Genetic Polymorphisms Affecting Tacrolimus Metabolism and the Relationship to Post-Transplant Outcomes in Kidney Transplant Recipients

Cheng, Fang; Li, Qiang; Wang, Jinglin; Hu, Min; Zeng, Fang; Wang, Zhendi

doi:10.2147/pgpm.s337947

Cited by 11 publications

(8 citation statements)

References 53 publications

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“…These contrasting findings may be attributable to the differential use of cytolytic induction therapy, which was nearly universal in our CYP3A5 expressors (96%) versus 63.2% in Asempa et al's [23] study. The use of cytolytic induction therapy has demonstrated efficacy in reducing acute rejection rates while allowing delayed initiation or therapeutic dosing of tac; thus, mitigating the influence of CYP3A5 genotype on subtherapeutic tac-induced rejection risk [24][25][26][27]. Conversely, nonexpressors experienced higher rates of supratherapeutic tac trough concentrations, which have been found to lead to neurotoxicity, nephrotoxicity, and GI complications [28].…”

Section: Discussionmentioning

confidence: 99%

Impact of CYP3A5 genotype on de-novo LCP tacrolimus dosing and monitoring in kidney transplantation

Rao¹,

Carcella²,

Patel³

et al. 2023

Pharmacogenetics and Genomics

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Objectives LCP tac has a recommended starting dose of 0.14 mg/kg/day in kidney transplant. The goal of this study was to assess the influence of CYP3A5 on perioperative LCP tac dosing and monitoring. MethodsThis was a prospective observational cohort study of adult kidney recipients receiving de-novo LCP tac. CYP3A5 genotype was measured and 90-day pharmacokinetic and clinical were assessed. Patients were classified as CYP3A5 expressors (*1 homozygous or heterozygous) or nonexpressors (LOF *3/*6/*7 allele). ResultsIn this study, 120 were screened, 90 were contacted and 52 provided consent; 50 had genotype results, and 22 patients expressed CYP3A5*1. African Americans (AA) comprised 37.5% of nonexpressors versus 81.8% of expressors (P = 0.001). Initial LCP tac dose was similar between CYP3A5 groups (0.145 vs. 0.137 mg/kg/ day; P = 0.161), whereas steady state dose was higher in expressors (0.150 vs. 0.117 mg/kg/day; P = 0.026). CYP3A5*1 expressors had significantly more tac trough concentrations of less than 6 ng/ml and significantly fewer tac trough concentrations of more than 14 ng/ml. Providers were significantly more likely to under-adjust LCP tac by 10 and 20% in CYP3A5 expressors versus nonexpressors (P < 0.03). In sequential modeling, CYP3A5 genotype status explained the LCP tac dosing requirements significantly more than AA race. Conclusion CYP3A5*1 expressors require higher doses of LCP tac to achieve therapeutic concentrations and are at higher risk of subtherapeutic trough concentrations, persisting for 30-day posttransplant. LCP tac dose changes in CYP3A5 expressors are more likely to be under-adjusted by providers. Pharmacogenetics and Genomics 33: 59-65

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Section: Discussionmentioning

confidence: 99%

Impact of CYP3A5 genotype on de-novo LCP tacrolimus dosing and monitoring in kidney transplantation

Rao¹,

Carcella²,

Patel³

et al. 2023

Pharmacogenetics and Genomics

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“…Tacrolimus is generally known to be metabolized by cytochrome P450 3A5 CYP3A5 and CYP3A4 enzymes. Therefore, the pharmacokinetic variability of tacrolimus could be secondary to an allelic variation of CYP3A5 and CYP3A4 genes [ 13 ].…”

Section: Discussionmentioning

confidence: 99%

Beware of Rhabdomyolysis After a Renal Graft

Bardai¹,

Chouhani²,

Haddane³

et al. 2022

Cureus

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In recent years, there has been a significant advancement in the field of immunosuppressive therapy in renal transplantation. However, these treatments have side effects, including rhabdomyolysis. In this article, we report the case of a transplant patient with rhabdomyolysis secondary to tacrolimus and shed light on different aggravating factors. Treatment withdrawal, hydration, and forced diuresis are allowed in the majority of cases.

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“…With the exception of grapefruit juice, St. John’s wort, and cannabis, the tabularized medicinal items presented do not cover foods and substances related to complementary and alternative medicine (CAM), such as dietary supplements, herbs, and other manufactured ingredients, although they have been shown to have a further relevant impact, especially in outpatients, as in cancer therapy, with a likelihood of interactions as high as 37% in the case of CAM supplements, and 29% of all patients for foods [ 186 , 187 ]. There is no reference to CYP3A4, CYP3A5, or MDR-1 genotype metabolism for additional pharmacokinetic genotype-based individualized dosing aspects of, e.g., CSA or TAC in genetic polymorphism that also affects outcomes [ 188 ].…”

Section: Strengths and Weaknessesmentioning

confidence: 99%

A Drug Safety Briefing (II) in Transplantation from Real-World Individual Pharmacotherapy Management to Prevent Patient and Graft from Polypharmacy Risks at the Very Earliest Stage

Wolf

2024

Pharmaceuticals

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For early and long-term patient and graft survival, drug therapy in solid organ and hematopoietic stem cell transplantation inevitably involves polypharmacy in patients with widely varying and even abruptly changing conditions. In this second part, relevant medication briefing is provided, in addition to the scores defined in the previously published first part on the design of the Individual Pharmacotherapy Management (IPM). The focus is on the growing spectrum of contemporary polypharmacy in transplant patients, including early and long-term follow-up medications. 1. Unlike the available drug–drug interaction (DDI) tables, for the first time, this methodological all-in-one device refers to the entire risks, including contraindications, special warnings, adverse drug reactions (ADRs), and DDIs. The selection of 65 common critical drugs results from 10 years of daily IPM with real-world evidence from more than 60,800 IPM inpatient and outpatient medication analyses. It includes immunosuppressants and typical critical antimicrobials, analgesics, antihypertensives, oral anticoagulants, antiarrhythmics, antilipids, antidepressants, antipsychotics, antipropulsives, antiemetics, propulsives, proton pump inhibitors (PPIs), sedatives, antineoplastics, and protein kinase inhibitors. As a guide for the attending physician, the drug-related risks are presented in an alphabetical overview based on the Summaries of Product Characteristics (SmPCs) and the literature. 2. Further briefing refers to own proven clinical measures to manage unavoidable drug-related high-risk situations. Drug-induced injuries to the vulnerable graft and the immunosuppressed comorbid patient require such standardized, intensive IPM and the comprehensive preventive briefing toolset to optimize the outcomes in the polypharmacy setting.

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Genetic Polymorphisms Affecting Tacrolimus Metabolism and the Relationship to Post-Transplant Outcomes in Kidney Transplant Recipients

Cited by 11 publications

References 53 publications

Impact of CYP3A5 genotype on de-novo LCP tacrolimus dosing and monitoring in kidney transplantation

Impact of CYP3A5 genotype on de-novo LCP tacrolimus dosing and monitoring in kidney transplantation

Beware of Rhabdomyolysis After a Renal Graft

A Drug Safety Briefing (II) in Transplantation from Real-World Individual Pharmacotherapy Management to Prevent Patient and Graft from Polypharmacy Risks at the Very Earliest Stage

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