/s00228-020-03014-8] [Citation(s) in RCA: 127] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 10/01/2020] [Indexed: 02/06/2023]
Abstract
PURPOSE This review provides an overview of the current challenges in oral targeted antineoplastic drug (OAD) dosing and outlines the unexploited value of therapeutic drug monitoring (TDM). Factors influencing the pharmacokinetic exposure in OAD therapy are depicted together with an overview of different TDM approaches. Finally, current evidence for TDM for all approved OADs is reviewed. METHODS A comprehensive literature search (covering literature published until April 2020), including primary and secondary scientific literature on pharmacokinetics and dose individualisation strategies for OADs, together with US FDA Clinical Pharmacology and Biopharmaceutics Reviews and the Committee for Medicinal Products for Human Use European Public Assessment Reports was conducted. RESULTS OADs are highly potent drugs, which have substantially changed treatment options for cancer patients. Nevertheless, high pharmacokinetic variability and low treatment adherence are risk factors for treatment failure. TDM is a powerful tool to individualise drug dosing, ensure drug concentrations within the therapeutic window and increase treatment success rates. After reviewing the literature for 71 approved OADs, we show that exposure-response and/or exposure-toxicity relationships have been established for the majority. Moreover, TDM has been proven to be feasible for individualised dosing of abiraterone, everolimus, imatinib, pazopanib, sunitinib and tamoxifen in prospective studies. There is a lack of experience in how to best implement TDM as part of clinical routine in OAD cancer therapy. CONCLUSION Sub-therapeutic concentrations and severe adverse events are current challenges in OAD treatment, which can both be addressed by the application of TDM-guided dosing, ensuring concentrations within the therapeutic window.
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Affiliation(s)
- Anna Mueller-Schoell
- Dept. of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Berlin, Germany
- Graduate Research Training Program, PharMetrX, Berlin/Potsdam, Germany
| | - Stefanie L Groenland
- Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
| | - Oliver Scherf-Clavel
- Institute of Pharmacy and Food Chemistry, Julius-Maximilians-Universität Würzburg, Würzburg, Germany
| | - Madelé van Dyk
- College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
| | - Wilhelm Huisinga
- Institute of Mathematics, University of Potsdam, Potsdam, Germany
| | - Robin Michelet
- Dept. of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Berlin, Germany
| | - Ulrich Jaehde
- Department of Clinical Pharmacy, Institute of Pharmacy, University of Bonn, Bonn, Germany
| | - Neeltje Steeghs
- Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
| | - Alwin D R Huitema
- Department of Pharmacy & Pharmacology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, The Netherlands
- Department of Clinical Pharmacy, University Medical Center, Utrecht University, Utrecht, The Netherlands
| | - Charlotte Kloft
- Dept. of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, Berlin, Germany.
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16
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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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17
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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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18
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Ivanov A, Semenova E. Gilbert's Syndrome, Bilirubin Level and UGT1A1∗28 Genotype in Men of North-West Region of Russia. J Clin Exp Hepatol 2021; 11:691-699. [PMID: 34866848 PMCID: PMC8617539 DOI: 10.1016/j.jceh.2021.01.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 01/25/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND/OBJECTIVES Gilbert's syndrome (GS) is a hereditary pathology that affects approximately 10% of the world's population. In most cases, GS is associated with the UGT1A1∗28 polymorphism of UGT1A1 gene coding the enzyme bilirubin uridine diphosphate glucuronosyltransferase (UGT-1A) which plays a key role in the bilirubin metabolism. The presence of an additional TA repeat in the TATA box of the UGT1A1 gene promoter (the allelic variant of 7TA, abbreviated as UGT1A1∗28) leads to a significant decrease in the enzymatic activity of UGT-1A in the liver and to decrease in glucuronidation process as a consequence. The aim of the study is to estimate the prevalence of the 6TA/6TA, 6TA/7TA, and 7TA/7TA genotypes of UGT1A1 promoter and to analyze the effect of these variants on bilirubin levels in healthy men in North-West Russia and patients with a clinical diagnosis of GS. METHODS Genotyping of the UGT1A1 ∗28 (rs8175347) polymorphism was carried out by real-time PCR. RESULTS The results obtained indicate an increased probability of GS developing in residents of the North-West region of Russia compared with other representatives of the Caucasians. CONCLUSIONS Despite the fact that the level of serum bilirubin increases with the rise in the number of additional TA dinucleotides in the UGT1A1 gene promoter tests of clinical manifestations only (jaundice, fatigue, sleep disturbances, nausea, belching, and so on) and increased bilirubin levels in patients with normal liver function do not allow unequivocally diagnose GS. UGT1A1∗28 genotyping should be used as a prognostic risk factor for such pathology development.
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Affiliation(s)
- Andrei Ivanov
- Human Genetics Department, Saint-Petersburg State University Hospital, 154, Fontanka River Embankment, St.Petersburg, 198103, Russia
- Address for correspondence. Ivanov Andrei V., Human Genetics Department, Saint-Petersburg State University Hospital, 154, Fontanka River Embankment, St.Petersburg, 198103, Russia.
| | - Elena Semenova
- Division of Molecular and Radiation Biophysics, National Research Center “Kurchatov Institute” B.P.Konstantinov St Petersburg Nuclear Physics Institute, Gatchina, 188300, Russia
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19
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Abumiya M, Akamine Y, Sato S, Takahashi S, Yoshioka T, Kameoka Y, Takahashi N, Miura M. Effects of proprotein convertase subtilisin/kexin type 9 and nilotinib plasma concentrations on nilotinib-induced hypercholesterolaemia in patients with chronic myeloid leukaemia. J Clin Pharm Ther 2020; 46:382-387. [PMID: 33108009 DOI: 10.1111/jcpt.13294] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 09/24/2020] [Accepted: 09/28/2020] [Indexed: 12/31/2022]
Abstract
WHAT IS KNOWN AND OBJECTIVE The purpose of this study was to investigate the relationships among nilotinib plasma trough concentration (C0 ), low-density lipoprotein (LDL) cholesterol, and PCSK9 plasma concentration in 31 patients with chronic myeloid leukaemia. METHODS Plasma concentrations of nilotinib and PCSK9 were measured by high-performance liquid chromatography and enzyme-linked immunosorbent assays, respectively. RESULTS AND DISCUSSION LDL cholesterol concentrations at 1 month after nilotinib treatment were significantly increased compared with those before therapy. The mean C0 (±SD) of nilotinib at 1, 2, and 3 months after nilotinib treatment were 645 ± 516, 902 ± 623, and 951 ± 1088 ng/mL, respectively. Mean PCSK9 concentrations at 3 months after nilotinib treatment were significantly higher than those at the start of therapy (320 vs 257 ng/mL, respectively, P = .019). When the change rate in the PCSK9 concentration induced by nilotinib was classified with a cut-off value of +40%, the change rate in LDL cholesterol in patients with a change rate in PCSK9 of ≥40% was significantly higher than that in patients with a PCSK9 change rate of <40% (67.1% vs 38.0%, P = .043); however, there were no differences in mean nilotinib C0 . WHAT IS NEW AND CONCLUSION Nilotinib may lead to hypercholesterolaemia by increasing plasma concentrations of PCSK9 after indirect inhibition of mammalian target of rapamycin (mTOR) complex 1. In addition, certain patients seem to have high sensitivity for nilotinib in a signalling cascade of the PI3K/Akt/mTOR pathway, despite low plasma concentrations of nilotinib. Consequently, nilotinib-induced hypercholesterolaemia could not be predicted based on the plasma concentration of nilotinib.
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Affiliation(s)
- Maiko Abumiya
- Department of Pharmacy, Akita University Hospital, Akita, Japan
| | - Yumiko Akamine
- Department of Pharmacy, Akita University Hospital, Akita, Japan
| | - Shiori Sato
- Department of Pharmacy, Akita University Hospital, 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, Akita, Japan
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20
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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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21
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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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22
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Henriksen JN, Bøttger P, Hermansen CK, Ladefoged SA, Nissen PH, Hamilton-Dutoit S, Fink TL, Donskov F. Pazopanib-Induced Liver Toxicity in Patients With Metastatic Renal Cell Carcinoma: Effect of UGT1A1 Polymorphism on Pazopanib Dose Reduction, Safety, and Patient Outcomes. Clin Genitourin Cancer 2020; 18:62-68.e2. [DOI: 10.1016/j.clgc.2019.09.013] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Revised: 08/19/2019] [Accepted: 09/10/2019] [Indexed: 11/16/2022]
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23
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García-Ferrer M, Wojnicz A, Mejía G, Koller D, Zubiaur P, Abad-Santos F. Utility of Therapeutic Drug Monitoring of Imatinib, Nilotinib, and Dasatinib in Chronic Myeloid Leukemia: A Systematic Review and Meta-analysis. Clin Ther 2019; 41:2558-2570.e7. [PMID: 31812340 DOI: 10.1016/j.clinthera.2019.10.009] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 09/26/2019] [Accepted: 10/15/2019] [Indexed: 12/29/2022]
Abstract
PURPOSE This study examined the utility of therapeutic drug monitoring (TDM) of imatinib, nilotinib, and dasatinib in adult patients with chronic-phase chronic myeloid leukemia (CML). TDM in CML entails the measurement of plasma tyrosine kinase inhibitor (TKI) concentration to predict efficacy and tolerability outcomes and to aid in clinical decision making. TDM was to be deemed useful if it could be used for predicting the effectiveness of a drug and/or the occurrence of adverse reactions. It was expected that the findings from the present study would allow for the definition of a therapeutic range of each TKI. METHODS A systematic review of studies reporting trough TKI levels (Cmin) and clinical outcomes was performed. We included randomized clinical trials, nonrandomized controlled studies, interrupted time series studies, and case series studies that provided information about plasma levels of imatinib, nilotinib, or dasatinib and relevant clinical end points in adult patients with chronic-phase CML treated with the corresponding TKI as the single antiproliferative therapy. Meta-analyses, Student t tests, and receiver operating characteristic analyses were performed to detect mean differences between groups of patients with or without: (1) the achievement of major molecular response and (2) adverse reactions. FINDINGS A total of 38 studies (28 for imatinib, 7 for nilotinib, and 3 for dasatinib) were included in the systematic review. TDM was found useful in predicting the efficacy of imatinib, with a Cmin cutoff value of 1000 ng/mL, consistent with guideline recommendations. We suggest a therapeutic range of imatinib at a Cmin of 1000-1500 ng/mL because higher concentrations did not increase efficacy. The findings from the rest of the comparisons were inconclusive. IMPLICATIONS TDM is useful in predicting the efficacy of imatinib in CML. Further research is needed to determine its validity with nilotinib and dasatinib.
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Affiliation(s)
- Manuel García-Ferrer
- Department of Radiology, Hospital Universitario Virgen del Rocío, Seville, Spain
| | - Aneta Wojnicz
- Department of Clinical Pharmacology, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Facultad de Medicina, Universidad Autónoma de Madrid, Instituto de Investigación Sanitaria La Princesa, Madrid, Spain
| | - Gina Mejía
- Department of Clinical Pharmacology, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Facultad de Medicina, Universidad Autónoma de Madrid, Instituto de Investigación Sanitaria La Princesa, Madrid, Spain; UICEC Hospital Universitario de La Princesa, Plataforma Spanish Clinical Research Network, Instituto de Investigación Sanitaria La Princesa, Madrid, Spain
| | - Dora Koller
- Department of Clinical Pharmacology, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Facultad de Medicina, Universidad Autónoma de Madrid, Instituto de Investigación Sanitaria La Princesa, Madrid, Spain
| | - Pablo Zubiaur
- Department of Clinical Pharmacology, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Facultad de Medicina, Universidad Autónoma de Madrid, Instituto de Investigación Sanitaria La Princesa, Madrid, Spain
| | - Francisco Abad-Santos
- Department of Clinical Pharmacology, Hospital Universitario de La Princesa, Instituto Teófilo Hernando, Facultad de Medicina, Universidad Autónoma de Madrid, Instituto de Investigación Sanitaria La Princesa, Madrid, Spain; UICEC Hospital Universitario de La Princesa, Plataforma Spanish Clinical Research Network, Instituto de Investigación Sanitaria La Princesa, Madrid, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Instituto de Salud Carlos III, Madrid, Spain.
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24
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Negoro Y, Yano R, Yoshimura M, Suehiro Y, Yamashita S, Kodawara T, Watanabe K, Tsukamoto H, Nakamura T, Kadowaki M, Morikawa M, Umeda Y, Anzai M, Ishizuka T, Goto N. Influence of UGT1A1 polymorphism on etoposide plus platinum-induced neutropenia in Japanese patients with small-cell lung cancer. Int J Clin Oncol 2018; 24:256-261. [PMID: 30328531 DOI: 10.1007/s10147-018-1358-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Accepted: 10/10/2018] [Indexed: 12/17/2022]
Abstract
BACKGROUND The association between UGT1A1 polymorphism and etoposide-induced toxicities is still not clear. The aim of this study was to assess the association between uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene polymorphism and severe hematologic toxicities in Japanese patients receiving etoposide plus platinum chemotherapy for small-cell lung cancer. METHODS This retrospective analysis included patients with small-cell lung cancer who had received their first-line chemotherapy with etoposide plus cisplatin or carboplatin, between October 2008 and April 2018, at the University of Fukui Hospital. The relationship between UGT1A1 polymorphisms and first-cycle neutropenia as well as thrombocytopenia was evaluated. RESULTS A total of 55 patients were enrolled. The incidence of grade 4 neutropenia during the first cycle of etoposide-based chemotherapy was higher in patients with homozygous (hmz) polymorphisms for UGT1A1*28 and *6 (*28/*28, *6/*6, and *6/*28) than in patients with wild-type (wt) (*1/*1) and heterozygous (htz) (*1/*28 and *1/*6) polymorphisms (88% vs 43% P = 0.03). The incidence of febrile neutropenia and grade 4 thrombocytopenia, however, was not significantly different. Multivariate analysis suggested that grade 4 neutropenia associated significantly with an hmz UGT1A1 genotype [odds ratio (OR) 11.3; P = 0.04] and administration of granulocyte colony-stimulating factor (G-CSF) before the neutrophil counts dropped to < 500 cells/µL (OR; P = 0.01). CONCLUSIONS UGT1A1*28 and UGT1A1*6 mutations might be regarded as predictors for etoposide-induced grade 4 neutropenia.
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Affiliation(s)
- Yutaka Negoro
- Department of Pharmacy, University of Fukui Hospital, 23-3 Matsuoka-shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan.
| | - Ryoichi Yano
- Department of Pharmacy, University of Fukui Hospital, 23-3 Matsuoka-shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan
| | - Mari Yoshimura
- Department of Pharmacy, University of Fukui Hospital, 23-3 Matsuoka-shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan
| | - Yoko Suehiro
- Department of Pharmacy, University of Fukui Hospital, 23-3 Matsuoka-shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan
| | - Shinji Yamashita
- Department of Pharmacy, University of Fukui Hospital, 23-3 Matsuoka-shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan
| | - Takaaki Kodawara
- Department of Pharmacy, University of Fukui Hospital, 23-3 Matsuoka-shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan
| | - Kyohei Watanabe
- Department of Pharmacy, University of Fukui Hospital, 23-3 Matsuoka-shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan
- Medical Research Support Center, University of Fukui Hospital, Yoshida-gun, Fukui, Japan
| | - Hitoshi Tsukamoto
- Department of Pharmacy, University of Fukui Hospital, 23-3 Matsuoka-shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan
| | - Toshiaki Nakamura
- Education and Research Center for Clinical Pharmacy, Osaka Pharmaceutical University, Takatsuki, Osaka, Japan
| | - Maiko Kadowaki
- Third Department of Internal Medicine, University of Fukui Hospital, Yoshida-gun, Fukui, Japan
| | - Miwa Morikawa
- Third Department of Internal Medicine, University of Fukui Hospital, Yoshida-gun, Fukui, Japan
| | - Yukihiro Umeda
- Third Department of Internal Medicine, University of Fukui Hospital, Yoshida-gun, Fukui, Japan
| | - Masaki Anzai
- Third Department of Internal Medicine, University of Fukui Hospital, Yoshida-gun, Fukui, Japan
| | - Tamotsu Ishizuka
- Third Department of Internal Medicine, University of Fukui Hospital, Yoshida-gun, Fukui, Japan
| | - Nobuyuki Goto
- Department of Pharmacy, University of Fukui Hospital, 23-3 Matsuoka-shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan
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25
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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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Ha VH, Jupp J, Tsang RY. Oncology Drug Dosing in Gilbert Syndrome Associated with UGT1A1: A Summary of the Literature. Pharmacotherapy 2017; 37:956-972. [DOI: 10.1002/phar.1946] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Affiliation(s)
- Vincent H. Ha
- Pharmacy Department; Cross Cancer Institute; Edmonton AB Canada
| | - Jennifer Jupp
- Pharmacy Department; Foothills Medical Centre; Calgary AB Canada
| | - Roger Y. Tsang
- Department of Oncology; Tom Baker Cancer Centre; University of Calgary; Calgary AB Canada
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27
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Simultaneous Determination of Imatinib, Dasatinib, and Nilotinib by Liquid Chromatography-Tandem Mass Spectrometry and Its Application to Therapeutic Drug Monitoring. Ther Drug Monit 2017; 39:252-262. [DOI: 10.1097/ftd.0000000000000406] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Bloom AN, Tian H, Schoen C, Winograd N. Label-free visualization of nilotinib-functionalized gold nanoparticles within single mammalian cells by C 60- SIMS imaging. Anal Bioanal Chem 2017; 409:3067-3076. [PMID: 28283715 DOI: 10.1007/s00216-017-0262-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Revised: 02/01/2017] [Accepted: 02/16/2017] [Indexed: 10/20/2022]
Abstract
Obtaining a comprehensive grasp of the behavior and interaction of pharmaceutical compounds within single cells provides some of the fundamental details necessary for more effective drug development. In particular, the changes ensuing in the carrier, drug, and host environment in targeted drug therapy applications must be explored in greater detail, as these are still not well understood. Here, nilotinib-functionalized gold nanoparticles are examined within single mammalian cells with use of imaging cluster secondary ion mass spectrometry in a model study designed to enhance our understanding of what occurs to these particles once that have been internalized. Nilotinib, several types of gold nanoparticles, and the functionalized combination of the two were surveyed and successfully imaged within single cells to determine uptake and performance. Both nilotinib and the gold particle are able to be distinguished and visualized in the functionalized nanoparticle assembly within the cell. These compounds, while both internalized, do not appear to be present in the same pixels of the chemical image, indicating possible cleavage of nilotinib from the particle after cell uptake. The method provided in this work is a direct measurement of uptake and subcellular distribution of an active drug and its carrier within a framework. The results obtained from this study have the potential to be applied to future studies to provide more effective and specific cellular delivery of a relevant pharmaceutical compound.
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Affiliation(s)
- Anna N Bloom
- Department of Chemistry, The Pennsylvania State University, 104 Chemistry Building, University Park, PA, 16802, USA.
| | - Hua Tian
- Department of Chemistry, The Pennsylvania State University, 104 Chemistry Building, University Park, PA, 16802, USA
| | | | - Nicholas Winograd
- Department of Chemistry, The Pennsylvania State University, 104 Chemistry Building, University Park, PA, 16802, USA
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29
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de Souza MMT, Vaisberg VV, Abreu RM, Ferreira AS, daSilvaFerreira C, Nasser PD, Paschoale HS, Carrilho FJ, Ono SK. UGT1A1*28 relationship with abnormal total bilirubin levels in chronic hepatitis C patients: Outcomes from a case-control study. Medicine (Baltimore) 2017; 96:e6306. [PMID: 28296739 PMCID: PMC5369894 DOI: 10.1097/md.0000000000006306] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Gilbert syndrome (GS) is a frequent benign clinical condition, marked by intermittent unconjugated hyperbilirubinemia, mostly due to the polymorphism uridine diphosphate-glucuronosyltransferase 1A1*28 (UGT1A1*28). Hyperbilirubinemia has been reported in a GS patient undergoing hepatitis C treatment, and other UGT isoforms polymorphisms have been linked to worse outcomes in viral hepatitis. Yet, little is known to GS contributions' to the liver disease scenario. Our aim was to assess UGT1A1 genotypes' frequency in chronic hepatitis C (CHC) patients and correlate with total bilirubin (TB). This is a case-control study in a large tertiary medical center. Cases were CHC patients confirmed by hepatitis C virus (HCV)-polymerase chain reaction. Exclusion criteria were hepatitis B virus or human immunodeficiency virus (HIV) coinfection. Control were healthy blood donors. UGT1A1 promoter region gene genotyping was performed, and bilirubin serum levels were available for HCV patients. Genotypes and alleles frequencies were similar in case (n = 585; P = 0.101) and control groups (n = 313; P = 0.795). Total bilirubin increase was noticed according to thymine-adenine repeats in genotypes (P < 0.001), and the TB greater than 1 mg/dL group had more UGT1A1*28 subjects than in the group with TB values <1 mg/dL (18.3 vs 5.3; P < 0.001). Bilirubin levels are linked to the studied polymorphisms, and this is the first time that these findings are reported in a chronic liver disease sample. Among patients with increased TB levels, the frequency of UGT1A1*28 is higher than those with normal TB. Personalized care should be considered to GS, regarding either abnormal bilirubin levels or drug metabolism.
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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: 118] [Impact Index Per Article: 13.1] [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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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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Miura M, Takahashi N. Routine therapeutic drug monitoring of tyrosine kinase inhibitors by HPLC-UV or LC-MS/MS methods. Drug Metab Pharmacokinet 2015; 31:12-20. [PMID: 26732608 DOI: 10.1016/j.dmpk.2015.09.002] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2015] [Revised: 09/14/2015] [Accepted: 09/20/2015] [Indexed: 10/22/2022]
Abstract
Analytical methods using high performance liquid chromatography coupled to ultraviolet detection (HPLC-UV) or liquid chromatography-tandem mass spectrometry (LC-MS/MS) have been reported for the quantification of oral tyrosine kinase inhibitors (TKIs) such as imatinib, nilotinib, and dasatinib in biological fluids. An LC-MS/MS method can simultaneously assay multiple TKIs and their metabolites with high sensitivity and selectivity for low plasma concentrations less than 1 ng/mL. For quantification of imatinib, nilotinib, and dasatinib, a limit of quantification (LOQ) of less than 10 ng/mL, 10 ng/mL, and 0.1 ng/mL, respectively, in the clinical setting is necessary. Because simpler and more cost-efficient methodology is desired for clinical analysis, plasma concentrations of imatinib and nilotinib (target trough concentrations of 1000 ng/mL and 800 ng/mL, respectively) could be assayed by an HPLC-UV method after comparison with results obtained from the standard LC-MS/MS method. However, in the quantification of dasatinib, the LC-MS/MS method that has high sensitivity and selectivity and is free from interference by endogenous impurities is superior to the HPLC-UV method. Highly precise analytical methods are needed for individualized treatment via dose adjustment of oral anticancer drugs, in particular those with low target plasma concentrations less than 10 ng/mL.
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Affiliation(s)
- Masatomo Miura
- Department of Pharmacy, Akita University Hospital, Akita, Japan.
| | - Naoto Takahashi
- Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan
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Germline oncopharmacogenetics, a promising field in cancer therapy. Cell Oncol (Dordr) 2015; 38:65-89. [PMID: 25573079 DOI: 10.1007/s13402-014-0214-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/15/2014] [Indexed: 12/14/2022] Open
Abstract
Pharmacogenetics (PGx) is the study of the relationship between inter-individual genetic variation and drug responses. Germline variants of genes involved in drug metabolism, drug transport, and drug targets can affect individual response to medications. Cancer therapies are characterized by an intrinsically high toxicity; therefore, the application of pharmacogenetics to cancer patients is a particularly promising method for avoiding the use of inefficacious drugs and preventing the associated adverse effects. However, despite continuing efforts in this field, very few labels include information about germline genetic variants associated with drug responses. DPYD, TPMT, UGT1A1, G6PD, CYP2D6, and HLA are the sole loci for which the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) report specific information. This review highlights the germline PGx variants that have been approved to date for anticancer treatments, and also provides some insights about other germline variants with potential clinical applications. The continuous and rapid evolution of next-generation sequencing applications, together with the development of computational methods, should help to refine the implementation of personalized medicine. One day, clinicians may be able to prescribe the best treatment and the correct drug dosage based on each patient's genotype. This approach would improve treatment efficacy, reduce toxicity, and predict non-responders, thereby decreasing chemotherapy-associated morbidity and improving health benefits.
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