Personalized tacrolimus dose requirement by CYP3A5 but not ABCB1 or ACE genotyping in both recipient and donor after pediatric liver transplantation.

Yi-Kuan Chen,Tai-Hua Yang,Qiang Xia,Jian-Jun Zhang,Feng Xue,Long-Zhi Han,Jun Lu,Cong-Huan Shen,Lorna Marson

doi:10.1371/journal.pone.0109464

Abstract

Tacrolimus (TAC) is the backbone of an immunosuppressive drug used in most solid organ transplant recipients. A single nucleotide polymorphism (SNP) at position 6986G>A in CYP3A5 has been notably involved in the pharmacokinetic variability of TAC. It is hypothesized that CYP3A5 genotyping in patients may provide a guideline for TAC therapeutic regimen. To further evaluate the impact of CYP3A5 variants in donors and recipients, ABCB1 and ACE SNPs in recipients on TAC disposition, clinical and laboratory data were retrospectively reviewed from 90 pediatric patients with liver transplantation and their corresponding donors after 1 year of transplantation. The recipients with CYP3A5 *1/*1 or *1/*3 required more time to achieve TAC therapeutic range during the induction phase, and needed more upward dose during the late induction and the maintained phases, with lower C/D ratio, compared with those with CYP3A5 *3/*3. And donor CYP3A5 genotypes were found to impact on TAC trough concentrations after liver transplantation. No association between ABCB1 or ACE genotypes and TAC disposition post-transplantation was found. These results strongly suggest that CYP3A5 genotyping both in recipient and donor, not ABCB1 or ACE is necessary for establishing a personalized TAC dosage regimen in pediatric liver transplant patients.

Highlights

Tacrolimus (TAC) is the backbone of immunosuppressive drug used worldwide in organ transplantation and characterized by a narrow therapeutic range and high inter-individual variability in its pharmacokinetics [1,2]
We evaluated the effect of CYP3A5, ABCB1 and angiotensin converting enzyme (ACE) variants on the clinical outcomes in our pediatric liver recipients, and attempted understanding the relationship between CYP3A5, ABCB1 or ACE genotype and TAC pharmacokinetics may improve our knowledge of how to most effectively administer this drug, leading to considerable benefit to pediatric liver transplant patients
We found that the initial, induction and maintenance doses are very close to those in recipients with expressor/the donor with expressor (ReDe), recipients with expressor/the donor with nonexpressor (ReDn) and recipients with nonexpressor/the donor with expressor (RnDe) groups, Table 3

Summary

Introduction

Tacrolimus (TAC) is the backbone of immunosuppressive drug used worldwide in organ transplantation and characterized by a narrow therapeutic range and high inter-individual variability in its pharmacokinetics [1,2]. Concerning the concept that young children need a higher TAC dose than adult patients [4,6], the blood TAC concentration should be monitored regularly to maintain a therapeutic range, especially during the induction phase post-transplantation therapy, when the risk of rejection is the highest. Various factors, such as age, sex, body weight, drug interactions and other factors lead to the wide range of interpatient variability ineffective dosage of TAC [7], among them genetic factors play a critical role in the pharmacokinetic properties and therapeutic levels of TAC

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