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Chen H, Liu S, Yu L, Hou X, Zhao R. Factors and interventions affecting tacrolimus intrapatient variability: A systematic review and meta-analysis. Transplant Rev (Orlando) 2024; 38:100878. [PMID: 39260119 DOI: 10.1016/j.trre.2024.100878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 08/16/2024] [Accepted: 08/17/2024] [Indexed: 09/13/2024]
Abstract
BACKGROUNDS Tacrolimus is a cornerstone of posttransplantation immunosuppressive regimens. Despite routine monitoring, the efficacy of its trough concentrations in reflecting drug concentration fluctuations is limited. Intrapatient variability (IPV) emerges as a novel monitoring marker for predicting clinical outcomes. However, understanding the factors affecting IPV and assessing interventions to address it remain enigmatic, posing a conundrum in clinical management. OBJECTIVES This systematic review aimed to investigate a spectrum of factors affecting IPV and assess the effect of strategic interventions, thereby charting a course for enhanced clinical stewardship. METHODS We electronically searched of PubMed, Embase, and the Cochrane Library databases for studies investigating factors and interventions affecting IPV up to October 2023. Two reviewers independently screened literature, extracted data, and assessed quality, using RevMan 5.4.1 software for meta-analysis. RESULTS A total of 15 randomized controlled trials (RCTs), 34 cohort studies, and 20 self-controlled studies were included. The results indicated that IPV was significantly higher in cytochrome P450 3A5 (CYP3A5) expressers, nonadherent patients, patients taking proton pump inhibitors or statins, and Black or African American recipients, whereas recipients consuming extended-release formulation exhibited lower IPV. Additionally, the participation of pharmacists had a positive effect on improving IPV. CONCLUSIONS Factors affecting IPV encompassed genotype, formulation, adherence, drug combinations, and ethnicity, with each factor exerting varying degrees of effect. Identifying these factors was crucial for developing targeted intervention strategies. While the participation of pharmacists held a promise in improving IPV, further investigation of interventions such as mobile technology, educational measures to enhance adherence, and personalized dosing regimens was warranted.
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Affiliation(s)
- Hongsheng Chen
- Department of Pharmacy, Peking University Third Hospital, Beijing, China; Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing, China.
| | - Shuang Liu
- Department of Pharmacy, Peking University Third Hospital, Beijing, China
| | - Lingling Yu
- Department of Pharmacy, Peking University Third Hospital, Beijing, China; Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Xiaofei Hou
- Department of Urology, Peking University Third Hospital, Beijing, China
| | - Rongsheng Zhao
- Department of Pharmacy, Peking University Third Hospital, Beijing, China.
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Kim H, Han A, Ahn S, Min SK, Ha J, Min S. Association of high intra-patient variability in tacrolimus exposure with calcineurin inhibitor nephrotoxicity in kidney transplantation. Sci Rep 2023; 13:16502. [PMID: 37783764 PMCID: PMC10545770 DOI: 10.1038/s41598-023-43755-x] [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: 03/14/2023] [Accepted: 09/27/2023] [Indexed: 10/04/2023] Open
Abstract
Tacrolimus intra-patient variability (IPV) is a novel predictive marker for long-term kidney transplantation outcomes. We examined the association between IPV and calcineurin inhibitor (CNI) nephrotoxicity and the impact of pharmacogenes on CNI nephrotoxicity and IPV. Among kidney transplant recipients at our hospital between January 2013 and December 2015, the records of 80 patients who underwent 1-year protocol renal allograft biopsy and agreed to donate blood samples for genetic analysis were retrospectively reviewed. The cohort was divided into the low and high IPV groups based on a coefficient variability cutoff value (26.5%). In multivariate analysis, the IPV group was involved in determining CNI nephrotoxicity (HR 4.55; 95% CI 0.05-0.95; p = 0.043). The 5-year graft survival was superior in the low IPV group than in the high IPV group (100% vs 92.4% respectively, p = 0.044). Analysis of the time above therapeutic range (TATR) showed higher CNI nephrotoxicity in the high IPV with high TATR group than in the low IPV with low TATR group (35.7% versus 6.7%, p = 0.003). Genetic analysis discovered that CYP3A4 polymorphism (rs2837159) was associated with CNI nephrotoxicity (HR 28.23; 95% CI 2.2-355.9; p = 0.01). In conclusion, high IPV and CYP3A4 polymorphisms (rs2837159) are associated with CNI nephrotoxicity.
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Affiliation(s)
- Hyokee Kim
- Department of Surgery, Korea University College of Medicine, Seoul, South Korea
| | - Ahram Han
- Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea
| | - Sanghyun Ahn
- Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea
| | - Seung-Kee Min
- Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea
| | - Jongwon Ha
- Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea
| | - Sangil Min
- Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea.
- Division of Transplantation and Vascular Surgery, Department of Surgery, Seoul National University Hospital, 101, Daehak-ro, Jongno-gu, Seoul, 03080, South Korea.
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Vaisbourd Y, Dahhou M, Zhang X, Sapir-Pichhadze R, Cardinal H, Johnston O, Blydt-Hansen TD, Tibbles LA, Hamiwka L, Urschel S, Birk P, Bissonnette J, Matsuda-Abedini M, BScPhm JH, Schiff J, Phan V, De Geest S, Allen U, Avitzur Y, Mital S, Foster BJ. Differences in medication adherence by sex and organ type among adolescent and young adult solid organ transplant recipients. Pediatr Transplant 2023; 27:e14446. [PMID: 36478059 DOI: 10.1111/petr.14446] [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: 06/22/2022] [Revised: 10/26/2022] [Accepted: 11/11/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND Identification of differences in medication adherence by sex or organ type may help in planning interventions to optimize outcomes. We compared immunosuppressive medication adherence between males and females, and between kidney, liver and heart transplant recipients. METHODS This multicenter study of prevalent kidney, liver and heart transplant recipients 14-25 years assessed adherence 3 times (0, 3, 6 months post-enrollment) with the BAASIS self-report tool. At each visit, participants were classified as adherent if they missed no doses in the prior 4 weeks and non-adherent otherwise. Adherence was also assessed using the coefficient of variation (CV) of tacrolimus trough levels; CV < 30% was classified as adherent. We used multivariable mixed effects logistic regression models adjusted for potential confounders to compare adherence by sex and by organ. RESULTS Across all visits, males (n = 150, median age 20.4 years, IQR 17.2-23.3) had lower odds of self-reported adherence than females (n = 120, median age 19.8 years, IQR 17.1-22.7) (OR 0.41, 95% CI 0.21-0.80) but higher odds of adherence by tacrolimus CV (OR 2.50, 95% CI 1.30-4.82). No significant differences in adherence (by self-report or tacrolimus CV) were noted between the 184 kidney, 58 liver, and 28 heart recipients. CONCLUSION Females show better self-reported adherence than males but greater variability in tacrolimus levels. Social desirability bias, more common in females than males, may contribute to better self-reported adherence among females. Higher tacrolimus variability among females may reflect biologic differences in tacrolimus metabolism between males and females rather than sex differences in adherence. There were no significant differences in adherence by organ type.
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Affiliation(s)
| | - Mourad Dahhou
- Research Institute of The McGill University Health Centre, Quebec, Canada
| | - Xun Zhang
- Research Institute of The McGill University Health Centre, Quebec, Canada
| | - Ruth Sapir-Pichhadze
- Research Institute of The McGill University Health Centre, Quebec, Canada.,Department of Medicine, McGill University, Quebec, Canada.,Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Quebec, Canada
| | | | - Olwyn Johnston
- Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Tom D Blydt-Hansen
- Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada
| | - Lee Anne Tibbles
- Department of Medicine and Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Lorraine Hamiwka
- Department of Paediatrics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Simon Urschel
- Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
| | - Patricia Birk
- Section of Pediatric Nephrology, University of Manitoba, Winnipeg, Manitoba, Canada
| | | | - Mina Matsuda-Abedini
- Department of Pediatrics, The Hospital for Sick Children and The University of Toronto, Toronto, Ontario, Canada
| | - Jennifer Harrison BScPhm
- Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.,Ajmera Transplant Centre, Toronto General Hospital, Toronto, Ontario, Canada
| | - Jeffrey Schiff
- Ajmera Transplant Centre, Toronto General Hospital, Toronto, Ontario, Canada
| | | | - Sabina De Geest
- Department Public Health, Institute of Nursing Science, University of Basel, Basel, Switzerland.,Department of Primary Care and Public Health, Academic Center of Nursing and Midwifery, KU Leuven, Leuven, Belgium
| | - Upton Allen
- Department of Pediatrics, The Hospital for Sick Children and The University of Toronto, Toronto, Ontario, Canada
| | - Yaron Avitzur
- Department of Pediatrics, The Hospital for Sick Children and The University of Toronto, Toronto, Ontario, Canada
| | - Seema Mital
- Department of Pediatrics, The Hospital for Sick Children and The University of Toronto, Toronto, Ontario, Canada
| | - Bethany J Foster
- Department of Pediatrics, McGill University, Quebec, Canada.,Research Institute of The McGill University Health Centre, Quebec, Canada.,Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Quebec, Canada
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Intrapatient Variability (IPV) and the Blood Concentration Normalized by the Dose (C/D Ratio) of Tacrolimus-Their Correlations and Effects on Long-Term Renal Allograft Function. Biomedicines 2022; 10:biomedicines10112860. [PMID: 36359380 PMCID: PMC9687762 DOI: 10.3390/biomedicines10112860] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 11/02/2022] [Accepted: 11/04/2022] [Indexed: 11/11/2022] Open
Abstract
Tacrolimus, in combination with mycophenolate mofetil and glucocorticoids, is the basis of immunosuppressive therapy after renal transplantation. Tacrolimus intrapatient variability (IPV) and the blood concentration normalized by the dose (concentration/dose ratio, C/D ratio) both have an effect on the function of the transplanted kidney. In this study, we examined whether the metabolism rate affected IPV, whether the C/D ratio value was stable in the long-term follow-up, and whether it could be used for IPV measurements. In addition, our study population was examined for the effect of the C/D ratio and IPV on long-term renal function. The C/D ratio and IPV were examined in 170 patients at appointments held at 3, 6, 12 and 24 months after RTx. The average time post renal transplantation was 70 months. Renal function defined as creatinine concentration at the last appointment was examined. Results: the mean C/D ratio in the study group was 1.63. A negative correlation between the C/D ratio and creatinine concentration at the end of the follow-up was observed. Between the C/D ratio < and ≥1.63 groups, significant differences in creatinine concentration at the last appointment were found. No relationship was identified between the mean C/D ratio and IPV. The C/D ratio values increased significantly over a longer post-transplant period (12, 24, 60 and 120 m). We did not find a correlation between the mean IPV and the creatinine concentration from the last appointment. Our study group was divided into terciles according to IPV, while no renal graft function differences were found at the same appointment. Conclusion: the C/D ratio is useful for assessing the effects of the metabolism rate of tacrolimus on the long-term renal graft function. The C/D ratio does not affect the IPV value. IPV calculated from variability of the C/D ratio does not influence transplanted kidney function. The C/D changes over time.
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Comparison of Tacrolimus Intra-Patient Variability during 6-12 Months after Kidney Transplantation between CYP3A5 Expressers and Nonexpressers. J Clin Med 2022; 11:jcm11216320. [PMID: 36362548 PMCID: PMC9658797 DOI: 10.3390/jcm11216320] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 10/19/2022] [Accepted: 10/24/2022] [Indexed: 12/05/2022] Open
Abstract
A high intra-patient variability (IPV) of tacrolimus exposure is associated with poor long-term kidney transplantation outcomes. To assess the influence of cytochrome P450 (CYP) 3A5 genetic polymorphisms on tacrolimus IPV, 188 clinically stable kidney transplant recipients, who had received an immediate-release tacrolimus-based immunosuppressive regimen, were enrolled in this retrospective cohort study. Genotyping of CYP3A5*3 (rs776746) was performed and 110 (58.5%) were identified as CYP3A5 expressers and 78 (41.5%) as nonexpressers. Whole blood tacrolimus concentrations were analyzed by chemiluminescent microparticle immunoassay. Dose-adjusted trough tacrolimus concentrations (C0/D) measured at months 6, 9, and 12 were used to determine IPV. There were no significant differences in the IPV estimated by the coefficient of variation, the IPV calculated by mean absolute deviation method, and the proportions of recipients with the IPV estimated by the coefficient of variation of 30% or more between CYP3A5 expressers and nonexpressers (p = 0.613, 0.686, and 0.954, respectively). Tacrolimus C0/D in CYP3A5 expressers was approximately half of those in nonexpressers, overall (p < 0.001). In both CYP3A5 expressers and nonexpressers, tacrolimus C0/D increased gradually from month 6 to month 12 (p = 0.021). There was no evidence that the CYP3A5 polymorphisms significantly influence tacrolimus IPV during the 6 to 12 months after kidney transplantation.
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Choi JS, Ko H, Kim HK, Chung C, Han A, Min SK, Ha J, Kang HG, Ha IS, Min S. Effects of tacrolimus intrapatient variability and CYP3A5 polymorphism on the outcomes of pediatric kidney transplantation. Pediatr Transplant 2022; 26:e14297. [PMID: 35466485 DOI: 10.1111/petr.14297] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 03/16/2022] [Accepted: 04/07/2022] [Indexed: 12/17/2022]
Abstract
BACKGROUND The intrapatient variability (IPV) of tacrolimus (Tac) is associated with the long-term outcome of kidney transplantation. The CYP3A single-nucleotide polymorphism (SNP) may affect the IPV of Tac. We investigated the impact of IPV and genetic polymorphism in pediatric patients who received kidney transplantation. METHODS A total of 202 pediatric renal transplant recipients from 2000 to 2016 were analyzed retrospectively. The IPV was calculated between 6 and 12 months after surgery. Among these patients, CYP3A5 polymorphism was analyzed in 67 patients. RESULTS The group with high IPV had a significantly higher rate of de novo donor-specific human leukocyte antigen antibodies (dnDSA) development (35.7% vs. 16.7%, p = .003). The high IPV group also had a higher incidence of T-cell-mediated rejection (TCMR; p < .001). The high IPV had no significant influence on Epstein-Barr virus, cytomegalovirus, and BK virus viremia but was associated with the incidence of posttransplant lymphoproliferative disorders (p = .003). Overall, the graft survival rate was inferior in the high IPV group (p < .001). The CYP3A5 SNPs did not significantly affect the IPV of Tac. In the CYP3A5 expressor group, however, the IPV was significantly associated with the TCMR-free survival rate (p < .001). CONCLUSION The IPV of Tac had a significant impact on dnDSA development, occurrence of acute TCMR, and graft failure in pediatric patients who received renal transplantation. CYP3A5 expressors with high IPV of Tac showed worse outcomes, while the CYP3A5 polymorphism had no impact on IPV of Tac.
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Affiliation(s)
- Jin Sun Choi
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Hyunmin Ko
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Hyo Kee Kim
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Chris Chung
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Ahram Han
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Seung-Kee Min
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Jongwon Ha
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.,Transplantation Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hee Gyung Kang
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Il Soo Ha
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Sangil Min
- Department of Surgery, Seoul National University College of Medicine, Seoul, Korea
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Brunet M, Pastor-Anglada M. Insights into the Pharmacogenetics of Tacrolimus Pharmacokinetics and Pharmacodynamics. Pharmaceutics 2022; 14:1755. [PMID: 36145503 PMCID: PMC9503558 DOI: 10.3390/pharmaceutics14091755] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 07/28/2022] [Accepted: 08/10/2022] [Indexed: 11/27/2022] Open
Abstract
The influence of pharmacogenetics in tacrolimus pharmacokinetics and pharmacodynamics needs further investigation, considering its potential in assisting clinicians to predict the optimal starting dosage and the need for a personalized adjustment of the dose, as well as to identify patients at a high risk of rejection, drug-related adverse effects, or poor outcomes. In the past decade, new pharmacokinetic strategies have been developed to improve personalized tacrolimus treatment. Several studies have shown that patients with tacrolimus doses C0/D < 1 ng/mL/mg may demonstrate a greater incidence of drug-related adverse events and infections. In addition, C0 tacrolimus intrapatient variability (IPV) has been identified as a potential biomarker to predict poor outcomes related to drug over- and under-exposure. With regard to tacrolimus pharmacodynamics, inconsistent genotype-phenotype relationships have been identified. The aim of this review is to provide a concise summary of currently available data regarding the influence of pharmacogenetics on the clinical outcome of patients with high intrapatient variability and/or a fast metabolizer phenotype. Moreover, the role of membrane transporters in the interindividual variability of responses to tacrolimus is critically discussed from a transporter scientist’s perspective. Indeed, the relationship between transporter polymorphisms and intracellular tacrolimus concentrations will help to elucidate the interplay between the biological mechanisms underlying genetic variations impacting drug concentrations and clinical effects.
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Affiliation(s)
- Mercè Brunet
- Farmacologia i Toxicologia, Servei de Bioquímica i Genètica Molecular, Centre de Diagnòstic Biomèdic. Hospital Clínic de Barcelona, Universitat de Barcelona, 08036 Barcelona, Spain
- Institut d’Investigacions Biomèdiques August Pí i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Spain
| | - Marçal Pastor-Anglada
- Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Spain
- Molecular Pharmacology and Experimental Therapeutics (MPET), Departament de Bioquímica i Biomedicina Molecular, Institut de Biomedicina, Universitat de Barcelona (IBUB), 08028 Barcelona, Spain
- Institut de Recerca Sant Joan de Déu (IRSJD), 08950 Esplugues de Llobregat, Spain
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Use of Pharmacogenetics to Optimize Immunosuppressant Therapy in Kidney-Transplanted Patients. Biomedicines 2022; 10:biomedicines10081798. [PMID: 35892699 PMCID: PMC9332547 DOI: 10.3390/biomedicines10081798] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 07/18/2022] [Accepted: 07/22/2022] [Indexed: 12/17/2022] Open
Abstract
Immunosuppressant drugs (ISDs) are routinely used in clinical practice to maintain organ transplant survival. However, these drugs are characterized by a restricted therapeutic index, a high inter- and intra-individual pharmacokinetic variability, and a series of severe adverse effects. In particular, genetic factors have been estimated to play a role in this variability because of polymorphisms regarding genes encoding for enzymes and transporters involved in the ISDs pharmacokinetic. Several studies showed important correlations between genetic polymorphisms and ISDs blood levels in transplanted patients; therefore, this review aims to summarize the pharmacogenetics of approved ISDs. We used PubMed database to search papers on pharmacogenetics of ISDs in adults or pediatric patients of any gender and ethnicity receiving immunosuppressive therapy after kidney transplantation. We utilized as search term: “cyclosporine or tacrolimus or mycophenolic acid or sirolimus or everolimus and polymorphism and transplant”. Our data showed that polymorphisms in CYP3A5, CYP3A4, ABCB1, and UGT1A9 genes could modify the pharmacokinetics of immunosuppressants, suggesting that patient genotyping could be a helpful strategy to select the ideal ISDs dose for each patient.
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9
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Dopazo C, Bilbao I, García S, Gómez-Gavara C, Caralt M, Campos-Varela I, Castells L, Hidalgo E, Moreso F, Montoro B, Charco R. High intrapatient variability of tacrolimus exposure associated with poorer outcomes in liver transplantation. Clin Transl Sci 2022; 15:1544-1555. [PMID: 35373449 PMCID: PMC9199878 DOI: 10.1111/cts.13276] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 03/03/2022] [Accepted: 03/14/2022] [Indexed: 11/29/2022] Open
Abstract
Tacrolimus (TAC) is a dose‐dependent immunosuppressor with considerable intrapatient variability (IPV) in its pharmacokinetics. The aim of this work is to ascertain the association between TAC IPV at 6 months after liver transplantation (LT) and patient outcome. This single‐center cohort study retrospectively analyzed adult patients who underwent transplantation from 2015 to 2019 who survived the first 6 months with a functioning graft. The primary end point was the patient’s probability of death and the secondary outcome was the loss of renal function between month 6 and the last follow‐up. TAC IPV was estimated by calculating the coefficient of variation (CV) of the dose‐corrected concentration (C0/D) between the third and sixth months post‐LT. Of the 140 patients who underwent LT included in the study, the low‐variability group (C0/D CV < 27%) comprised 105 patients and the high‐variability group (C0/D CV ≥ 27%) 35 patients. One‐, 3‐, and 5‐year patient survival rates were 100%, 82%, and 72% in the high‐variability group versus 100%, 97%, and 93% in the low‐variability group, respectively (p = 0.005). Moreover, significant impaired renal function was observed in the high‐variability group at 1 year (69 ± 16 ml/min/1.73 m2 vs. 78 ± 16 ml/min/1.73 m2, p = 0.004) and at 2 years post‐LT (69 ± 17 ml/min/1.73 m2 vs. 77 ± 15 ml/min/1.73 m2, p = 0.03). High C0/D CV 3–6 months remained independently associated with worse survival (hazard ratio = 3.57, 95% CI = 1.32–9.67, p = 0.012) and loss of renal function (odds ratio = 3.47, 95% CI = 1.30–9.20, p = 0.01). Therefore, high IPV between the third and sixth months appears to be an early and independent predictor of patients with poorer liver transplant outcomes.
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Affiliation(s)
- Cristina Dopazo
- Department of HPB Surgery and Transplants, Hospital Universitario Vall d´Hebron, Universidad Autónoma de Barcelona, Barcelona, Spain
| | - Itxarone Bilbao
- Department of HPB Surgery and Transplants, Hospital Universitario Vall d´Hebron, Universidad Autónoma de Barcelona, Barcelona, Spain
| | - Sonia García
- Department of Pharmacy, Barcelona Hospital Campus, Universitat Autónoma de Barcelona, Barcelona, Spain
| | - Concepción Gómez-Gavara
- Department of HPB Surgery and Transplants, Hospital Universitario Vall d´Hebron, Universidad Autónoma de Barcelona, Barcelona, Spain
| | - Mireia Caralt
- Department of HPB Surgery and Transplants, Hospital Universitario Vall d´Hebron, Universidad Autónoma de Barcelona, Barcelona, Spain
| | - Isabel Campos-Varela
- Liver Unit, Vall d'Hebron Hospital Universitari, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autónoma de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Lluis Castells
- Liver Unit, Vall d'Hebron Hospital Universitari, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Universitat Autónoma de Barcelona, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain
| | - Ernest Hidalgo
- Department of HPB Surgery and Transplants, Hospital Universitario Vall d´Hebron, Universidad Autónoma de Barcelona, Barcelona, Spain
| | - Francisco Moreso
- Department of Nephrology, Hospital Universitario Vall d´Hebron, Barcelona, Spain
| | - Bruno Montoro
- Department of Pharmacy, Barcelona Hospital Campus, Universitat Autónoma de Barcelona, Barcelona, Spain
| | - Ramón Charco
- Department of HPB Surgery and Transplants, Hospital Universitario Vall d´Hebron, Universidad Autónoma de Barcelona, Barcelona, Spain
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10
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The Role of Intra-Patient Variability of Tacrolimus Drug Concentrations in Solid Organ Transplantation: A Focus on Liver, Heart, Lung and Pancreas. Pharmaceutics 2022; 14:pharmaceutics14020379. [PMID: 35214111 PMCID: PMC8878862 DOI: 10.3390/pharmaceutics14020379] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 02/02/2022] [Accepted: 02/05/2022] [Indexed: 11/17/2022] Open
Abstract
Tacrolimus, the keystone immunosuppressive drug administered after solid organ transplantation, presents a narrow therapeutic index and wide inter- and intra-patient pharmacokinetic variability (IPV). The latter has been fairly studied in kidney transplantation, where it could impact outcomes. However, literature about other transplanted organ recipients remains inconclusive. This review aimed at summarizing the evidence about the IPV of tacrolimus concentrations outside of the scope of kidney transplantation. First, factors influencing IPV will be presented. Then, the potential of IPV as a biomarker predictive of graft outcomes will be discussed in liver, heart, lung and pancreas transplantation. Lastly, strategies to reduce IPV will be reviewed, with the ultimate objective being ready-to-implement solutions in clinical practice by transplantation professionals.
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11
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Bunthof KLW, Al-Hassany L, Nakshbandi G, Hesselink DA, van Schaik RHN, Ten Dam MAGJ, Baas MC, Hilbrands LB, van Gelder T. A randomized crossover study comparing different tacrolimus formulations to reduce intrapatient variability in tacrolimus exposure in kidney transplant recipients. Clin Transl Sci 2021; 15:930-941. [PMID: 34905302 PMCID: PMC9010272 DOI: 10.1111/cts.13206] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 10/23/2021] [Accepted: 11/17/2021] [Indexed: 12/05/2022] Open
Abstract
A high intrapatient variability (IPV) in tacrolimus exposure is a risk factor for poor long‐term outcomes after kidney transplantation. The main objective of this trial was to investigate whether tacrolimus IPV decreases after switching patients from immediate‐release (IR)‐tacrolimus to either extended‐release (ER)‐tacrolimus or LifeCyclePharma (LCP)‐tacrolimus. In this randomized, prospective, open‐label, cross‐over trial, adult kidney transplant recipients on a stable immunosuppressive regimen, including IR‐tacrolimus, were randomized for conversion to ER‐tacrolimus or LCP‐tacrolimus, and for the order in which IR‐tacrolimus and the once‐daily formulations were taken. Patients were followed 6 months for each formulation, with monthly tacrolimus predose concentration assessments to calculate the IPV. The IPV was defined as the coefficient of variation (%) of dose corrected predose concentrations. Ninety‐two patients were included for analysis of the primary outcome. No significant differences between the IPV of IR‐tacrolimus (16.6%) and the combined once‐daily formulations (18.3%) were observed (% difference +1.7%, 95% confidence interval [CI] −1.1% to ‒4.5%, p = 0.24). The IPV of LCP‐tacrolimus (20.1%) was not significantly different from the IPV of ER‐tacrolimus (16.5%, % difference +3.6%, 95% CI −0.1% to 7.3%, p = 0.06). In conclusion, the IPV did not decrease after switching from IR‐tacrolimus to either ER‐tacrolimus or LCP‐tacrolimus. These results provide no arguments to switch kidney transplant recipients from twice‐daily (IR) tacrolimus formulations to once‐daily (modified‐release) tacrolimus formulations when the aim is to lower the IPV.
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Affiliation(s)
- Kim L W Bunthof
- Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands.,Department of Internal Medicine, Bravis Hospital, Roosendaal, The Netherlands
| | - Linda Al-Hassany
- Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Gizal Nakshbandi
- Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Dennis A Hesselink
- Internal Medicine, Division of Nephrology and Transplantation, Erasmus University Medical Center, Rotterdam, The Netherlands.,Erasmus University Medical Center, Erasmus MC Transplant Institute, Rotterdam, The Netherlands
| | - Ron H N van Schaik
- Clinical Chemistry, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Marc A G J Ten Dam
- Department of Internal Medicine, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands
| | - Marije C Baas
- Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Luuk B Hilbrands
- Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Teun van Gelder
- Internal Medicine, Division of Nephrology and Transplantation, Erasmus University Medical Center, Rotterdam, The Netherlands.,Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
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12
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Leino AD, Park JM, Pasternak AL. Impact of CYP3A5 phenotype on tacrolimus time in therapeutic range and clinical outcomes in pediatric renal and heart transplant recipients. Pharmacotherapy 2021; 41:649-657. [PMID: 34129685 DOI: 10.1002/phar.2601] [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: 03/23/2021] [Revised: 06/01/2021] [Accepted: 06/02/2021] [Indexed: 11/11/2022]
Abstract
STUDY OBJECTIVE This study investigated the effect of CYP3A5 phenotype on time in therapeutic range (TTR) of tacrolimus post-transplant in pediatric patients. DESIGN AND DATA SOURCE This retrospective study assessed medical records of pediatric kidney and heart recipients with available CYP3A5 genotype for tacrolimus dosing, troughs, and the clinical events (biopsy-proven acute rejection [BPAR] and de novo donor-specific antibodies [dnDSA]). MEASUREMENTS AND MAIN RESULTS The primary outcome, mean TTR in the first 90 days post-transplant, was 9.0% (95% CI: -16.1, -1.9) lower in CYP3A5 expressers (p = 0.014) when adjusting for time to therapeutic concentration and organ type. There was no difference between CYP3A5 phenotypes in time to the first clinical event using TTR during the first 90 days. When applying TTR over the first year, there was a significant difference in event-free survival (EFS) which was 50.0% for CYP3A5 expressers/TTR < 35%, 45.5% for expressers/TTR ≥ 35%, 38.1% for nonexpressers/TTR < 35%, and 72.9% for nonexpressers/TTR ≥ 35% (log-rank p = 0.03). A post hoc analysis of EFS identified CYP3A5 expressers had lower EFS compared to nonexpressers in patients with TTR ≥ 35% (p = 0.04) but no difference among patients with TTR < 35% (p = 0.6). CONCLUSIONS The relationship between TTR and CYP3A5 phenotype suggests that achieving a TTR ≥ 35% during the first year may be a modifiable factor to attenuate the risk of BPAR and dnDSA.
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Affiliation(s)
- Abbie D Leino
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
| | - Jeong M Park
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
| | - Amy L Pasternak
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan, USA
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13
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Stefanović NZ, Veličković-Radovanović RM, Danković KS, Mitić BP, Paunović GJ, Cvetković MB, Cvetković TP. Combined Effect of Inter- and Intrapatient Variability in Tacrolimus Exposure on Graft Impairment Within a 3-Year Period Following Kidney Transplantation: A Single-Center Experience. Eur J Drug Metab Pharmacokinet 2020; 45:749-760. [PMID: 32886348 DOI: 10.1007/s13318-020-00644-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND AND OBJECTIVE Tacrolimus is a cornerstone of the most immunosuppressive protocols after kidney transplantation, but its use is complicated by notable interpatient and intrapatient variability (IPV). The goal of this study was to evaluate whether or not tacrolimus IPV, or average dose-adjusted trough concentration (C0/D), during 6-12 months post-transplantation might have contributed to graft function decline in a 3-year period following kidney transplantation. After primary evaluation of individual effects of tacrolimus IPV and C0/D, the study aimed to estimate the combined effect of tacrolimus IPV and C0/D on composite endpoint (consisting of graft failure, chronic allograft dysfunction, chronic rejection, and doubling of serum creatinine concentration) in the period between 13 and 36 months after kidney transplantation. In addition, the goal was to analyze the impact of genetics on interpatient variability in tacrolimus exposure in the early and late post-transplantation periods. METHODS The study enrolled 104 Caucasian patients and included 2541 patient examinations up to 36 months after kidney transplantation. All patients were genotyped on CYP3A5 6986A>G and ABCB1 3435C>T gene polymorphism. Patients were divided into groups based on the tacrolimus IPV tertiles and the median value of average C0/D during 6-12 months post-transplantation. RESULTS The results showed a more pronounced decline in estimated glomerular filtration rate values within the high IPV tertile group (p = 0.018), as well as within the low C0/D group (p = 0.013) in a 3-year period after kidney transplantation. The carriers of CYP3A5*1/*3 genotype had lower C0/D compared to the CYP3A5*3/*3 carriers during the entire study period, while the results for ABCB1 were inconsistent when considering tacrolimus C0/D. Patients with high IPV/low C0/D had significantly reduced graft survival compared to the other tacrolimus IPV/C0/D combination groups (i.e., high IPV/high C0/D, low IPV/low C0/D, low IPV/high C0/D) with the hazard ratio of 3.14 in Cox analysis for reaching the composite endpoint. CONCLUSION The findings of this study suggest that combined assessment of tacrolimus IPV and tacrolimus C0/D may categorize patients towards risk of graft deterioration in the long-term post-transplantation period.
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Affiliation(s)
- Nikola Z Stefanović
- Department of Pharmacy, Faculty of Medicine, University of Nis, Dr Zorana Djindjica 81 Blvd., 18000, Nis, Serbia.
| | - Radmila M Veličković-Radovanović
- Department of Pharmacology With Toxicology, Faculty of Medicine, University of Nis, Dr Zorana Djindjica 81 Blvd., , 18000, Nis, Serbia
- Clinic of Nephrology, Clinical Center Nis, Dr Zorana Djindjica 48 Blvd., 18000, Nis, Serbia
| | - Katarina S Danković
- Faculty of Medicine, University of Nis, Dr Zorana Djindjica 81 Blvd., 18000, Nis, Serbia
| | - Branka P Mitić
- Clinic of Nephrology, Clinical Center Nis, Dr Zorana Djindjica 48 Blvd., 18000, Nis, Serbia
- Department of Internal Medicine, Faculty of Medicine, University of Nis, Dr Zorana Djindjica 81 Blvd., 18000, Nis, Serbia
| | - Goran J Paunović
- Clinic of Nephrology, Clinical Center Nis, Dr Zorana Djindjica 48 Blvd., 18000, Nis, Serbia
| | - Mina B Cvetković
- Clinic of Nephrology, Clinical Center Nis, Dr Zorana Djindjica 48 Blvd., 18000, Nis, Serbia
- Faculty of Medicine, University of Nis, Dr Zorana Djindjica 81 Blvd., 18000, Nis, Serbia
| | - Tatjana P Cvetković
- Clinic of Nephrology, Clinical Center Nis, Dr Zorana Djindjica 48 Blvd., 18000, Nis, Serbia
- Department of Biochemistry, Faculty of Medicine, University of Nis, Dr Zorana Djindjica 81 Blvd., 18000, Nis, Serbia
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14
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Pallio G, Irrera N, Bitto A, Mannino F, Minutoli L, Rottura M, Pallio S, Altavilla D, Alibrandi A, Marciano MC, Righi M, Mannucci C, Arcoraci V, Squadrito F. Failure of Achieving Tacrolimus Target Blood Concentration Might Be Avoided by a Wide Genotyping of Transplanted Patients: Evidence from a Retrospective Study. J Pers Med 2020; 10:jpm10020047. [PMID: 32492825 PMCID: PMC7354451 DOI: 10.3390/jpm10020047] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 05/22/2020] [Accepted: 05/29/2020] [Indexed: 01/08/2023] Open
Abstract
Precise tacrolimus treatment in transplanted patients is achieved in the clinical setting by performing therapeutic drug monitoring (TDM) and consequently adjusting therapy. The aim of this study was to retrospectively analyze the variability in tacrolimus blood levels throughout 2 years of observation in 75 transplanted patients and to investigate if tacrolimus blood levels correlate with presence of genetic polymorphisms, thus modifying tacrolimus pharmacokinetics. CYP3A5*1 (G6986A), CYP3A4*1B (A392G), CYP3A4*22, ABCB1 (C3435T; C1236T; G2677A/T), SLCO1B1 (T521C), polymorphisms were analyzed. Based on the effect of their genotypes, patients were stratified into 5 groups: (1) reduced tacrolimus metabolism (RM), (2) increased metabolism (IM), (3) transporters polymorphisms (TM), (4) metabolism and transporter polymorphisms (AM) and (5) no mutations (Wild Type, WT). The percentage of the samples out of therapeutic range was significantly higher in the IM group than in the WT group (p = 0.001), as well as compared to the TM group (p = 0.004). Only IM pattern (p = 0.015) resulted as an independent predictor of number of tacrolimus blood levels out of therapeutic range. RM pattern (p = 0.006) was inversely related to the administered dose. Therefore, genotyping could become a standard practice before tacrolimus prescription thus decreasing side effects, increasing efficacy and reducing the economic burden for the national health system.
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Affiliation(s)
- Giovanni Pallio
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (G.P.); (N.I.); (A.B.); (F.M.); (L.M.); (M.R.); (S.P.); (F.S.)
| | - Natasha Irrera
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (G.P.); (N.I.); (A.B.); (F.M.); (L.M.); (M.R.); (S.P.); (F.S.)
| | - Alessandra Bitto
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (G.P.); (N.I.); (A.B.); (F.M.); (L.M.); (M.R.); (S.P.); (F.S.)
| | - Federica Mannino
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (G.P.); (N.I.); (A.B.); (F.M.); (L.M.); (M.R.); (S.P.); (F.S.)
| | - Letteria Minutoli
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (G.P.); (N.I.); (A.B.); (F.M.); (L.M.); (M.R.); (S.P.); (F.S.)
| | - Michelangelo Rottura
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (G.P.); (N.I.); (A.B.); (F.M.); (L.M.); (M.R.); (S.P.); (F.S.)
| | - Socrate Pallio
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (G.P.); (N.I.); (A.B.); (F.M.); (L.M.); (M.R.); (S.P.); (F.S.)
| | - Domenica Altavilla
- Department of Biomedical, Dental, Morphological and Functional Imaging Sciences, University of Messina, Via C. Valeria, 98125 Messina, Italy; (D.A.); (M.R.); (C.M.)
| | - Angela Alibrandi
- Department of Economics Section of Statistical and Mathematical Sciences, University of Messina, Via dei Verdi, 98122 Messina, Italy;
| | - Maria Concetta Marciano
- Grande Ospedale Metropolitano: “Bianchi-Melacrino-Morelli”, Via Giuseppe Melacrino, 89124 Reggio Calabria, Italy;
| | - Maria Righi
- Department of Biomedical, Dental, Morphological and Functional Imaging Sciences, University of Messina, Via C. Valeria, 98125 Messina, Italy; (D.A.); (M.R.); (C.M.)
| | - Carmen Mannucci
- Department of Biomedical, Dental, Morphological and Functional Imaging Sciences, University of Messina, Via C. Valeria, 98125 Messina, Italy; (D.A.); (M.R.); (C.M.)
| | - Vincenzo Arcoraci
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (G.P.); (N.I.); (A.B.); (F.M.); (L.M.); (M.R.); (S.P.); (F.S.)
- Correspondence:
| | - Francesco Squadrito
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (G.P.); (N.I.); (A.B.); (F.M.); (L.M.); (M.R.); (S.P.); (F.S.)
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15
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Kuypers DRJ. Intrapatient Variability of Tacrolimus Exposure in Solid Organ Transplantation: A Novel Marker for Clinical Outcome. Clin Pharmacol Ther 2019; 107:347-358. [PMID: 31449663 DOI: 10.1002/cpt.1618] [Citation(s) in RCA: 79] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 08/14/2019] [Indexed: 12/12/2022]
Abstract
The calcineurin-inhibitor tacrolimus (Tac) provides an acceptable balance between prevention of allograft rejection and drug-related adverse effects, making it the standard of care in all types of solid organ transplantation for the last 2 decades. Recent data have demonstrated that high intrapatient variability (IPV) in Tac predose trough concentrations has deleterious effects on allograft survival. The underlying mechanisms by which a high Tac IPV shortens allograft survival are acute and chronic rejection, donor-specific anti-HLA antibodies, and progressive fibrotic damage to the graft. Modifiable causes of high Tac IPV include medication nonadherence (MNA), drug interactions, nutritional interferences, and concurrent diseases. Recognizing high Tac IPV as an important prognostic risk factor after solid organ transplantation requires understanding of the definitions, the use of correct diagnostic metrics, and methodology. Therapeutic interventions aimed at reducing Tac IPV are targeted on improving MNA, avoiding or adjusting drug interactions, drug dosing assists, and educational support of recipients.
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Affiliation(s)
- Dirk R J Kuypers
- Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium.,Department of Microbiology and Immunology, Catholic University of Leuven, Leuven, Belgium
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16
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Cheung CY, Chan KM, Wong YT, Chak WL, Bekers O, van Hooff JP. Impact of CYP3A5 Genetic Polymorphism on Intrapatient Variability of Tacrolimus Exposure in Chinese Kidney Transplant Recipients. Transplant Proc 2019; 51:1754-1757. [DOI: 10.1016/j.transproceed.2019.04.019] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 04/24/2019] [Accepted: 04/25/2019] [Indexed: 01/05/2023]
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17
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Leino AD, King EC, Jiang W, Vinks AA, Klawitter J, Christians U, Woodle ES, Alloway RR, Rohan JM. Assessment of tacrolimus intrapatient variability in stable adherent transplant recipients: Establishing baseline values. Am J Transplant 2019; 19:1410-1420. [PMID: 30506623 DOI: 10.1111/ajt.15199] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 11/14/2018] [Accepted: 11/26/2018] [Indexed: 01/25/2023]
Abstract
The purpose of this study was to determine the intrapatient (within the same patient) variability of tacrolimus in adherent patients. Daily tacrolimus trough levels were obtained at home using dried blood spot technology in kidney and liver transplant recipients. Patients were randomized to receive 3 formulations of tacrolimus, each for two 1-week periods. Adherence was monitored by patient diary, pill counts, and use of the Medication Event Monitoring System (MEMS). Variability was quantified as the coefficient of variation (CV). Comparison of CV between groups was by independent t test or one-way ANOVA as appropriate. The population was found to be adherent with a rate of 99.9% with a mean interval between the evening and morning dose of tacrolimus of 11.86 hours. The median CV for the entire population was 15.2% (range 4.8%-110%). There were no differences in CV by allograft type or tacrolimus formulation. The multivariate analysis did not identify any demographic characteristics associated with a CV > 30%. In a highly adherent population, tacrolimus did not display high intrapatient variability. Given the association between IPV and poor allograft outcomes, future studies are needed to quantitate the influence of adherence and establish target IPV goals.
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Affiliation(s)
- Abbie D Leino
- Division of Transplantation, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Eileen C King
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.,Division of Biostatistics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Wenlei Jiang
- Office of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, U.S. Food & Drug Administration, Silver Spring, Maryland
| | - Alexander A Vinks
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.,Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Jost Klawitter
- iC42 Clinical Research and Development, University of Colorado, Aurora, Colorado
| | - Uwe Christians
- iC42 Clinical Research and Development, University of Colorado, Aurora, Colorado
| | - E Steve Woodle
- Division of Transplantation, Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Rita R Alloway
- Division of Nephrology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio
| | - Jennifer M Rohan
- Division of Hematology and Oncology, Children's Hospital of Richmond, Richmond, Virginia
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18
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Seibert SR, Schladt DP, Wu B, Guan W, Dorr C, Remmel RP, Matas AJ, Mannon RB, Israni AK, Oetting WS, Jacobson PA. Tacrolimus trough and dose intra-patient variability and CYP3A5 genotype: Effects on acute rejection and graft failure in European American and African American kidney transplant recipients. Clin Transplant 2018; 32:e13424. [PMID: 30318646 PMCID: PMC6317347 DOI: 10.1111/ctr.13424] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Revised: 09/18/2018] [Accepted: 10/08/2018] [Indexed: 02/01/2023]
Abstract
BACKGROUND Suboptimal immunosuppression after kidney transplantation contributes to toxicity and loss of efficacy. Little is known regarding the impact of intra-patient variability of tacrolimus (TAC) doses and troughs in the early post-transplant period or the influence of genetic variants on variability. METHODS Coefficients of variation (CV) of TAC troughs and doses of 1226 European American (EA) and 246 African American (AA) adult recipients enrolled in DeKAF Genomics were compared for association with acute rejection and graft failure. Additionally, the influence of recipients' number of CYP3A5 loss-of-function alleles was assessed. RESULTS Acute rejection was associated with greater CV of dose in AA (P < 0.001) and EA recipients (P = 0.012). Graft failure was associated with a greater CV of dose (P = 0.022) and trough (P < 0.001) in AA, and higher CV of trough (P = 0.024) in EA recipients. In EA, CYP3A5 loss-of-function alleles were associated with decreased CV of trough (P = 0.0042) and increased CV of dose (P < 0.0001). CONCLUSION CYP3A5 loss-of-function alleles influence intra-patient TAC trough and dose variability. High variability of TAC dose increases risk of acute rejection. High variability of TAC trough increases risk of graft failure. Early clinical recognition of TAC dose and trough variability may improve patient management and outcomes.
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Affiliation(s)
- Stephan R Seibert
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota
| | - David P Schladt
- Chronic Disease Research Group, Minneapolis Medical Research Foundation, Hennepin County Medical Center, Minneapolis, Minnesota
| | - Baolin Wu
- Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota
| | - Weihua Guan
- Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota
| | - Casey Dorr
- Minneapolis Medical Research Foundation, Hennepin County Medical Center, Minneapolis, Minnesota
| | - Rory P Remmel
- Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota
| | - Arthur J Matas
- Department of Surgery, University of Minnesota, Minneapolis, Minnesota
| | - Roslyn B Mannon
- Department of Nephrology, University of Alabama, Birmingham, Alabama
| | - Ajay K Israni
- Division of Nephrology, Hennepin County Medical Center, Epidemiology & Community Health, University of Minnesota, Minneapolis, Minnesota
| | - William S Oetting
- Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota
| | - Pamala A Jacobson
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota
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19
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Glander P, Waiser J, Kasbohm S, Friedersdorff F, Peters R, Rudolph B, Wu K, Budde K, Liefeldt L. Bioavailability and costs of once-daily and twice-daily tacrolimus formulations in de novo kidney transplantation. Clin Transplant 2018; 32:e13311. [DOI: 10.1111/ctr.13311] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/06/2018] [Indexed: 11/27/2022]
Affiliation(s)
- Petra Glander
- Department of Nephrology and Internal Intensive Care Medicine; Charité - Universitätsmedizin Berlin; Berlin Germany
| | - Johannes Waiser
- Department of Nephrology and Internal Intensive Care Medicine; Charité - Universitätsmedizin Berlin; Berlin Germany
| | - Silke Kasbohm
- Department of Nephrology and Internal Intensive Care Medicine; Charité - Universitätsmedizin Berlin; Berlin Germany
| | | | - Robert Peters
- Department of Urology; Charité - Universitätsmedizin Berlin; Berlin Germany
| | - Birgit Rudolph
- Department of Pathology; Charité - Universitätsmedizin Berlin; Berlin Germany
| | - Kaiyin Wu
- Department of Pathology; Charité - Universitätsmedizin Berlin; Berlin Germany
| | - Klemens Budde
- Department of Nephrology and Internal Intensive Care Medicine; Charité - Universitätsmedizin Berlin; Berlin Germany
| | - Lutz Liefeldt
- Department of Nephrology and Internal Intensive Care Medicine; Charité - Universitätsmedizin Berlin; Berlin Germany
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20
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Chen L, Prasad GVR. CYP3A5 polymorphisms in renal transplant recipients: influence on tacrolimus treatment. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2018; 11:23-33. [PMID: 29563827 PMCID: PMC5846312 DOI: 10.2147/pgpm.s107710] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Tacrolimus is a commonly used immunosuppressant after kidney transplantation. It has a narrow therapeutic range and demonstrates wide interindividual variability in pharmacokinetics, leading to potential underimmunosuppression or toxicity. Genetic polymorphism in CYP3A5 enzyme expression contributes to differences in tacrolimus bioavailability between individuals. Individuals carrying one or more copies of the wild-type allele *1 express CYP3A5, which increases tacrolimus clearance. CYP3A5 expressers require 1.5 to 2-fold higher tacrolimus doses compared to usual dosing to achieve therapeutic blood concentrations. Individuals with homozygous *3/*3 genotype are CYP3A5 nonexpressers. CYP3A5 nonexpression is the most frequent phenotype in most ethnic populations, except blacks. Differences between CYP3A5 genotypes in tacrolimus disposition have not translated into differences in clinical outcomes, such as acute rejection and graft survival. Therefore, although genotype-based dosing may improve achievement of therapeutic drug concentrations with empiric dosing, its role in clinical practice is unclear. CYP3A5 genotype may predict differences in absorption of extended-release and immediate-release oral formulations of tacrolimus. Two studies found that CYP3A5 expressers require higher doses of tacrolimus in the extended-release formulation compared to immediate release. CYP3A5 genotype plays a role in determining the impact of interacting drugs, such as fluconazole, on tacrolimus pharmacokinetics. Evidence conflicts regarding the impact of CYP3A5 genotype on risk of nephrotoxicity associated with tacrolimus. Further study is required.
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Affiliation(s)
- Lucy Chen
- Kidney Transplant Program, St Michael's Hospital, Toronto, ON, Canada
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21
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Tacrolimus Trough Concentration Variability and Disparities in African American Kidney Transplantation. Transplantation 2017; 101:2931-2938. [PMID: 28658199 DOI: 10.1097/tp.0000000000001840] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Low tacrolimus concentrations have been associated with higher risk of acute rejection, particularly within African American (AA) kidney transplant recipients; little is known about intrapatient tacrolimus variabilities impact on racial disparities. METHODS Ten year, single-center, longitudinal cohort study of kidney recipients. Intrapatient tacrolimus variability was assessed using the coefficient of variation (CV) measured between 1 month posttransplant and the clinical event, with a comparable period assessed in those without events. Pediatrics, nontacrolimus/mycophenolate regimens, and nonrenal transplants were excluded. Multivariable Cox regression models were used to analyze data. RESULTS One thousand four hundred eleven recipients were included (54.4% AA) with 39 521 concentrations used to assess intrapatient tacrolimus CV. Overall, intrapatient tacrolimus CV was higher in AAs versus non-AAs (39.9 ± 19.8 % vs 34.8 ± 15.8% P < 0.001). Tacrolimus variability was a significant risk factor for deleterious clinical outcomes. A 10% increase in tacrolimus CV augmented the risk of acute rejection by 20% (adjusted hazard ratio, 1.20, 1.13-1.28; P < 0.001) and the risk of graft loss by 30% (adjusted hazard ratio, 1.30, 1.23-1.37; P < 0.001), with significant effect modification by race for acute rejection, but not graft loss. High tacrolimus variability (CV >40%) was a significant explanatory variable for disparities in AAs; the crude relative risk of acute rejection in AAs was reduced by 46% when including tacrolimus variability in modeling and reduced by 40% for graft loss. CONCLUSIONS These data demonstrate that intrapatient tacrolimus variability is strongly associated with acute rejection in AAs and graft loss in all patients. Tacrolimus variability is a significant explanatory variable for disparities in AA recipients.
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Shuker N, Bouamar R, Hesselink DA, van Gelder T, Caliskan K, Manintveld OC, Balk AH, Constantinescu AA. Intrapatient Variability in Tacrolimus Exposure Does Not Predict The Development of Cardiac Allograft Vasculopathy After Heart Transplant. EXP CLIN TRANSPLANT 2017; 16:326-332. [PMID: 28969528 DOI: 10.6002/ect.2016.0366] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVE A high intrapatient variability in tacrolimus exposure is associated with poor long-term outcomes after kidney transplant. We hypothesized that a high intrapatient variability of tacrolimus exposure after heart transplant may be associated with cardiac allograft vasculopathy as a determinant of long-term survival of heart transplant recipients. MATERIALS AND METHODS Eighty-six heart transplant recipients were included. Patients underwent coronary angiography at years 1 and 4 after transplant and were divided according to low and high intrapatient variability of tacrolimus exposure, with the median variability as cut-off. The primary outcome was the association between tacrolimus intrapatient variability and the progression of cardiac allograft vasculopathy score between years 1 and 4. Secondary outcome was this association with acute cellular rejection. RESULTS There was no significant difference in the proportion of patients with high tacrolimus intrapatient variability in the group that progressed to higher grades of cardiac allograft vasculopathy (n = 15) versus the group without progression (n = 71) at 4-year follow-up (60.0% vs 47.9%; P = .57). There was no significant difference in the proportion of patients with high tacrolimus intrapatient variability between the 58 patients with 1 or more acute cellular rejection episodes and the 28 patients without rejection (51.7% vs 46.4%; P = .82). CONCLUSIONS A high intrapatient variability in tacrolimus exposure does not appear to influence heart transplant outcomes, unlike its influence on kidney transplant function. A higher immunosuppression exposure after heart transplant, including the use of prednisone often in a combination of 3 immunosuppressive drugs, may protect against the effects of high intrapatient tacrolimus variability.
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Affiliation(s)
- Nauras Shuker
- Department of Hospital Pharmacy, Clinical Pharmacology Unit, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
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Ramey P, Osborn MR, Lowen KM, Reed RC, Abou-Khalil B. Unexplained spikes in lamotrigine serum concentration: nonlinear elimination? Acta Neurol Scand 2017; 135:240-246. [PMID: 27029219 DOI: 10.1111/ane.12588] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/24/2016] [Indexed: 11/29/2022]
Abstract
OBJECTIVES The objective of this study was to evaluate possible nonlinear lamotrigine (LTG) pharmacokinetics at elevated concentration. LTG is reported to have linear kinetics, so that elimination rate is linearly proportional to blood concentration and a change in dose is accompanied by a proportionate change in serum concentration. We encountered patients in whom LTG serum concentration increased dramatically in response to minor or no change in LTG dose. We studied this phenomenon in patients with LTG toxicity in one clinic. MATERIALS AND METHODS Using electronic medical records from 1997 to 2014, we identified patients who developed clinical LTG toxicity with LTG serum concentrations >20 mg/l, after tolerating lamotrigine at lower serum concentrations. We reviewed LTG dose change and other changes that preceded the episode of toxicity. RESULTS Twenty-two patients had at least one episode of LTG toxicity with levels higher than 20 mg/l (of 922 patients with available levels). The peak serum concentration varied from 21.1 to 40.3 mg/l (mean 28.7). The increase in level was explained in three patients (post-delivery in one, addition of valproate in two). In the 18 others, the increase was not explained or it was disproportionate to an increase in LTG dose. CONCLUSIONS Spikes in LTG levels and associated clinical toxicity may occur unexpectedly, suggesting that elimination kinetics may be nonlinear in some individuals at serum concentrations in the upper range. Measurement and close monitoring of LTG levels is warranted for new symptoms that could be consistent with lamotrigine toxicity, particularly when the baseline serum concentration has been >10 mg/l.
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Affiliation(s)
- P. Ramey
- Department of Neurology; Vanderbilt University; Nashville TN USA
| | - M. R. Osborn
- Department of Neurology; Vanderbilt University; Nashville TN USA
| | - K. M. Lowen
- Department of Neurology; Vanderbilt University; Nashville TN USA
| | - R. C. Reed
- Husson University School of Pharmacy; Bangor ME USA
| | - B. Abou-Khalil
- Department of Neurology; Vanderbilt University; Nashville TN USA
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Shuker N, Shuker L, van Rosmalen J, Roodnat JI, Borra LCP, Weimar W, Hesselink DA, van Gelder T. A high intrapatient variability in tacrolimus exposure is associated with poor long-term outcome of kidney transplantation. Transpl Int 2016; 29:1158-1167. [PMID: 27188932 DOI: 10.1111/tri.12798] [Citation(s) in RCA: 107] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2015] [Revised: 01/15/2016] [Accepted: 05/13/2016] [Indexed: 12/30/2022]
Abstract
Tacrolimus is a critical dose drug with a considerable intrapatient variability (IPV) in its pharmacokinetics. We investigated whether a high IPV in tacrolimus exposure is associated with adverse long-term renal transplantation outcomes. Tacrolimus IPV was calculated from predose concentrations measured between 6 and 12 months post-transplantation of 808 renal transplant recipients (RTRs) transplanted between 2000 and 2010. One hundred and eighty-eight (23.3%) patients reached the composite end point consisting of graft loss, late biopsy-proven rejection, transplant glomerulopathy, or doubling of serum creatinine concentration between month 12 and the last follow-up. The cumulative incidence of the composite end point was significantly higher in patients with high IPV than in patients with low IPV (hazard ratio: 1.41, 95% CI: 1.06-1.89; P = 0.019). After the adjustment for several factors, the higher incidence of the composite end point for RTRs with a high IPV remained statistically significant (hazard ratio: 1.42, 95% CI: 1.06-1.90; P = 0.019). Younger recipient age at transplantation, previous transplantation, worse graft function (at month 6 post-transplantation), and low mean tacrolimus concentration at 1 year post-transplantation were additional predictors for worse long-term transplant outcome. A high tacrolimus IPV is an independent risk factor for adverse kidney transplant outcomes that can be used as an easy monitoring tool to help identify high-risk RTRs.
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Affiliation(s)
- Nauras Shuker
- Department of Internal Medicine, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands. .,Department of Hospital Pharmacy, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands.
| | - Lamis Shuker
- Department of Internal Medicine, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands
| | - Joost van Rosmalen
- Department of Biostatistics, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands
| | - Joke I Roodnat
- Department of Internal Medicine, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands
| | - Lennaert C P Borra
- Department of Hospital Pharmacy, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands
| | - Willem Weimar
- Department of Internal Medicine, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands
| | - Dennis A Hesselink
- Department of Internal Medicine, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands
| | - Teun van Gelder
- Department of Internal Medicine, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands.,Department of Hospital Pharmacy, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands
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Abstract
PURPOSE OF REVIEW Pharmacogenomics is the study of differences in drug response on the basis of individual genetic background. With rapidly advancing genomic technologies and decreased costs of genotyping, the field of pharmacogenomics continues to develop. Application to patients with kidney disease provides growing opportunities for improving drug therapy. RECENT FINDINGS Pharmacogenomics studies are lacking in patients with chronic kidney disease and dialysis, but are abundant in the kidney transplant field. A potentially clinically actionable genetic variant exists in the CYP3A5 gene, with the initial tacrolimus dose selection being optimized based on CYP3A5 genotype. Although many pharmacogenomics studies have focused on transplant immunosuppression pharmacokinetics, an expanding literature on pharmacodynamic outcomes, such as calcineurin inhibitor toxicity and new onset diabetes, is providing new information on patients at risk. SUMMARY Appropriately powered pharmacogenomics studies with well-defined phenotypes are needed to validate existing studies and unearth new findings in patients with kidney disease, especially the chronic kidney disease and dialysis population.
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Shuker N, van Gelder T, Hesselink DA. Intra-patient variability in tacrolimus exposure: causes, consequences for clinical management. Transplant Rev (Orlando) 2015; 29:78-84. [PMID: 25687818 DOI: 10.1016/j.trre.2015.01.002] [Citation(s) in RCA: 167] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2014] [Revised: 12/22/2014] [Accepted: 01/11/2015] [Indexed: 12/18/2022]
Abstract
Tacrolimus (Tac) is widely used for the prevention of rejection after solid organ transplantation. Finding the optimal balance between effective Tac concentrations and toxicity is a challenge and requires therapeutic drug monitoring. In addition to the well-known inter-patient variability, the clinical use of Tac is also complicated by considerable intra-patient variability (IPV) in Tac exposure. Tac IPV is defined as the amount of fluctuation of whole-blood concentrations over a certain period of time during which the Tac dose remains unchanged. A high IPV in Tac exposure has recently been recognized as a strong risk factor for acute rejection and poor long-term kidney transplantation outcome. In addition to non-adherence, several other factors determine the magnitude of the IPV in Tac exposure. Quantification of IPV is easy and can be easily incorporated into everyday clinical practice as a tool for optimizing transplantation outcomes.
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Affiliation(s)
- Nauras Shuker
- Department of Internal Medicine, Division of Nephrology and Renal Transplantation, Erasmus MC, University Medical Center, Rotterdam, the Netherlands; Hospital Pharmacy, Clinical Pharmacology Unit, Erasmus MC, University Medical Center, Rotterdam, the Netherlands.
| | - Teun van Gelder
- Department of Internal Medicine, Division of Nephrology and Renal Transplantation, Erasmus MC, University Medical Center, Rotterdam, the Netherlands; Hospital Pharmacy, Clinical Pharmacology Unit, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
| | - Dennis A Hesselink
- Department of Internal Medicine, Division of Nephrology and Renal Transplantation, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
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Provenzani A, Santeusanio A, Mathis E, Notarbartolo M, Labbozzetta M, Poma P, Provenzani A, Polidori C, Vizzini G, Polidori P, D’Alessandro N. Pharmacogenetic considerations for optimizing tacrolimus dosing in liver and kidney transplant patients. World J Gastroenterol 2013; 19:9156-9173. [PMID: 24409044 PMCID: PMC3882390 DOI: 10.3748/wjg.v19.i48.9156] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2013] [Revised: 10/16/2013] [Accepted: 10/22/2013] [Indexed: 02/06/2023] Open
Abstract
The introduction of tacrolimus in clinical practice has improved patient survival after organ transplant. However, despite the long use of tacrolimus in clinical practice, the best way to use this agent is still a matter of intense debate. The start of the genomic era has generated new research areas, such as pharmacogenetics, which studies the variability of drug response in relation to the genetic factors involved in the processes responsible for the pharmacokinetics and/or the action mechanism of a drug in the body. This variability seems to be correlated with the presence of genetic polymorphisms. Genotyping is an attractive option especially for the initiation of the dosing of tacrolimus; also, unlike phenotypic tests, the genotype is a stable characteristic that needs to be determined only once for any given gene. However, prospective clinical studies must show that genotype determination before transplantation allows for better use of a given drug and improves the safety and clinical efficacy of that medication. At present, research has been able to reliably show that the CYP3A5 genotype, but not the CYP3A4 or ABCB1 ones, can modify the pharmacokinetics of tacrolimus. However, it has not been possible to incontrovertibly show that the corresponding changes in the pharmacokinetic profile are linked with different patient outcomes regarding tacrolimus efficacy and toxicity. For these reasons, pharmacogenetics and individualized medicine remain a fascinating area for further study and may ultimately become the face of future medical practice and drug dosing.
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