Association of CYP3A4*1B genotype with Cyclosporin A pharmacokinetics in renal transplant recipients: A meta-analysis

Objective: Cyclosporine (CsA) is a substrate of cytochrome P450 (CYP) 3A4 with a narrow therapeutic index and large individual difference. CYP3A4*1B is reported to be associated with CsA pharmacokinetics parameters, but the relevance is still in dispute. Therefore, a meta-analysis was employed to evaluate the influence of CYP3A4*1B on CsA pharmacokinetics at different post-transplantation times in adult renal transplant recipients. Methods: Studies on evaluating the CYP3A4*1B genotype and CsA pharmacokinetics were retrieved through a systematical search of relevant database including PubMed, Emabase, Web of science, the Cochrane Library, Clinical Trials.gov and three Chinese literature databases (up to 15 October 2017). The pharmacokinetic parameters: weight-adjusted CsA daily dose (Dose), cyclosporine trough concentration (C0) and trough concentration/weight-adjusted CsA daily dose ratio (C0/Dose ratio) were extracted, and all statistical analysis were performed by using Review Manager 5.1.0. Results: Four studies (involving 452 adult renal transplant recipients) were included in this meta-analysis. For the C0/Dose ratio, in all included renal transplant recipients, CYP3A4*1B carriers exhibited higher C0/Dose ratio than CYP3A4*1 (WMD 7.38, 95% CI 1.26-13.51; P = 0.02). The differences between CYP3A4*1B carriers and CYP3A4*1 in Dose (WMD 0.36, 95% CI 0.85-0.12; P = 0.14), Co (WMD 10.81, 95% CI 77.72-99.34; P = 0.81) were not statistically significant. According to post-transplantation time, subgroup analysis also showed no significant statistical significance between CYP3A4*1B carriers and CYP3A4*1 carriers in Dose or Co. However, this result should be further explored because only four studies were included. Conclusions: CYP3A4*1B is associated with CsA C0/Dose ratio in renal transplant recipients which indicates patients with CYP3A4*1B allele require lower dose of CsA to reach target blood concentration compared with the CYP3A4*1 carriers.