Title:Effects of CPY3A5 Genetic Polymorphisms on the Pharmacokinetics of Extendedrelease and Immediate-release Tacrolimus Formulations in Renal Transplant Recipients: A Systematic Review and Meta-analysis
Volume: 22
Issue: 10
Author(s): Qiufen Xie, Qian Xiang, Zhiyan Liu, Guangyan Mu, Shuang Zhou, Zhuo Zhang, Lingyue Ma and Yimin Cui*
Affiliation:
- Department of Pharmacy, Peking University First Hospital, No. 6, Dahongluochang Street, Xicheng District, Beijing 100034,China
Keywords:
Tacrolimus, CYP3A5*3, pharmacogenetics, pharmacokinetics, renal transplantation, extended-release, immediate-release.
Abstract:
Background: Although the pharmacokinetic variability of Tacrolimus (Tac) metabolism is primarily influenced
by CYP3A5 genotypes, the potential effect according to CYP3A5 polymorphisms in Tac extended-release
(Tac-ER) and immediate-release (Tac-IR) and between these formulations’ conversion needs further investigation.
The purpose of this study was to clarify the association of CYP3A5 genotypes and pharmacokinetics of different Tac
formulations in renal transplant recipients.
Methods: PubMed, EMBASE, and Cochrane Library databases were searched for eligible studies (protocol registration
No. CRD 42019133790 in PROSPERO network). The summary weighted mean difference with 95% confidence
intervals was calculated for pharmacokinetic parameters using the random-effects model according to posttransplantation
periods, genotypes and formulations. Sensitivity analysis, publication bias, and subgroup analyses
were conducted.
Results: A total of 27 studies involving 2,713 renal transplant recipients were adopted. Whether patients treated with
Tac-ER or Tac-IR, CYP3A5 non-expressors (*3/*3) had a decreased daily dose and CL/F, an increased Ctrough,
Ctrough/D, AUC0-24h/D and Cmax/D than expressors (*1/*1 or *1/*3) at most post-transplantation periods. Furthermore,
when 1:1 dose conversion from Tac-IR to Tac-ER (all at ≥12 months post-transplantation), Ctrough and Cmax were
decreased in both CYP3A5 non-expressors and expressors, while daily dose was only decreased in CYP3A5 nonexpressors
and AUC0-24h was only decreased in CYP3A5 expressors. Finally, subgroup analyses indicated that ethnicity,
mean age, and male percentage influenced daily dose and Ctrough of Tac, especially for Tac-IR.
Conclusion: The results indicated that CYP3A5 genotypes affect the pharmacokinetics of Tac in renal transplant
recipients in both formulations and between formulations’ conversion. Future studies should be exploring more other
associations of CYP3A5 genotypes and the pharmacodynamics of Tac.
