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1
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Naldi GDAR, Minari AB, Pereira TDM, Fossaluza V, Eugenio NW, Ferreira MA, Gregório GH, Nacif L, D Albuquerque LAC, di Lazzaro Filho R, Cançado ELR, Ono SK. CYP3A5 and POR gene polymorphisms as predictors of infection and graft rejection in post-liver transplant patients treated with tacrolimus - a cohort study. THE PHARMACOGENOMICS JOURNAL 2025; 25:4. [PMID: 39994182 DOI: 10.1038/s41397-025-00363-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 01/30/2025] [Accepted: 02/14/2025] [Indexed: 02/26/2025]
Abstract
Liver transplantation is the only curative option for patients with advanced stages of liver disease, with tacrolimus used as the immunosuppressive drug of choice. Genetic variability can interfere with drug response, potentially leading to overexposure or underexposure. This study aims to investigate the association of CYP3A4 (rs2740574, rs2242480, rs35599367), CYP3A5 (rs776746, rs10264272), POR (rs1057868) and ABCB1 (rs1128503, rs2229109, rs9282564) gene polymorphisms with infection, acute rejection, and renal failure. The logistic regression model found an influence of CYP3A5 (rs776746) and POR28 (rs1057868) on the development of acute rejection after liver transplantation (p = 0.028). It also found an association between carriers of the variant allele of the POR*28 gene and infection.
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Affiliation(s)
| | - Ariane Boccoli Minari
- Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil
| | - Thales D M Pereira
- Institute of Mathematics and Statistics of the University of São Paulo, São Paulo, Brazil
| | - Victor Fossaluza
- Institute of Mathematics and Statistics of the University of São Paulo, São Paulo, Brazil
| | | | | | | | - Lucas Nacif
- Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil
| | | | | | | | - Suzane Kioko Ono
- Department of Gastroenterology, University of São Paulo School of Medicine, São Paulo, Brazil
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2
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Belardi R, Pacifici F, Baldetti M, Velocci S, Minieri M, Pieri M, Campione E, Della-Morte D, Tisone G, Anselmo A, Novelli G, Bernardini S, Terrinoni A. Trends in Precision Medicine and Pharmacogenetics as an Adjuvant in Establishing a Correct Immunosuppressive Therapy for Kidney Transplant: An Up-to-Date Historical Overview. Int J Mol Sci 2025; 26:1960. [PMID: 40076585 PMCID: PMC11900248 DOI: 10.3390/ijms26051960] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 02/17/2025] [Accepted: 02/20/2025] [Indexed: 03/14/2025] Open
Abstract
Kidney transplantation is currently the treatment of choice for patients with end-stage kidney diseases. Although significant advancements in kidney transplantation have been achieved over the past decades, the host's immune response remains the primary challenge, often leading to potential graft rejection. Effective management of the immune response is essential to ensure the long-term success of kidney transplantation. To address this issue, immunosuppressives have been developed and are now fully integrated into the clinical management of transplant recipients. However, the considerable inter- and intra-patient variability in pharmacokinetics (PK) and pharmacodynamics (PD) of these drugs represents the primary cause of graft rejection. This variability is primarily attributed to the polymorphic nature (genetic heterogeneity) of genes encoding xenobiotic-metabolizing enzymes, transport proteins, and, in some cases, drug targets. These genetic differences can influence drug metabolism and distribution, leading to either toxicity or reduced efficacy. The main objective of the present review is to report an historical overview of the pharmacogenetics of immunosuppressants, shedding light on the most recent findings and also suggesting how relevant is the research and investment in developing validated NGS-based commercial panels for pharmacogenetic profiling in kidney transplant recipients. These advancements will enable the implementation of precision medicine, optimizing immunosuppressive therapies to improve graft survival and kidney transplanted patient outcomes.
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Affiliation(s)
- Riccardo Belardi
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (R.B.); (M.B.); (S.V.); (M.M.); (M.P.); (S.B.)
| | - Francesca Pacifici
- Department of Human Sciences and Quality of Life Promotion, San Raffaele University, 00166 Rome, Italy; (F.P.); (D.D.-M.)
- Interdisciplinary Center for Advanced Studies on Lab-on-Chip and Organ-on-Chip Applications (ICLOC), University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
| | - Matteo Baldetti
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (R.B.); (M.B.); (S.V.); (M.M.); (M.P.); (S.B.)
| | - Silvia Velocci
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (R.B.); (M.B.); (S.V.); (M.M.); (M.P.); (S.B.)
| | - Marilena Minieri
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (R.B.); (M.B.); (S.V.); (M.M.); (M.P.); (S.B.)
| | - Massimo Pieri
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (R.B.); (M.B.); (S.V.); (M.M.); (M.P.); (S.B.)
| | - Elena Campione
- Dermatology Unit, Policlinico Tor Vergata, System Medicine Department, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy;
| | - David Della-Morte
- Department of Human Sciences and Quality of Life Promotion, San Raffaele University, 00166 Rome, Italy; (F.P.); (D.D.-M.)
- Interdisciplinary Center for Advanced Studies on Lab-on-Chip and Organ-on-Chip Applications (ICLOC), University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
- Department of Neurology, Evelyn F. McKnight Brain Institute, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy;
| | - Giuseppe Tisone
- Department of Surgery, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (G.T.)
| | - Alessandro Anselmo
- Department of Surgery, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (G.T.)
| | - Giuseppe Novelli
- Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy;
| | - Sergio Bernardini
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (R.B.); (M.B.); (S.V.); (M.M.); (M.P.); (S.B.)
| | - Alessandro Terrinoni
- Department of Experimental Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; (R.B.); (M.B.); (S.V.); (M.M.); (M.P.); (S.B.)
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Manomaisantiphap S, Boon-Yasidhi P, Tanathitiphuwarat N, Thammanatsakul K, Puwanant S, Ariyachaipanich A, Sinphurmsukskul S, Pachinburavan M, Chariyavilaskul P, Siwamogsatham S, Ongcharit P. Advancement of Heart Transplantation in Thai Recipients: Survival Trends and Pharmacogenetic Insights. Clin Transplant 2025; 39:e70092. [PMID: 39876635 DOI: 10.1111/ctr.70092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 01/06/2025] [Accepted: 01/19/2025] [Indexed: 01/30/2025]
Abstract
Since 1987, King Chulalongkorn Memorial Hospital (KCMH) has performed a substantial number of heart transplants as a specific therapy for advanced-stage heart failure. This descriptive study aimed to analyze post-transplant survival in the recent era compared to earlier periods and examine the pharmacogenetics of related immunosuppressants. Data from all recipients who underwent heart transplants from 1987 to 2021 were retrospectively retrieved from the electronic medical record. The genotypes of relevant pharmacogenes were analyzed in recipients who were alive during the enrollment period. Kaplan-Meier analysis revealed improved overall survival rates in the recent era compared to the past. Dilated cardiomyopathy was identified as the most common pretransplant diagnosis, while infection remained the leading cause of mortality. In conclusion, the findings demonstrate significant advancements in the quality of heart transplantation in Thailand. Future studies are warranted to explore the correlation between pharmacogenetic variations identified in this study and subsequent clinical outcomes, with a focus on genetic-guided treatment to optimize patient care.
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Affiliation(s)
| | - Pasawat Boon-Yasidhi
- Faculty of Medicine, Department of Pharmacology, Chulalongkorn University, Bangkok, Thailand
| | - Napatsanan Tanathitiphuwarat
- Center of Excellence in Clinical Pharmacokinetics and Pharmacogenomics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Kanokwan Thammanatsakul
- Excellence Center for Organ Transplantation, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
| | - Sarinya Puwanant
- Excellence Center for Organ Transplantation, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
- Faculty of Medicine, Division of Cardiovascular Medicine, Department of Medicine, Chulalongkorn University, Bangkok, Thailand
- Cardiac Center, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
| | - Akekarach Ariyachaipanich
- Excellence Center for Organ Transplantation, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
- Faculty of Medicine, Division of Cardiovascular Medicine, Department of Medicine, Chulalongkorn University, Bangkok, Thailand
- Cardiac Center, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
| | - Supanee Sinphurmsukskul
- Excellence Center for Organ Transplantation, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
- Cardiac Center, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
| | - Monvasi Pachinburavan
- Faculty of Medicine, Division of Critical Care Medicine, Department of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Pajaree Chariyavilaskul
- Faculty of Medicine, Department of Pharmacology, Chulalongkorn University, Bangkok, Thailand
- Center of Excellence in Clinical Pharmacokinetics and Pharmacogenomics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Sarawut Siwamogsatham
- Cardiac Center, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
- Maha Chakri Sirindhorn Clinical Research Center (Chula CRC), Research Affairs, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Pat Ongcharit
- Excellence Center for Organ Transplantation, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
- Faculty of Medicine, Division of Cardiothoracic Surgery, Department of Surgery, Chulalongkorn University, Bangkok, Thailand
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Gao Y, Ma J. The impact of CYP3A5, NR1I2, and POR polymorphisms on tacrolimus dose-adjusted concentration and clinical outcomes in adult allogeneic haematopoietic stem cell transplantation. Xenobiotica 2025; 55:16-24. [PMID: 39754510 DOI: 10.1080/00498254.2024.2448967] [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: 11/20/2024] [Revised: 12/23/2024] [Accepted: 12/24/2024] [Indexed: 01/06/2025]
Abstract
Polymorphisms in genes related to drug-metabolising enzymes may affect tacrolimus exposure. This study aimed to assess the influence of CYP3A5, NR1I2, and POR polymorphisms on tacrolimus pharmacokinetics and outcomes in allogeneic haematopoietic stem cell transplantation (HSCT).Forty-six adult patients receiving oral tacrolimus at an initial dose of 0.03 mg/kg/day for acute graft versus host disease (GVHD) prophylaxis after allogeneic HSCT were enrolled in this retrospective study. Genetic polymorphisms were detected in relation to concentration/dose (C/D) ratios of tacrolimus and the incidence of acute GVHD and acute kidney injury (AKI).The CYP3A5 *3/*3 genotype and co-administration of voriconazole were significantly associated with increased C/D ratios of tacrolimus (p < 0.05). NR1I2 8055CC presents a significantly higher tacrolimus C/D ratio compared with carriers of 8055CT and 8055TT genotypes in allogeneic HSCT recipients with the CYP3A5*1 allele (p = 0.033). Younger age and recipients with the CYP3A5*1 allele were significantly associated with higher incidence of II-IV acute GVHD post-transplantation.CYP3A5*3, NR1I2 8055C > T, and concomitant use of voriconazole are important determinants affecting tacrolimus pharmacokinetics. Moreover, CYP3A5*1 allele and younger age are independent risk factors for II-IV acute GVHD in HSCT recipients.
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Affiliation(s)
- Yuan Gao
- Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jingjing Ma
- Department of Pharmacy, The Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Medical Center of Soochow University, Suzhou, China
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John S, Klumsathian S, Own‐eium P, Charoenyingwattana A, Eu‐ahsunthornwattana J, Sura T, Dejsuphong D, Sritara P, Vathesatogkit P, Thongchompoo N, Thabthimthong W, Teerakulkittipong N, Chantratita W, Sukasem C. Thai pharmacogenomics database -2 (TPGxD-2) sequel to TPGxD-1, analyzing genetic variants in 26 non-VIPGx genes within the Thai population. Clin Transl Sci 2024; 17:e70019. [PMID: 39449569 PMCID: PMC11502937 DOI: 10.1111/cts.70019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 06/20/2024] [Accepted: 07/11/2024] [Indexed: 10/26/2024] Open
Abstract
Next-generation sequencing (NGS) has transformed pharmacogenomics (PGx), enabling thorough profiling of pharmacogenes using computational methods and advancing personalized medicine. The Thai Pharmacogenomic Database-2 (TPGxD-2) analyzed 948 whole genome sequences, primarily from the Electricity Generating Authority of Thailand (EGAT) cohort. This study is an extension of the previous Thai Pharmacogenomic Database (TPGxD-1) and specifically focused on 26 non-very important pharmacogenes (VIPGx) genes. Variant calling was conducted using Sentieon (version 201808.08) following GATK's best workflow practices. We then annotated variant call format (VCF) files using Golden Helix VarSeq 2.5.0. Star allele analysis was performed with Stargazer v2.0.2, which called star alleles for 22 of 26 non-VIPGx genes. The variant analysis revealed a total of 14,529 variants in 26 non-VIPGx genes, with TBXAS1 had the highest number of variants (27%). Among the 14,529 variants, 2328 were novel (without rsID), with 87 identified as clinically relevant. We also found 56 known PGx variants among the known variants (n = 12,201), with UGT2B7 (19.64%), CYP1B1 (8.9%), SLCO2B1 (8.9%), and POR (8.9%) being the most common. We reported a high frequency of intermediate metabolizers (IMs) in CYP2F1 (34.6%) and CYP4A11 (8.6%), and a high frequency of decreased functional alleles in POR (53.9%) and SLCO1B3 (34.9%) genes. This study enhances our understanding of pharmacogenomic profiling of 26 non-VIPGx genes of notable clinical importance in the Thai population. However, further validation with additional computational and reference genotyping methods is necessary, and novel alleles identified in this study should undergo further orthogonal validation.
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Affiliation(s)
- Shobana John
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi HospitalMahidol UniversityBangkokThailand
- Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC)Ramathibodi HospitalBangkokThailand
| | - Sommon Klumsathian
- Center for Medical Genomics, Faculty of Medicine Ramathibodi HospitalMahidol UniversityBangkokThailand
| | - Paravee Own‐eium
- Center for Medical Genomics, Faculty of Medicine Ramathibodi HospitalMahidol UniversityBangkokThailand
| | | | | | - Thanyachai Sura
- Division of Medical Genetics and Molecular Medicine, Department of Internal Medicine, Faculty of Medicine Ramathibodi HospitalMahidol UniversityBangkokThailand
| | - Donniphat Dejsuphong
- Program in Translational Medicine, Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathobodi HospitalMahidol UniversityBang PhliSamutprakarnThailand
| | - Piyamitr Sritara
- Department of Medicine, Faculty of Medicine Ramathibodi HospitalMahidol UniversityBangkokThailand
| | - Prin Vathesatogkit
- Department of Medicine, Faculty of Medicine Ramathibodi HospitalMahidol UniversityBangkokThailand
| | - Nartthawee Thongchompoo
- Center for Medical Genomics, Faculty of Medicine Ramathibodi HospitalMahidol UniversityBangkokThailand
| | - Wiphaporn Thabthimthong
- Center for Medical Genomics, Faculty of Medicine Ramathibodi HospitalMahidol UniversityBangkokThailand
| | - Nuttinee Teerakulkittipong
- Department of Pharmacology and Biopharmaceutical Sciences, Faculty of Pharmaceutical SciencesBurapha UniversityChonburiThailand
| | - Wasun Chantratita
- Center for Medical Genomics, Faculty of Medicine Ramathibodi HospitalMahidol UniversityBangkokThailand
| | - Chonlaphat Sukasem
- Division of Pharmacogenomics and Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi HospitalMahidol UniversityBangkokThailand
- Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC)Ramathibodi HospitalBangkokThailand
- Department of Pharmacology and Biopharmaceutical Sciences, Faculty of Pharmaceutical SciencesBurapha UniversityChonburiThailand
- Department of Pharmacology and Therapeutics, MRC Centre for Drug Safety ScienceInstitute of Systems, Molecular and Integrative Biology, University of LiverpoolLiverpoolUK
- Pharmacogenomics and Precision Medicine, The Preventive Genomics & Family Check‐up Services CenterBumrungrad International HospitalBangkokThailand
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Mao J, Zeng F, Qin W, Hu M, Xu L, Cheng F, Zhong M, Zhang Y. A joint population pharmacokinetic model to assess the high variability of whole-blood and intracellular tacrolimus in early adult renal transplant recipients. Int Immunopharmacol 2024; 137:112535. [PMID: 38908078 DOI: 10.1016/j.intimp.2024.112535] [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: 04/22/2024] [Revised: 06/17/2024] [Accepted: 06/18/2024] [Indexed: 06/24/2024]
Abstract
Tacrolimus (TAC) has high pharmacokinetic (PK) variability during the early transplantation period. The relationships between whole-blood and intracellular TAC concentrations and clinical outcomes remain controversial. This study identifies the factors affecting the PK variability of TAC and characterizes the relationships between whole-blood and intracellular TAC concentrations. Data regarding whole-blood TAC concentrations of 1,787 samples from 215 renal transplant recipients (<90 days postoperative) across two centers and intracellular TAC concentrations (648 samples) digitized from previous studies were analyzed using nonlinear mixed-effects modeling. The effects of potential covariates were screened, and the distribution of whole-blood to intracellular TAC concentration ratios (RWB:IC) was estimated. The final model was evaluated using bootstrap, goodness of fit, and prediction-corrected visual predictive checks. The optimal dosing regimens and target ranges for each type of immune cell subsets were determined using Monte Carlo simulations. A two-compartment model adequately described the data, and the estimated mean TAC CL/F was 23.6 L·h-1 (relative standard error: 11.5 %). The hematocrit level, CYP3A5*3 carrier status, co-administration with Wuzhi capsules, and tapering prednisolone dose may contribute to the high variability of TAC PK variability during the early post-transplant period. The estimated RWB:IC of all TAC concentrations in peripheral blood mononuclear cells (PBMCs) was 4940, and inter-center variability of PBMCs was observed. The simulated TAC target range in PBMCs was 20.2-85.9 pg·million cells-1. Inter-center variability in intracellular concentrations should be taken into account in further analyses. TAC dosage adjustments can be guided based on PK/PD variability and simulated intracellular concentrations.
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Affiliation(s)
- Junjun Mao
- Department of Pharmacy, Huashan Hospital, Fudan University, 12 Middle Urumqi Road, Shanghai 200040, China.
| | - Fang Zeng
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jie Fang Road, Wuhan, Hubei 430022, China; Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, 1277 Jie Fang Road, Wuhan, Hubei 430022, China
| | - Weiwei Qin
- Department of Pharmacy, Huashan Hospital, Fudan University, 12 Middle Urumqi Road, Shanghai 200040, China
| | - Min Hu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jie Fang Road, Wuhan, Hubei 430022, China; Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, 1277 Jie Fang Road, Wuhan, Hubei 430022, China
| | - Luyang Xu
- Department of Pharmacy, Huashan Hospital, Fudan University, 12 Middle Urumqi Road, Shanghai 200040, China
| | - Fang Cheng
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jie Fang Road, Wuhan, Hubei 430022, China; Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, 1277 Jie Fang Road, Wuhan, Hubei 430022, China
| | - Mingkang Zhong
- Department of Pharmacy, Huashan Hospital, Fudan University, 12 Middle Urumqi Road, Shanghai 200040, China.
| | - Yu Zhang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jie Fang Road, Wuhan, Hubei 430022, China; Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, 1277 Jie Fang Road, Wuhan, Hubei 430022, China.
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Hussaini SA, Waziri B, Dickens C, Duarte R. Pharmacogenetics of Calcineurin inhibitors in kidney transplant recipients: the African gap. A narrative review. Pharmacogenomics 2024; 25:329-341. [PMID: 39109483 PMCID: PMC11404701 DOI: 10.1080/14622416.2024.2370761] [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: 03/16/2024] [Accepted: 06/18/2024] [Indexed: 09/13/2024] Open
Abstract
Calcineurin inhibitors (CNIs) are the mainstay of immunosuppression in kidney transplantation. Interpatient variability in the disposition of calcineurin inhibitors is a well-researched phenomenon and has a well-established genetic contribution. There is great diversity in the makeup of African genomes, but very little is known about the pharmacogenetics of CNIs and transplant outcomes. This review focuses on genetic variants of calcineurin inhibitors' metabolizing enzymes (CYP3A4, CYP3A5), related molecules (POR, PPARA) and membrane transporters involved in the metabolism of calcineurin inhibitors. Given the genetic diversity across the African continent, it is imperative to generate pharmacogenetic data, especially in the era of personalized medicine and emphasizes the need for studies specific to African populations. The study of allelic variants in populations where they have greater frequencies will help answer questions regarding their impact. We aim to fill the knowledge gaps by reviewing existing research and highlighting areas where African research can contribute.
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Affiliation(s)
- Sadiq Aliyu Hussaini
- Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
- Department of Internal Medicine, Ibrahim Badamasi Babangida Specialist Hospital, Minna, Nigeria
- Department of Pharmacology, Ibrahim Badamasi Babangida University, Lapai, Nigeria
| | - Bala Waziri
- Department of Internal Medicine, Ibrahim Badamasi Babangida Specialist Hospital, Minna, Nigeria
| | - Caroline Dickens
- Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Raquel Duarte
- Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
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8
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Li Z, Wang X, Li D, Cheng S, Li Z, Guo H, Dong Y, Zheng Y, Li X. Effects of CYP3A4*22 and POR*28 variations on the pharmacokinetics of tacrolimus in renal transplant recipients: a meta-analysis of 18 observational studies. BMC Nephrol 2024; 25:48. [PMID: 38321419 PMCID: PMC10848431 DOI: 10.1186/s12882-024-03467-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 01/16/2024] [Indexed: 02/08/2024] Open
Abstract
PURPOSE This study aimed to investigate the association between cytochrome P450 (CYP) 3A4*22 and cytochrome P450 oxidoreductase (POR)*28 variations and the pharmacokinetics of tacrolimus. METHODS Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science (SCI), MEDLINE, and Embase were systematically searched from inception to August 2022. The outcomes were weight-adjusted daily dose and dose-adjusted trough concentration (C0/Dose). RESULTS The study included 2931 renal transplant recipients from 18 publications. Weight-adjusted daily dose of CYP3A4*1/*1 carriers was 0.04 (WMD = 0.04, 95% CI: 0.02 to 0.06), 0.03 (WMD = 0.03, 95% CI: 0.02 to 0.05), 0.02 (WMD = 0.02, 95% CI: 0.01 to 0.03), or 0.02 mg/kg/day (WMD = 0.02, 95% CI: 0.00 to 0.04) higher than CYP3A4*22 carriers in Caucasians at 1 month, 3 months, 6 months, or 12 months post-transplantation. Conversely, C0/Dose was lower for CYP3A4*1/*1 carriers at 3 days (SMD = -0.35, 95% CI: -0.65 to -0.06), 1 month (SMD = -0.67, 95% CI: -1.16 to -0.18), 3 months (SMD = -0.60, 95% CI: -0.89 to -0.31), 6 months (SMD = -0.76, 95% CI: -1.49 to -0.04), or 12 months post-transplantation (SMD = -0.69, 95% CI: -1.37 to 0.00). Furthermore, C0/Dose of POR*1/*1 carriers was 22.64 (WMD = 22.64, 95% CI: 2.54 to 42.74) or 19.41 (ng/ml)/(mg/kg/day) (WMD = 19.41, 95% CI: 9.58 to 29.24) higher than POR*28 carriers in CYP3A5 expressers at 3 days or 7 days post-transplantation, and higher in Asians at 6 months post-transplantation (SMD = 0.96, 95% CI: 0.50 to 1.43). CONCLUSIONS CYP3A4*22 variant in Caucasians restrains the metabolism of tacrolimus, while POR*28 variant in CYP3A5 expressers enhances the metabolism of tacrolimus for renal transplant recipients. However, further well-designed prospective studies are necessary to substantiate these conclusions given some limitations.
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Affiliation(s)
- Ze Li
- Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, 95 Yong An Road, Xi Cheng District, Beijing, China
| | - Xiaozhen Wang
- Central Laboratory, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Dandan Li
- Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, 95 Yong An Road, Xi Cheng District, Beijing, China
| | - Sheng Cheng
- Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, 95 Yong An Road, Xi Cheng District, Beijing, China
| | - Zhe Li
- Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, 95 Yong An Road, Xi Cheng District, Beijing, China
| | - Heng Guo
- Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, 95 Yong An Road, Xi Cheng District, Beijing, China
| | - Yiwen Dong
- Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, 95 Yong An Road, Xi Cheng District, Beijing, China
| | - Yingming Zheng
- Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, 95 Yong An Road, Xi Cheng District, Beijing, China
| | - Xingang Li
- Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, 95 Yong An Road, Xi Cheng District, Beijing, China.
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Ebid AHI, Ismail DA, Lotfy NM, Mahmoud MA, El-Sharkawy M. Effect of CYP3A4*22, CYP3A5*3 and POR*28 genetic polymorphisms on calcineurin inhibitors dose requirements in early phase renal transplant patients. Pharmacogenet Genomics 2024; 34:43-52. [PMID: 38050720 DOI: 10.1097/fpc.0000000000000516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/06/2023]
Abstract
OBJECTIVE This study aimed to investigate the combined effect of CYP3A5*3, CYP3A4*22, and POR*28 genetic polymorphisms on tacrolimus and cyclosporine dose requirements. METHODS One hundred thirty renal transplant patients placed on either tacrolimus or cyclosporine were recruited, where the effect of CYP3A5*3, CYP3A4*22, and POR*28 genetic polymorphisms on their dose requirements were studied at days 14, 30, and 90 post-transplantations. RESULTS The POR*28 allele frequency in the studied population was 29.61%. The tacrolimus dose-adjusted trough concentration ratio (C0/D) was significantly lower in the fast metabolizers group ( CYP3A5*1/POR*28(CT/TT ) carriers) than in the poor metabolizers group ( CYP3A5*3/*3/CYP3A4*22 carriers) throughout the study (14, 30, and 90 days) ( P = 0.001, <0.001, and 0.003, respectively). Meanwhile, there was no significant effect of this gene combination on cyclosporine C0/D. CONCLUSION Combining the CYP3A5*3, POR*28 , and CYP3A4*22 genotypes can have a significant effect on early tacrolimus dose requirements determination and adjustments. However, it does not have such influence on cyclosporine dose requirements.
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Affiliation(s)
| | - Dina A Ismail
- Department of Clinical Pharmacy and Pharmacy Practice, Faculty of Pharmacy, Misr International University
| | - Neama M Lotfy
- Department of Technology of Medical Laboratory, Faculty of Applied Health Sciences Technology, Badr University
| | - Mohamed A Mahmoud
- Department of Pharmacy Practice, Faculty of Pharmacy, Helwan University
| | - Magdy El-Sharkawy
- Department of Internal Medicine & Nephrology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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10
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Abderahmene A, Francke MI, Andrews LM, Hesselink DA, Amor D, Sahtout W, Ajmi M, Mastouri H, Bouslama A, Zellama D, Omezzine A, De Winter BCM. A Population Pharmacokinetic Model to Predict the Individual Starting Dose of Tacrolimus for Tunisian Adults after Renal Transplantation. Ther Drug Monit 2024; 46:57-66. [PMID: 38018879 DOI: 10.1097/ftd.0000000000001147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 07/23/2023] [Indexed: 11/30/2023]
Abstract
BACKGROUND Tacrolimus is the most frequently used immunosuppressive drug for preventing renal rejection. However, its use is hampered by its narrow therapeutic index and large intra and interpatient variability in pharmacokinetics. The objective of this study was to externally validate a tacrolimus population pharmacokinetic model developed for the Dutch population and adjust the model for the Tunisian population for use in predicting the starting dose requirement after kidney transplantation. METHODS Data on tacrolimus exposure were obtained from kidney transplant recipients (KTRs) during the first 3 months post-transplantation. External validation of the Dutch model and its adjustment for the Tunisian population was performed using nonlinear mixed-effects modeling. RESULTS In total, 1901 whole-blood predose tacrolimus concentrations from 196 adult KTRs were analyzed. According to a visual predictive check, the Dutch model underestimated the starting dose for the Tunisian adult population. The effects of age, together with the CYP3A5*3 and CYP3A4*22 genotypes on tacrolimus clearance were significantly different in the Tunisian population than in the Dutch population. Based on a bodyweight-based dosing, only 21.9% of tacrolimus concentrations were within the target range, whereas this was estimated to be 54.0% with the newly developed model-based dosing. After adjustment, the model was successfully validated internally in a Tunisian population. CONCLUSIONS A starting-dose population pharmacokinetic model of tacrolimus for Tunisian KTRs was developed based on a previously published Dutch model. Using this starting dose could potentially increase the percentage of patients achieving target tacrolimus concentrations after the initial starting dose.
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Affiliation(s)
- Amani Abderahmene
- Department of Biochemistry , LR12SP11, Sahloul University Hospital, Sousse, University of Monastir Faculty of Pharmacy of Monastir, Monastir, Tunisia
- Rotterdam Clinical Pharmacometrics Group, Rotterdam, the Netherlands
| | - Marith I Francke
- Rotterdam Clinical Pharmacometrics Group, Rotterdam, the Netherlands
- Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
- Erasmus MC Transplant Institute, Rotterdam, the Netherlands
| | - Louise M Andrews
- Department of Hospital Pharmacy, Meander MC, Amersfoort, the Netherlands
| | - Dennis A Hesselink
- Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, the Netherlands
- Erasmus MC Transplant Institute, Rotterdam, the Netherlands
| | - Dorra Amor
- Department of Biochemistry , LR12SP11, Sahloul University Hospital, Sousse, University of Monastir Faculty of Pharmacy of Monastir, Monastir, Tunisia
| | - Wissal Sahtout
- Department of Nephrology, Sahloul University Hospital, Sousse, Tunisia; and
| | - Marwa Ajmi
- Department of Biochemistry , LR12SP11, Sahloul University Hospital, Sousse, University of Monastir Faculty of Pharmacy of Monastir, Monastir, Tunisia
| | - Hayfa Mastouri
- Department of Biochemistry , LR12SP11, Sahloul University Hospital, Sousse, University of Monastir Faculty of Pharmacy of Monastir, Monastir, Tunisia
| | - Ali Bouslama
- Department of Biochemistry , LR12SP11, Sahloul University Hospital, Sousse, University of Monastir Faculty of Pharmacy of Monastir, Monastir, Tunisia
| | - Dorsaf Zellama
- Department of Nephrology, Sahloul University Hospital, Sousse, Tunisia; and
| | - Asma Omezzine
- Department of Biochemistry , LR12SP11, Sahloul University Hospital, Sousse, University of Monastir Faculty of Pharmacy of Monastir, Monastir, Tunisia
| | - Brenda C M De Winter
- Rotterdam Clinical Pharmacometrics Group, Rotterdam, the Netherlands
- Erasmus MC Transplant Institute, Rotterdam, the Netherlands
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, the Netherlands
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11
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Zhai Q, Moes DJAR, van Gelder T, van der Lee M, Sanders J, Bemelman FJ, de Fijter JW, Klein K, Schwab M, Swen JJ. The effect of genetic variants in the transcription factor TSPYL family on the CYP3A4 mediated cyclosporine metabolism in kidney transplant patients. Clin Transl Sci 2024; 17:e13729. [PMID: 38380703 PMCID: PMC10880038 DOI: 10.1111/cts.13729] [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: 12/18/2023] [Accepted: 01/02/2024] [Indexed: 02/22/2024] Open
Abstract
CYP3A4 activity shows considerable interindividual variability. Although studies indicate 60%-80% is heritable, common single nucleotide variants (SNVs) in CYP3A4 together only explain ~10%. Transcriptional factors, such as the testis-specific Y-encoded-like proteins (TSPYLs) family, have been reported to regulate the expression of CYP enzymes including CYP3A4 in vitro. Here, we investigated the effect of genetic variants in TSPYL on CYP3A4 activity using data from a clinical study and a human liver bank. Five SNVs (rs3828743, rs10223646, rs6909133, rs1204807, and rs1204811) in TSPYL were selected because of a reported effect on CYP3A4 expression in vitro or suggested clinical effect. For the clinical study, whole blood concentrations, clinical data, and DNA were available from 295 kidney transplant recipients participating in the prospective MECANO study. A multivariate pharmacokinetic model adjusted for body weight, steroid treatment, and CYP3A4 genotype was used to assess the effect of the genetic variants on cyclosporine clearance. In multivariate analysis, homozygous carriers of rs3828743 had a 18% lower cyclosporin clearance compared to the wild-type and heterozygous patients (28.72 vs. 35.03 L/h, p = 0.018) indicating a lower CYP3A4 activity and an opposite direction of effect compared to the previously reported increased CYP3A4 expression. To validate, we tested associations between rs3828743 and CYP3A4 mRNA and protein expression as well as enzyme activity with data from a liver bank (n = 150). No association with any of these end points was observed. In conclusion, the totality of evidence is not in support of a significant role for TSPYL SNV rs3828743 in explaining variability in CYP3A4 activity.
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Affiliation(s)
- Qinglian Zhai
- Department of Clinical Pharmacy and ToxicologyLeiden University Medical CenterLeidenThe Netherlands
| | - Dirk Jan A. R. Moes
- Department of Clinical Pharmacy and ToxicologyLeiden University Medical CenterLeidenThe Netherlands
| | - Teun van Gelder
- Department of Clinical Pharmacy and ToxicologyLeiden University Medical CenterLeidenThe Netherlands
| | - Maaike van der Lee
- Department of Clinical Pharmacy and ToxicologyLeiden University Medical CenterLeidenThe Netherlands
| | - Jan‐Stephan Sanders
- Department of NephrologyUniversity Medical Center GroningenGroningenThe Netherlands
| | | | | | - Kathrin Klein
- Dr. Margarete Fischer‐Bosch Institute of Clinical PharmacologyStuttgartGermany
- Departments of Clinical Pharmacology, and Pharmacy and BiochemistryUniversity of TübingenTübingenGermany
| | - Matthias Schwab
- Dr. Margarete Fischer‐Bosch Institute of Clinical PharmacologyStuttgartGermany
- Departments of Clinical Pharmacology, and Pharmacy and BiochemistryUniversity of TübingenTübingenGermany
| | - Jesse J. Swen
- Department of Clinical Pharmacy and ToxicologyLeiden University Medical CenterLeidenThe Netherlands
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12
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Schagen MR, Ulu AN, Francke MI, van de Wetering J, van Buren MC, Schoenmakers S, Matic M, van Schaik RHN, Hesselink DA, de Winter BCM. Modelling changes in the pharmacokinetics of tacrolimus during pregnancy after kidney transplantation: A retrospective cohort study. Br J Clin Pharmacol 2024; 90:176-188. [PMID: 37596793 DOI: 10.1111/bcp.15886] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Revised: 07/19/2023] [Accepted: 08/05/2023] [Indexed: 08/20/2023] Open
Abstract
AIMS Pregnancy after kidney transplantation is realistic but immunosuppressants should be continued to prevent rejection. Tacrolimus is safe during pregnancy and is routinely dosed based on whole-blood predose concentrations. However, maintaining these concentrations is complicated as physiological changes during pregnancy affect tacrolimus pharmacokinetics. The aim of this study was to describe tacrolimus pharmacokinetics throughout pregnancy and explain the changes by investigating covariates in a population pharmacokinetic model. METHODS Data of pregnant women using a twice-daily tacrolimus formulation following kidney transplantation were retrospectively collected from 6 months before conception, throughout gestation and up to 6 months postpartum. Pharmacokinetic analysis was performed using nonlinear mixed effects modelling. Demographic, clinical and genetic parameters were evaluated as covariates. The final model was evaluated using goodness-of-fit plots, visual predictive checks and a bootstrap analysis. RESULTS A total of 260 whole-blood tacrolimus predose concentrations from 14 pregnant kidney transplant recipients were included. Clearance increased during pregnancy from 34.5 to 41.7 L/h, by 15, 19 and 21% in the first, second and third trimester, respectively, compared to prior to pregnancy. This indicates a required increase in the tacrolimus dose by the same percentage to maintain the prepregnancy concentration. Haematocrit and gestational age were negatively correlated with tacrolimus clearance (P ≤ 0.01), explaining 18% of interindividual and 85% of interoccasion variability in oral clearance. CONCLUSIONS Tacrolimus clearance increases during pregnancy, resulting in decreased exposure to tacrolimus, which is explained by gestational age and haematocrit. To maintain prepregnancy target whole-blood tacrolimus predose concentrations during pregnancy, increasing the dose is required.
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Affiliation(s)
- Maaike R Schagen
- Erasmus MC Transplant Institute, Department of Internal Medicine, Division of Nephrology and Transplantation, University Medical Center Rotterdam, Rotterdam, the Netherlands
- Rotterdam Clinical Pharmacometrics Group, Rotterdam, the Netherlands
| | - Asiye Nur Ulu
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Marith I Francke
- Erasmus MC Transplant Institute, Department of Internal Medicine, Division of Nephrology and Transplantation, University Medical Center Rotterdam, Rotterdam, the Netherlands
- Rotterdam Clinical Pharmacometrics Group, Rotterdam, the Netherlands
| | - Jacqueline van de Wetering
- Erasmus MC Transplant Institute, Department of Internal Medicine, Division of Nephrology and Transplantation, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Marleen C van Buren
- Erasmus MC Transplant Institute, Department of Internal Medicine, Division of Nephrology and Transplantation, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Sam Schoenmakers
- Department of Obstetrics and Gynaecology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Maja Matic
- Department of Clinical Chemistry, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Ron H N van Schaik
- Department of Clinical Chemistry, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Dennis A Hesselink
- Erasmus MC Transplant Institute, Department of Internal Medicine, Division of Nephrology and Transplantation, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Brenda C M de Winter
- Erasmus MC Transplant Institute, Department of Internal Medicine, Division of Nephrology and Transplantation, University Medical Center Rotterdam, Rotterdam, the Netherlands
- Rotterdam Clinical Pharmacometrics Group, Rotterdam, the Netherlands
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
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13
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Alghamdi A, Seay S, Hooper DK, Varnell CD, Darland L, Mizuno T, Lazear D, Ramsey LB. Tacrolimus pharmacokinetics are influenced by CYP3A5, age, and concomitant fluconazole in pediatric kidney transplant patients. Clin Transl Sci 2023; 16:1768-1778. [PMID: 37340713 PMCID: PMC10582663 DOI: 10.1111/cts.13571] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 05/17/2023] [Accepted: 05/31/2023] [Indexed: 06/22/2023] Open
Abstract
Tacrolimus, the most common immunosuppressant for organ transplant, has a narrow therapeutic range and is metabolized by CYP3A4/5. Trough concentration monitoring and dosing adjustments are used to reach a therapeutic range. CYP3A5 intermediate and normal metabolizers (*1 allele carriers; IM/NM) demonstrate faster tacrolimus metabolism than poor metabolizers (PM). We analyzed the electronic health records of 93 patients aged <21 years for the first 8 weeks after a kidney transplant between January 2010 and December 2021. The target tacrolimus trough was 10-15 ng/mL in the first 4 weeks and 7-10 ng/mL in the next 4 weeks. Banked DNA was collected and genotyped for CYP3A5*3, *6, *7, and *8 alleles. We found that CYP3A5 IM/NM (n = 21) took longer than PM (n = 72) to reach the therapeutic range (7 vs. 4 days, p = 0.048). IM/NM had more dose adjustments (8 vs. 6, p = 0.025) and needed >150% of the required daily dose compared with PM. The concentration/dose ratio was influenced by age and concomitant fluconazole (p = 0.0003, p = 0.034, respectively) and the average daily dose decreases with age in CYP3A5 PM (p = 0.001). Tremors were more common in patients who ever had a trough concentration >15 ng/mL compared with those who never had a trough concentration >15 ng/mL (OR 3.31, 95% CI 1.03-8.98, p = 0.038). Using standard dosing, CYP3A5 IM/NM took longer to reach the goal range and require more dose adjustments and higher doses than PM. Preemptive genotyping could decrease the number of dose changes necessary to reach a therapeutic dose. We have implemented pre-transplant CYP3A5 testing at our institution.
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Affiliation(s)
- Alaa Alghamdi
- Cincinnati Children's Hospital Medical Center, University of Cincinnati College of MedicineCincinnatiOhioUSA
- College of Clinical PharmacyImam Abdulrahman Bin Faisal UniversityDammamSaudi Arabia
| | - Sarah Seay
- Department of ChemistryVirginia Tech Center for Drug DiscoveryBlacksburgVirginiaUSA
| | - David K. Hooper
- Department of PediatricsUniversity of Cincinnati College of MedicineCincinnatiOhioUSA
- Division of Nephrology & Hypertension, James M. Anderson Center fo Health Systems ExcellenceCincinnati Children's Hospital Medical CenterCincinnatiOhioUSA
| | - Charles D. Varnell
- Department of PediatricsUniversity of Cincinnati College of MedicineCincinnatiOhioUSA
- Division of Nephrology & Hypertension, James M. Anderson Center fo Health Systems ExcellenceCincinnati Children's Hospital Medical CenterCincinnatiOhioUSA
| | - Leanna Darland
- Division of PharmacyCincinnati Children's Hospital Medical CenterCincinnatiOhioUSA
| | - Tomoyuki Mizuno
- Department of PediatricsUniversity of Cincinnati College of MedicineCincinnatiOhioUSA
- Division of Clinical PharmacologyCincinnati Children's Hospital Medical CenterCincinnatiOhioUSA
| | - Danielle Lazear
- Division of PharmacyCincinnati Children's Hospital Medical CenterCincinnatiOhioUSA
- Present address:
Eurofins Transplant Genomics, Framingham, Massachusetts, USA
| | - Laura B. Ramsey
- Department of PediatricsUniversity of Cincinnati College of MedicineCincinnatiOhioUSA
- Divisions of Clinical Pharmacology & Research in Patient ServicesCincinnati Children's Hospital Medical CenterCincinnatiOhioUSA
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14
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Concha J, Sangüesa E, Peña JL, Ribate MP, García CB. Retrospective pharmacogenetic study in a cohort of pediatric tuberous sclerosis complex patients using everolimus. Pharmacogenomics 2023; 24:797-808. [PMID: 37869874 DOI: 10.2217/pgs-2023-0140] [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] [Indexed: 10/24/2023] Open
Abstract
Aim: Tuberous sclerosis complex (TSC) is a rare disease that produces multisystemic disorders. Everolimus (EVR) is the only immunosuppressive drug approved to control the symptoms and progression of the disease. The aim was to evaluate the genotype-phenotype association to improve the pediatric TSC pharmacotherapeutic outcome. Patients & methods: Ten pediatric TSC patients were recruited. Concomitant treatment and main metabolic enzymes and transporter coding gene variants of EVR were analyzed. Results: Significant associations were found between CYP3A4*22 allele and concomitant treatment with valproic acid (CYP3A4-inhibitor) with a poor metabolizer phenotype and the presence of pneumonia. Conclusion: This is the first pharmacogenetic study of EVR in pediatric TSC patients. The authors propose to consider concomitant treatment and pharmacogenetics due to their multifactorial status.
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Affiliation(s)
- Julia Concha
- Faculty of Health Sciences, Universidad San Jorge, Zaragoza, Spain
| | - Estela Sangüesa
- Faculty of Health Sciences, Universidad San Jorge, Zaragoza, Spain
| | - Jose Luis Peña
- Neuropediatrics Area, Hospital Universitario Miguel Servet, Zaragoza, Spain
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15
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Feng H, Wang X, Zheng W, Liu S, Jiang H, Lin Y, Qiu H, Chan TF, Huang M, Li Y, Mo X, Li J. Initial dosage optimisation of cyclosporine in Chinese paediatric patients undergoing allogeneic haematopoietic stem cell transplantation based on population pharmacokinetics: a retrospective study. BMJ Paediatr Open 2023; 7:e002003. [PMID: 37643815 PMCID: PMC10465907 DOI: 10.1136/bmjpo-2023-002003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Accepted: 07/13/2023] [Indexed: 08/31/2023] Open
Abstract
OBJECTIVE Improved understanding of cyclosporine A (CsA) pharmacokinetics in children undergoing allogeneic haematopoietic stem cell transplantation (allo-HSCT) is crucial for effective prevention of acute graft-versus-host disease and medication safety. The aim of this study was to establish a population pharmacokinetic (Pop-PK) model that could be used for individualised therapy to paediatric patients undergoing allo-HSCT in China. DESIGN, SETTING AND PARTICIPANTS A retrospective analysis of 251 paediatric HSCT patients who received CsA intravenously in the early post transplantation period at Women and Children's Medical Center in Guangzhou was conducted. ANALYSIS MEASURES The model building dataset from 176 children was used to develop and analyse the CsA Pop-Pk model by using the nonlinear mixed effect model method. The basic information was collected by the electronic medical record system. Genotype was analysed by matrix-assisted time-of-flight mass spectrometry. The stability and predictability of the final model were verified internally, and a validation dataset of 75 children was used for external validation. Monte Carlo simulation is used to adjust and optimise the initial dose of CsA in paediatric allo-HSCT patients. RESULTS The typical values for clearance (CL) and volume of distribution ([Formula: see text]) were 14.47 L/hour and 2033.53 L, respectively. The body weight and haematocrit were identified as significant variables for V, while only body weight had an impact on CL. The simulation based on the final model suggests that paediatrics with HSCT required an appropriate intravenous dose of 5 mg/kg/day to reach the therapeutic trough concentration. CONCLUSIONS The CsA Pop-PK model established in this study can quantitatively describe the factors influencing pharmacokinetic parameters and precisely predict the intrinsic exposure to CsA in children. In addition, our dosage simulation results can provide evidence for the personalised medications TRIAL REGISTRATION NUMBER: ChiCTR2000040561.
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Affiliation(s)
- Huanwen Feng
- Institute of Clinical Pharmacology, Sun Yat-Sen University School of Pharmaceutical Sciences, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University School of Pharmaceutical Sciences, Guangzhou, Guangdong, China
| | - Xianggui Wang
- Institute of Clinical Pharmacology, Sun Yat-Sen University School of Pharmaceutical Sciences, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University School of Pharmaceutical Sciences, Guangzhou, Guangdong, China
| | - Wei Zheng
- Department of Pharmacy, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Sha Liu
- Department of Hematology/Oncology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Hua Jiang
- Department of Hematology/Oncology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Yuxian Lin
- Department of Pharmacy, The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Haojie Qiu
- Department of Pharmacy, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Teng Fong Chan
- Institute of Clinical Pharmacology, Sun Yat-Sen University School of Pharmaceutical Sciences, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University School of Pharmaceutical Sciences, Guangzhou, Guangdong, China
| | - Min Huang
- Institute of Clinical Pharmacology, Sun Yat-Sen University School of Pharmaceutical Sciences, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University School of Pharmaceutical Sciences, Guangzhou, Guangdong, China
| | - Yan Li
- Guangzhou Cord Blood Bank, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Xiaolan Mo
- Department of Pharmacy, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Jiali Li
- Institute of Clinical Pharmacology, Sun Yat-Sen University School of Pharmaceutical Sciences, Guangzhou, Guangdong, China
- Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, Sun Yat-Sen University School of Pharmaceutical Sciences, Guangzhou, Guangdong, China
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16
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Concha J, Sangüesa E, Saez-Benito AM, Aznar I, Berenguer N, Saez-Benito L, Ribate MP, García CB. Importance of Pharmacogenetics and Drug-Drug Interactions in a Kidney Transplanted Patient. Life (Basel) 2023; 13:1627. [PMID: 37629484 PMCID: PMC10455535 DOI: 10.3390/life13081627] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 07/20/2023] [Accepted: 07/24/2023] [Indexed: 08/27/2023] Open
Abstract
Tacrolimus (TAC) is a narrow-therapeutic-range immunosuppressant drug used after organ transplantation. A therapeutic failure is possible if drug levels are not within the therapeutic range after the first year of treatment. Pharmacogenetic variants and drug-drug interactions (DDIs) are involved. We describe a patient case of a young man (16 years old) with a renal transplant receiving therapy including TAC, mycophenolic acid (MFA), prednisone and omeprazole for prophylaxis of gastric and duodenal ulceration. The patient showed great fluctuation in TAC blood concentration/oral dose ratio, as well as pharmacotherapy adverse effects (AEs) and frequent diarrhea episodes. Additionally, decreased kidney function was found. A pharmacotherapeutic follow-up, including pharmacogenetic analysis, was carried out. The selection of the genes studied was based on the previous literature (CYP3A5, CYP3A4, POR, ABCB1, PXR and CYP2C19). A drug interaction with omeprazole was reported and the nephrologist switched to rabeprazole. A lower TAC concentration/dose ratio was achieved, and the patient's condition improved. In addition, the TTT haplotype of ATP Binding Cassette Subfamily B member 1 (ABCB1) and Pregnane X Receptor (PXR) gene variants seemed to affect TAC pharmacotherapy in the studied patient and could explain the occurrence of long-term adverse effects post-transplantation. These findings suggest that polymorphic variants and co-treatments must be considered in order to achieve the effectiveness of the immunosuppressive therapy with TAC, especially when polymedicated patients are involved. Moreover, pharmacogenetics could influence the drug concentration at the cellular level, both in lymphocyte and in renal tissue, and should be explored in future studies.
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Affiliation(s)
| | | | | | | | | | | | - M. Pilar Ribate
- Facultad de Ciencias de la Salud, Universidad San Jorge, Villanueva de Gállego, E-50830 Zaragoza, Spain; (J.C.); (E.S.); (A.M.S.-B.); (I.A.); (N.B.); (L.S.-B.); (C.B.G.)
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17
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Schagen MR, Volarevic H, Francke MI, Sassen SDT, Reinders MEJ, Hesselink DA, de Winter BCM. Individualized dosing algorithms for tacrolimus in kidney transplant recipients: current status and unmet needs. Expert Opin Drug Metab Toxicol 2023; 19:429-445. [PMID: 37642358 DOI: 10.1080/17425255.2023.2250251] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 08/17/2023] [Indexed: 08/31/2023]
Abstract
INTRODUCTION Tacrolimus is a potent immunosuppressive drug with many side effects including nephrotoxicity and post-transplant diabetes mellitus. To limit its toxicity, therapeutic drug monitoring (TDM) is performed. However, tacrolimus' pharmacokinetics are highly variable within and between individuals, which complicates their clinical management. Despite TDM, many kidney transplant recipients will experience under- or overexposure to tacrolimus. Therefore, dosing algorithms have been developed to limit the time a patient is exposed to off-target concentrations. AREAS COVERED Tacrolimus starting dose algorithms and models for follow-up doses developed and/or tested since 2015, encompassing both adult and pediatric populations. Literature was searched in different databases, i.e. Embase, PubMed, Web of Science, Cochrane Register, and Google Scholar, from inception to February 2023. EXPERT OPINION Many algorithms have been developed, but few have been prospectively evaluated. These performed better than bodyweight-based starting doses, regarding the time a patient is exposed to off-target tacrolimus concentrations. No benefit in reduced tacrolimus toxicity has yet been observed. Most algorithms were developed from small datasets, contained only a few tacrolimus concentrations per person, and were not externally validated. Moreover, other matrices should be considered which might better correlate with tacrolimus toxicity than the whole-blood concentration, e.g. unbound plasma or intra-lymphocytic tacrolimus concentrations.
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Affiliation(s)
- Maaike R Schagen
- Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
- Erasmus MC, Rotterdam Clinical Pharmacometrics Group, Rotterdam, the Netherlands
| | - Helena Volarevic
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Marith I Francke
- Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Sebastiaan D T Sassen
- Erasmus MC, Rotterdam Clinical Pharmacometrics Group, Rotterdam, the Netherlands
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Marlies E J Reinders
- Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Dennis A Hesselink
- Erasmus MC Transplant Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
| | - Brenda C M de Winter
- Erasmus MC, Rotterdam Clinical Pharmacometrics Group, Rotterdam, the Netherlands
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
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18
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Islam F, Islam MR, Nafady MH, Faysal M, Khan SL, Zehravi M, Emran TB, Rahman MH. Pharmacogenomics of immunosuppressants. Pharmacogenomics 2023:323-344. [DOI: 10.1016/b978-0-443-15336-5.00003-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/01/2023] Open
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19
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Gao Y, Ma J. Cytochrome P450 oxidoreductase variant A503V contributes to the increased CYP3A5 activity with tacrolimus in vitro. Expert Opin Drug Metab Toxicol 2022; 18:529-535. [PMID: 35946839 DOI: 10.1080/17425255.2022.2112174] [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: 11/04/2022]
Abstract
BACKGROUND Tacrolimus is a calcineurin inhibitor with a strong efficacy in prevention of graft rejection after transplantation. It is well known that cytochrome P450 3A5 (CYP3A5) has a high metabolic capacity for tacrolimus, and mutations in human cytochrome P450 oxidoreductase (POR) cause altered CYP3A5 activity. Recently, clinical studies have revealed that POR*28 contributes enhanced tacrolimus clearance in CYP3A5 expressers. A503V is an amino acid sequence variant encoded by POR*28. In this study, we first evaluated the impact of A503V on CYP3A5 activity with tacrolimus as the substrate in vitro. RESEARCH DESIGN & METHODS Wild-type (WT) and A503V POR, with WT CYP3A5 were expressed in recombinant HepG2 cells and reconstituted proteins. Michaelis constant (Km) and maximum velocity (Vmax) of CYP3A5 with tacrolimus as substrates were determined, and catalytic efficiency is expressed as Vmax/Km. RESULTS WT and A503V POR both down-regulated the CYP3A5 mRNA expression, and WT POR rather than A503V down-regulated the protein expression of CYP3A5 in recombinant HepG2 cells. Compared with WT POR, A503V increased metabolism of tacrolimus by CYP3A5 in both cellular and protein level. CONCLUSION A503V can affect CYP3A5-catalyzed tacrolimus metabolism in vitro, which suggests that A503V has the potential to serve as a biomarker for tacrolimus treatment in transplantation recipients.
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Affiliation(s)
- Yuan Gao
- Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jingjing Ma
- Department of Pharmacy, Medical center of Soochow University, Dushu Lake Hospital Affiliated to Soochow University, Suzhou, China
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20
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Sridharan K, Shah S, Jassim A, Hammad M, Ebrahim Al Gadhban J, Al Segai O. Evaluation of Pharmacogenetics of Drug-Metabolizing Enzymes and Drug Efflux Transporter in Renal Transplants Receiving Immunosuppressants. J Pers Med 2022; 12:jpm12050823. [PMID: 35629245 PMCID: PMC9147030 DOI: 10.3390/jpm12050823] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 05/12/2022] [Accepted: 05/14/2022] [Indexed: 02/06/2023] Open
Abstract
Cytochrome P450 (CYP) enzymes, such as CYP3A4, and CYP3A5, P450 oxidoreductase (POR), peroxisome proliferator activated receptor alpha (PPAR-alpha), and drug transporter (ABCB1) were observed to influence concentrations of immunosuppressants (cyclosporine, everolimus, sirolimus, and tacrolimus) and outcomes in renal transplants. We carried out the present study to evaluate the prevalence and impact of these single nucleotide polymorphisms (SNPs) in adult renal transplants. SNPs were evaluated using commercial TaqMan® assays. Serum drug concentrations were estimated using immunoassays. One hundred and forty-six patients were recruited. SNPs in CYP3A5*3 were significantly associated with greater dose-adjusted cyclosporine and tacrolimus concentrations. SNPs in POR*28 were observed with significantly lower dose-adjusted concentrations, particularly with cyclosporine and tacrolimus. ABCB1 homozygous polymorphisms were observed with significantly lower time spent in the therapeutic range with cyclosporine and everolimus/sirolimus. Cyclosporine was observed in a significantly greater proportion of patients with elevated GGT, and SNPs in PPAR-alpha were significantly associated with an increased risk of this adverse event. Hypertriglyceridemia with everolimus was significantly associated with POR*28 polymorphisms. There is a need to validate the influence of these SNPs in a prospective study and develop an algorithm predicting the achievement of target concentrations.
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Affiliation(s)
- Kannan Sridharan
- Department of Pharmacology & Therapeutics, College of Medicine & Medical Sciences, Arabian Gulf University, Manama 328, Bahrain
- Correspondence: ; Tel.: +973-33453123
| | - Shamik Shah
- Department of Nephrology, Salmaniya Medical Complex, Manama 328, Bahrain; (S.S.); (J.E.A.G.)
- Department of Internal Medicine, College of Medicine & Medical Sciences, Arabian Gulf University, Manama 328, Bahrain
| | - Anfal Jassim
- Department of Molecular Medicine, College of Medicine and Medical Sciences, Arabian Gulf University, Manama 328, Bahrain;
| | - Mona Hammad
- Salmaniya Medical Complex, Manama 328, Bahrain;
| | | | - Ola Al Segai
- Department of Biochemistry, Salmaniya Medical Complex, Manama 328, Bahrain;
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21
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Everton JBF, Patrício FJB, Faria MS, Ferreira TCA, Filho NS, Silva GEB, Romão EA, Magalhães M. Impact of POR*28 Variant on Tacrolimus Pharmacokinetics in Kidney Transplant Patients with Different CYP3A5 Genotypes. Curr Drug Metab 2022; 23:233-241. [PMID: 35578867 DOI: 10.2174/1389200223666220516094226] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 01/28/2022] [Accepted: 02/24/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUND The introduction of tacrolimus (TAC) in clinical practice was essential to the establishment of transplantation as therapy for patients with chronic renal disease. However, the higher interindividual variation of TAC metabolism has been an important limiting factor for its clinical use. Although the relationship between CYP3A5 polymorphisms and TAC pharmacokinetics (PK) is well established, the effects of other genetic variants on TAC metabolism, such as POR*28, still remain uncertain. OBJECTIVE To evaluate the impact of POR variants on TAC PK in renal transplant patients with different CYP3A5 genotypes (expressers and non-expressers). METHODS A total of 115 patients were included in this study. Genomic DNA was isolated from peripheral blood, and the real-time PCR technique was used to analyze the polymorphism POR rs1057868; C>T. RESULTS During the initial post-transplant period, variant allele carriers (*1/*28 and *28/*28) showed a lower TAC dose requirement than POR wild homozygotes (*1/*1). Regarding the influence of the different polymorphisms of POR within the CYP3A5 expresser and non-expresser groups, no differences were observed in any of the PK parameters analyzed during 12 months after transplantation. CONCLUSION In the studied population, the variant allelic POR*28 was significantly associated with lower TAC dose requirements and higher Co/D ratio in the first-month post-transplant. However, the effects of this polymorphism on the CYP3A5 enzyme activity were not observed.
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Affiliation(s)
- Janaina B F Everton
- Laboratory of Genomic and Histocompatibility Studies, University Hospital of the Federal University of Maranhão (HUUFMA/EBSERH), São Luís, Brazil.,Postgraduate Program in Adult Health (PPGSAD), Federal University of Maranhão (UFMA), São Luís, Brazil
| | - Fernando J B Patrício
- Laboratory of Genomic and Histocompatibility Studies, University Hospital of the Federal University of Maranhão (HUUFMA/EBSERH), São Luís, Brazil
| | - Manuel S Faria
- linical Research Center of the University Hospital of the Federal University of Maranhão (CEPEC/HUUFMA/EBSERH), São Luís, Brazil
| | - Teresa C A Ferreira
- Kidney Transplant Unit, University Hospital of the Federal University of Maranhão (HUUFMA/EBSERH), São Luís, Brazil
| | - Natalino Salgado Filho
- Nephrology Unit, University Hospital of the Federal University of Maranhão (HUUFMA/EBSERH), São Luís, Brazil
| | - Gyl E B Silva
- Pathology Unit, University Hospital of the Federal University of Maranhão (HUUFMA/EBSERH), São Luís, Brazil
| | - Elen A Romão
- Department of Internal Medicine, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil
| | - Marcelo Magalhães
- Research and Extension Nucleus (NUPE), UNDB University Center, São Luís, Brazil
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22
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Lee DH, Lee H, Yoon HY, Yee J, Gwak HS. Association of P450 Oxidoreductase Gene Polymorphism with Tacrolimus Pharmacokinetics in Renal Transplant Recipients: A Systematic Review and Meta-Analysis. Pharmaceutics 2022; 14:pharmaceutics14020261. [PMID: 35213993 PMCID: PMC8877595 DOI: 10.3390/pharmaceutics14020261] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 01/20/2022] [Accepted: 01/20/2022] [Indexed: 12/29/2022] Open
Abstract
There are conflicting results regarding the effect of the P450 oxidoreductase (POR) *28 genotype on the tacrolimus (TAC) pharmacokinetics (PKs) during the early post-transplantation period in adult renal transplant recipients. Thus, we characterized the impact of POR*28 on TAC PKs. We conducted a systematic review on the association between POR*28 and PKs of TAC in adult renal transplant recipients. Structured searches were conducted using PubMed, Web of Science, and Embase. TAC standardized trough concentration (ng/mL per mg/kg) data were extracted. Mean differences (MD) and their corresponding 95% confidence intervals (CIs) were used to identify the differences between the POR*28 genotype and PKs of TAC. The subgroup analysis was conducted according to CYP3A5 expression status. Six studies (n = 1061) were included. TAC standardized trough concentrations were significantly lower in recipients with the POR*28 allele compared to recipients with POR*1/*1 (MD: 8.30 ng/mL per mg/kg; 95% CI: 1.93, 14.67; p = 0.01). In the subgroup analysis, TAC standardized trough concentrations were lower for subjects who were POR*28 carriers than those who were POR*1/*1 in CYP3A5 expressers (MD: 20.21 ng/mL per mg/kg; 95% CI: 16.85, 23.56; p < 0.00001). No significant difference between POR*28 carriers and POR*1/*1 was found in the CYP3A5 non-expressers. The results of our meta-analysis demonstrated a definite correlation between the POR*28 genotype and PKs of TAC. Patients carrying the POR*28 allele may require a higher dose of TAC to achieve target levels compared to those with POR*1/*1, especially in CYP3A5 expressers.
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Affiliation(s)
- Da-Hoon Lee
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea; (D.-H.L.); (H.-Y.Y.)
| | - Hana Lee
- Graduate School of Clinical Biohealth, Ewha Womans University, Seoul 03760, Korea;
| | - Ha-Young Yoon
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea; (D.-H.L.); (H.-Y.Y.)
| | - Jeong Yee
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea; (D.-H.L.); (H.-Y.Y.)
- Correspondence: (J.Y.); (H.-S.G.); Tel.: +82-2-3277-3052 (J.Y.); +82-2-3277-4376 (H.-S.G.)
| | - Hye-Sun Gwak
- College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea; (D.-H.L.); (H.-Y.Y.)
- Correspondence: (J.Y.); (H.-S.G.); Tel.: +82-2-3277-3052 (J.Y.); +82-2-3277-4376 (H.-S.G.)
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23
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Lu H, Jiang H, Yang S, Li C, Li C, Shao R, Zhang P, Wang D, Liu Z, Qi H, Cai Y, Xu W, Bao X, Wang H, Li L. Trans-eQTLs of the CYP3A4 and CYP3A5 associated with tacrolimus trough blood concentration in Chinese renal transplant patients. Biomed Pharmacother 2021; 145:112407. [PMID: 34781138 DOI: 10.1016/j.biopha.2021.112407] [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: 06/20/2021] [Revised: 09/23/2021] [Accepted: 11/03/2021] [Indexed: 12/15/2022] Open
Abstract
This study aimed to systematically investigate trans-eQTLs of CYP3A4 and CYP3A5 affecting tacrolimus trough blood concentrations in Chinese renal transplant patients. We used Plink v1.90 to perform data quality control and linear regression analysis on GTEx v8 data. SNPs with p-value < 0.05 were selected and the GTEx eQTL Calculator was used to further prioritize the eQTLs of CYP3A4 and CYP3A5 in the liver and small intestine. The eQTLs with a p-value < 5 × 10-5 and MAF≥ 0.05 in the CHB population were selected as candidate eQTLs. The genotyping of candidate eQTLs was performed using high-resolution melting (HRM) assays and Sanger DNA sequencing. This study included 845 Chinese renal transplant patients who received tacrolimus as an immunosuppressive agent. Association between 103 candidate eQTLs and log-transformed tacrolimus concentration/dose ratio (log (C0/D)) in this cohort was conducted using the SNPassoc package of R software. In the end, a total of 75,632 liver eQTLs of CYP3A4, 69,558 liver eQTLs of CYP3A5, 48,596 small intestine eQTLs of CYP3A4 and 28,616 small intestine eQTLs of CYP3A5 were obtained using the GTEx v8 eQTL Calculator. Of the 103 candidate eQTLs, rs75727207, rs181294422 and rs28522676 were significantly associated with tacrolimus log(C0/D) in different genetic models. We discovered a substantial number of novel eQTLs of CYP3A4 and CYP3A5 in liver and small intestine, also found that rs75727207, rs181294422 and rs28522676 may affect tacrolimus trough blood concentrations in Chinese renal transplant patients.
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Affiliation(s)
- Huijie Lu
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China
| | - Haixia Jiang
- Department of Clinical Laboratory, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong, China
| | - Siyao Yang
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China
| | - Chengcheng Li
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China
| | - Chuanjiang Li
- Division of Hepatobiliopancreatic Surgery, Department of General Surgery，Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong, China
| | - Ruifan Shao
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China
| | - Pai Zhang
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China
| | - Daoyi Wang
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China
| | - Zhiwei Liu
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China
| | - Huana Qi
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China
| | - Yinuan Cai
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China
| | - Wenbin Xu
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China
| | - Xiaojie Bao
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China
| | - Hailan Wang
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China
| | - Liang Li
- Department of Medical Genetics, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, Guangdong, China; Experimental Education and Administration Center, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, China.
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24
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Wang L, Zeng G, Li J, Luo J, Li H, Zhang Z. Association of polymorphism of CYP3A4, ABCB1, ABCC2, ABCG2, NFKB1, POR, and PXR with the concentration of cyclosporin A in allogeneic haematopoietic stem cell transplantation recipients. Xenobiotica 2021; 51:852-858. [PMID: 33974505 DOI: 10.1080/00498254.2021.1928791] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Cyclosporin a (CsA) was characterized by a narrow therapeutic window and high interindividual pharmacokinetic variability. In this study, we aimed to identify the association of CYP3A4, ABCB1, ABCC2, ABCG2, NFKB1, POR, and PXR polymorphisms with CsA concentrations in patients with allogeneic haematopoietic cell transplantation (allo-HSCT) based on the route of administration.A total of 40 allo-HSCT recipients receiving CsA were genotyped for CYP3A4, ABCB1, ABCC2, ABCG2, NFKB1, POR, and PXR polymorphisms. The correlation between polymorphisms and CsA concentration was analysed.The CsA dose-adjusted trough concentration (Cssmin/D) of oral or intravenous administration was significantly different (p < 0.001). For CsA Cssmin/D of intravenous administration, CYP3A4 rs2246709 (p = 0.015), ABCC2 rs717620 (p = 0.024), ABCG2 rs2231142 (p = 0.042), PXR rs3732359 (p = 0.008), PXR rs3814058 (p = 0.028) and PXR rs6785049 (p < 0.001) had a significant effect on CsA Cssmin/D. For CsA Cssmin/D of oral administration, ABCC2 rs717620 (p = 0.009) and ABCG2 rs2231142 (p = 0.011) had a significant effect on CsA Cssmin/D.These results illustrated that the CYP3A4, ABCC2, ABCG2, and PXR genotypes were closely correlated with CsA Cssmin/D, suggesting these SNPs were suitable for determining the appropriate dose of CsA.
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Affiliation(s)
- Linlin Wang
- Department of Pharmacy, Xiangya Hospital, Central South University, Hunan, Changsha, China.,Institute for Rational and Safe Medication Practices, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Hunan, Changsha, China
| | - Guangting Zeng
- Department of Pharmacy, Xiangya Hospital, Central South University, Hunan, Changsha, China.,Institute for Rational and Safe Medication Practices, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Hunan, Changsha, China
| | - Jianqiang Li
- Department of Pharmacy, Xiangya Hospital, Central South University, Hunan, Changsha, China.,Institute for Rational and Safe Medication Practices, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Hunan, Changsha, China
| | - Jia Luo
- Department of Pharmacy, Xiangya Hospital, Central South University, Hunan, Changsha, China.,Institute for Rational and Safe Medication Practices, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Hunan, Changsha, China
| | - Huilan Li
- Department of Pharmacy, Xiangya Hospital, Central South University, Hunan, Changsha, China.,Institute for Rational and Safe Medication Practices, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Hunan, Changsha, China
| | - Zanling Zhang
- Department of Pharmacy, Xiangya Hospital, Central South University, Hunan, Changsha, China.,Institute for Rational and Safe Medication Practices, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Hunan, Changsha, China
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25
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Significance of Ethnic Factors in Immunosuppressive Therapy Management After Organ Transplantation. Ther Drug Monit 2021; 42:369-380. [PMID: 32091469 DOI: 10.1097/ftd.0000000000000748] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Clinical outcomes after organ transplantation have greatly improved in the past 2 decades with the discovery and development of immunosuppressive drugs such as calcineurin inhibitors, antiproliferative agents, and mammalian target of rapamycin inhibitors. However, individualized dosage regimens have not yet been fully established for these drugs except for therapeutic drug monitoring-based dosage modification because of extensive interindividual variations in immunosuppressive drug pharmacokinetics. The variations in immunosuppressive drug pharmacokinetics are attributed to interindividual variations in the functional activity of cytochrome P450 enzymes, UDP-glucuronosyltransferases, and ATP-binding cassette subfamily B member 1 (known as P-glycoprotein or multidrug resistance 1) in the liver and small intestine. Some genetic variations have been found to be involved to at least some degree in pharmacokinetic variations in post-transplant immunosuppressive therapy. It is well known that the frequencies and effect size of minor alleles vary greatly between different races. Thus, ethnic considerations might provide useful information for optimizing individualized immunosuppressive therapy after organ transplantation. Here, we review ethnic factors affecting the pharmacokinetics of immunosuppressive drugs requiring therapeutic drug monitoring, including tacrolimus, cyclosporine, mycophenolate mofetil, sirolimus, and everolimus.
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26
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Francke MI, Andrews LM, Le HL, van de Wetering J, Clahsen-van Groningen MC, van Gelder T, van Schaik RHN, van der Holt B, de Winter BCM, Hesselink DA. Avoiding Tacrolimus Underexposure and Overexposure with a Dosing Algorithm for Renal Transplant Recipients: A Single Arm Prospective Intervention Trial. Clin Pharmacol Ther 2021; 110:169-178. [PMID: 33452682 PMCID: PMC8359222 DOI: 10.1002/cpt.2163] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Accepted: 12/21/2020] [Indexed: 12/20/2022]
Abstract
Bodyweight‐based tacrolimus dosing followed by therapeutic drug monitoring is standard clinical care after renal transplantation. However, after transplantation, a meager 38% of patients are on target at first steady‐state and it can take up to 3 weeks to reach the target tacrolimus predose concentration (C0). Tacrolimus underexposure and overexposure is associated with an increased risk of rejection and drug‐related toxicity, respectively. To minimize subtherapeutic and supratherapeutic tacrolimus exposure in the immediate post‐transplant phase, a previously developed dosing algorithm to predict an individual’s tacrolimus starting dose was tested prospectively. In this single‐arm, prospective, therapeutic intervention trial, 60 de novo kidney transplant recipients received a tacrolimus starting dose based on a dosing algorithm instead of a standard, bodyweight‐based dose. The algorithm included cytochrome P450 (CYP)3A4 and CYP3A5 genotype, body surface area, and age as covariates. The target tacrolimus C0, measured for the first time at day 3, was 7.5–12.5 ng/mL. Between February 23, 2019, and July 7, 2020, 60 patients were included. One patient was excluded because of a protocol violation. On day 3 post‐transplantation, 34 of 59 patients (58%, 90% CI 47–68%) had a tacrolimus C0 within the therapeutic range. Markedly subtherapeutic (< 5.0 ng/mL) and supratherapeutic (> 20 ng/mL) tacrolimus concentrations were observed in 7% and 3% of the patients, respectively. Biopsy‐proven acute rejection occurred in three patients (5%). In conclusion, algorithm‐based tacrolimus dosing leads to the achievement of the tacrolimus target C0 in as many as 58% of the patients on day 3 after kidney transplantation.
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Affiliation(s)
- Marith I Francke
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.,Rotterdam Transplant Group, Rotterdam, The Netherlands.,Netherlands Institute for Health Sciences, Rotterdam, The Netherlands
| | - Louise M Andrews
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.,Department of Hospital Pharmacy, Meander Medical Center, Amersfoort, The Netherlands
| | - Hoang Lan Le
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Jacqueline van de Wetering
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.,Rotterdam Transplant Group, Rotterdam, The Netherlands
| | - Marian C Clahsen-van Groningen
- Rotterdam Transplant Group, Rotterdam, The Netherlands.,Department of Pathology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Teun van Gelder
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - Ron H N van Schaik
- Department of Clinical Chemistry, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Bronno van der Holt
- Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Brenda C M de Winter
- Rotterdam Transplant Group, Rotterdam, The Netherlands.,Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Dennis A Hesselink
- Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.,Rotterdam Transplant Group, Rotterdam, The Netherlands
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27
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Nobakht E, Jagadeesan M, Paul R, Bromberg J, Dadgar S. Precision Medicine in Kidney Transplantation: Just Hype or a Realistic Hope? Transplant Direct 2021; 7:e650. [PMID: 33437865 PMCID: PMC7793397 DOI: 10.1097/txd.0000000000001102] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 10/27/2020] [Accepted: 10/29/2020] [Indexed: 12/17/2022] Open
Abstract
Desirable outcomes including rejection- and infection-free kidney transplantation are not guaranteed despite current strategies for immunosuppression and using prophylactic antimicrobial medications. Graft survival depends on factors beyond human leukocyte antigen matching such as the level of immunosuppression, infections, and management of other comorbidities. Risk stratification of transplant patients based on predisposing genetic modifiers and applying precision pharmacotherapy may help improving the transplant outcomes. Unlike certain fields such as oncology in which consistent attempts are being carried out to move away from the "error and trial approach," transplant medicine is lagging behind in implementing personalized immunosuppressive therapy. The need for maintaining a precarious balance between underimmunosuppression and overimmunosuppression coupled with adverse effects of medications calls for a gene-based guidance for precision pharmacotherapy in transplantation. Technologic advances in molecular genetics have led to increased accessibility of genetic tests at a reduced cost and have set the stage for widespread use of gene-based therapies in clinical care. Evidence-based guidelines available for precision pharmacotherapy have been proposed, including guidelines from Clinical Pharmacogenetics Implementation Consortium, the Pharmacogenomics Knowledge Base National Institute of General Medical Sciences of the National Institutes of Health, and the US Food and Drug Administration. In this review, we discuss the implications of pharmacogenetics and potential role for genetic variants-based risk stratification in kidney transplantation. A single score that provides overall genetic risk, a polygenic risk score, can be achieved by combining of allograft rejection/loss-associated variants carried by an individual and integrated into practice after clinical validation.
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Affiliation(s)
- Ehsan Nobakht
- Division of Renal Diseases and Hypertension, Department of Medicine, George Washington University School of Medicine, Washington, DC
| | - Muralidharan Jagadeesan
- Division of Renal Diseases and Hypertension, Department of Medicine, George Washington University School of Medicine, Washington, DC
| | - Rohan Paul
- Division of Renal Diseases and Hypertension, Department of Medicine, George Washington University School of Medicine, Washington, DC
| | - Jonathan Bromberg
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD
| | - Sherry Dadgar
- Division of Renal Diseases and Hypertension, Department of Medicine, George Washington University School of Medicine, Washington, DC
- Personalized Medicine Care Diagnostics Laboratory (PMCDx), Inc., Germantown, MD
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Zhu J, Campagne O, Torrice CD, Flynn G, Miller JA, Patel T, Suzuki O, Ptachcinski JR, Armistead PM, Wiltshire T, Mager DE, Weiner DL, Crona DJ. Evaluation of the performance of a prior tacrolimus population pharmacokinetic kidney transplant model among adult allogeneic hematopoietic stem cell transplant patients. Clin Transl Sci 2021; 14:908-918. [PMID: 33502111 PMCID: PMC8212733 DOI: 10.1111/cts.12956] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 12/02/2020] [Accepted: 12/03/2020] [Indexed: 12/11/2022] Open
Abstract
Abstract Tacrolimus is a calcineurin inhibitor used to prevent acute graft versus host disease in adult patients receiving allogeneic hematopoietic stem cell transplantation (HCT). Previous population pharmacokinetic (PK) models have been developed in solid organ transplant, yet none exists for patients receiving HCT. The primary objectives of this study were to (1) use a previously published population PK model in adult patients who underwent kidney transplant and apply it to allogeneic HCT; (2) evaluate model‐predicted tacrolimus steady‐state trough concentrations and simulations in patients receiving HCT; and (3) evaluate covariates that affect tacrolimus PK in allogeneic HCT. A total of 252 adult patients receiving allogeneic HCT were included in the study. They received oral tacrolimus twice daily (0.03 mg/kg) starting 3 days prior to transplant. Data for these analyses included baseline clinical and demographic data, genotype data for single nucleotide polymorphisms in CYP3A4/5 and ABCB1, and the first tacrolimus steady‐state trough concentration. A dosing simulation strategy based on observed trough concentrations (rather than model‐based predictions) resulted in 12% more patients successfully achieving tacrolimus trough concentrations within the institutional target range (5–10 ng/ml). Stepwise covariate analyses identified HLA match and conditioning regimen (myeloablative vs. reduced intensity) as significant covariates. Ultimately, a previously published tacrolimus population PK model in kidney transplant provided a platform to help establish a model‐based dose adjustment strategy in patients receiving allogenic HCT, and identified HCT‐specific covariates to be considered for future prospective studies.
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