Personalized Tacrolimus Dose Requirement by CYP3A5 but Not ABCB1 or ACE Genotyping in Both Recipient and Donor after Pediatric Liver Transplantation

et al. (2014) Personalized Tacrolimus Dose Requirement by CYP3A5 but Not ABCB1 or ACE Genotyping in Both Recipient and Donor after Pediatric Liver Transplantation. PLoS ONE 9(10): e109464. doi:10.1371/journal.pone.0109464 Personalized Tacrolimus Dose Requirement by CYP3A5 but Not ABCB1 or ACE Genotyping in Both Recipient and Donor after Pediatric Liver Transplantation Yi-kuan Chen. 0 Long-zhi Han. 0 Feng Xue 0 Cong-huan Shen 0 Jun Lu 0 Tai-hua Yang 0 Jian-jun Zhang 0 Qiang Xia 0 Lorna Marson, Centre for Inflammation Research, United Kingdom 0 Department of Liver Surgery and Liver Transplantation, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai , P.R. China 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. - Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files. Funding: This project was supported by National Ministry of Public Health grant (IHECCO8-201213) (http://www.nhfpc.gov.cn/gjhzs/index.shtml) and Shanghai Science and Technology Committee grant (12ZR1418300) (http://www.stcsm.gov.cn/). The funders had roles in study design, data collection and analysis. Competing Interests: The authors have declared that no competing interests exist. . These authors contributed equally to this work. 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]. To achieve the desired target blood concentrations is of critical importance to avoid rejection and dose-related adverse effects after transplantation [3]. The variability makes it difficult to establish an empirical dose regimen for this drug, especially in pediatric patients, in whom 100-fold variability in pharmacokinetic parameters and blood concentration after a fixed dose is routinely observed [4,5]. Underexposure to TAC may result in immunosuppression failure and acute rejection in recipients. On the other hand, overexposure to it may put patients at risk for its considerable toxicity. Therefore, maintaining the drug exposure within this narrow safe therapeutic window becomes a critical aspect in patient management. 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. Although 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. Cytochrome P450 (CYP) 3A5 is the major enzyme responsible for the metabolism of TAC and is found in small intestine as well as in the liver [8]. A single nucleotide polymorphism (SNP) in the CYP3A5 gene involving an A to G transition at position 6986 within intron 3 was found strongly associated with CYP3A5 protein expression. At least one CYP3A5*1 allele were found to express large amounts of CYP3A5 protein, whereas homozygous for the CYP3A5*3 allele did not express significant quantities of CYP3A5 protein, which causes alternative splicing and results in a truncated protein and a severe decrease of functional CYP3A5 [9]. It has become clear that CYP3A5*1/*1 or *1/*3 (hereinafter defined expressor) are significantly associated with lower doseadjusted TAC exposure and increased TAC dose requirements in order to achieve target blood concentrations compared with variant CYP3A5*3/*3 (hereinafter defined nonexpressor) [7,9 12]. However, it is controversial that, for liver transplantation, the impact of the CYP3A5 genotype of both the recipients (intestine) and the donors (graft liver) should be taken into account when evaluating TAC pharmacokinetics. TAC is also substrate of P-glycoprotein, a member drug efflux transporter encoded by the multidrug resistance ABCB1 gene [13,14]. It has been suggested that some SNPs of the ABCB1 gene in exons 12 (1236C.T), 21 (2677G.A/T) and 26 (3435C.T) maybe affect synthesis and function of P-glycoprotein. In addition, angiotensin converting enzyme (ACE), which is a key enzyme in the renin-angiotensin system, catalyzes the conversion of angiotensin I to II in the liver and kidney. A line of evidence suggests that variation in intron 16 of the ACE gene (1409114378) may impact on pharmacokinetics and pharmacodynamics of TAC [15]. However, the impact of SNPs of ABCB1 and ACE on pediatric liver transplants remains unclear. Although much effort has been devoted to the better understanding of inter-individual differences in response to TAC, little data are available about these relationships in Chinese liver transplanted recipients [16,17], particularly in the pediatric population. Moreover, the effects of CYP3A5, ABCB1 and ACE variants on clinical outcomes are not well established in China. The aim of this study was, therefore to retrospectively determine the impact of CYP3A5 genotype of recipients (intestine) and donors (graft liver), age, sex, body weight, primary diseases and other factors on TAC dosing requirements and disposition in a cohort of pediatric liver recipients during the 12 months following transplantation. We evaluated the effect of CYP3A5, ABCB1 and ACE variants on the clinical outcomes in our pediatric liver recipients, and attempted understanding the relationship between CYP3A5, ABCB1 or ACE genotyp (...truncated)