Effects of CYP3A5 Genetic Polymorphisms on the Weight-adjusted through Concentration of Sirolimus in Renal Transplant Recipients: A Systematic Review and Meta-analysis

Background: Sirolimus, one of the immunosuppressive drugs administered to renal transplant recipients, is metabolized by cytochrome P450 (CYP) 3A5. Accordingly, CYP3A5 polymorphism is a genetic factor affecting sirolimus pharmacokinetics (PK). Therefore, we conducted a systematic review and meta-analysis on the association between sirolimus PK and CYP3A5*3 polymorphism. Methods: We searched for studies published up to 13 June 2024 from PubMed, Embase, Cochrane Library, and Web of Science. We reviewed studies on the relationship between CYP3A5*3 polymorphism and weight-adjusted trough concentration/dose (C₀/D) ratio and dosage of sirolimus in renal transplant recipients, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We evaluated mean differences (MDs) and 95% confidence intervals (CIs). Results: A total of seven studies were included. The weight-adjusted C₀/D ratio of sirolimus was significantly higher in patients with the CYP3A5*3/*3 rather than CYP3A5*1/*1 or CYP3A5*1/*3 genotype (MD 95.27 ng/mL per mg/kg; 95% CI: 58.06, 132.47; I2 = 74%; p < 0.00001). Also, the weight-adjusted dosage of sirolimus was significantly lower in patients with the CYP3A5*3/*3 rather than CYP3A5*1/*1 or CYP3A5*1/*3 genotype (MD-2.60 × 10^-3 mg/kg; 95% CI:-4.52,-0.69; I2 = 44%; p = 0.008). Conclusion: Our meta-analysis showed a significant effect for the CYP3A5*3 genotype on weight-adjusted C₀/D ratio and dosage of sirolimus in adult renal transplant recipients. PROSPERO Register Number: CRD42022354330.