Dynamic effects of CYP3A5 polymorphism on dose requirement and trough concentration of tacrolimus in renal transplant recipients

What is known and objective: Tacrolimus is a widely used immunosuppressive drug with marked pharmacokinetic variability partly due to CYP3A5 polymorphism. Our study aimed to investigate the dynamic effects of CYP3A5 genotypes on dose requirement and trough concentration (C₀ ) of tacrolimus in renal transplant recipients.

Methods: A total of 194 Chinese renal transplant recipients received oral tacrolimus twice daily. Whole-blood C₀ of tacrolimus were measured on the 3rd day, 7th day, 14th day, 1st month, 3rd month and 6th month post-transplantation. CYP3A5 genotypes were determined and the recipients were categorized as CYP3A5 expressers (CYP3A5*1 allele carriers) and non-expressers (homozygous CYP3A5*3). The correlated serum creatinine, haematocrit and albumin were also detected.

Results: The allele frequencies for CYP3A5*1/*1, *1/*3 and *3/*3 were 7·7%, 44·8% and 47·4%, respectively. There were no significant variability in serum creatinine, haematocrit and albumin values between CYP3A5 expressers and non-expressers. Larger doses were administered to CYP3A5 expressers than to non-expressers after surgery except the initial dose. C₀ were much lower in CYP3A5 expressers than in non-expressers on the 3rd day, 7th day, 14th day and 1st month post-transplantation (P < 0·01); however, no significant differences were found on the 3rd and 6th months post-transplantation. All of the dose-adjusted C₀ in CYP3A5 expressers were significantly lower than non-expressers (P < 0·01). Less of the recipients achieving target C₀ (4-8 ng/mL) were found in CYP3A5 expressers than in non-expressers after initial dose (35·7% vs. 50%). Meanwhile, CYP3A5 non-expressers were detected having higher C₀ (>8 ng/mL) during 3 months post-transplantation. Besides, the proportions in the two groups both increased gradually over time and up to 91·8% and 94% on the 6th month, respectively.

What is new and conclusion: There are no significant differences in serum creatinine, haematocrit and albumin values between CYP3A5 expressers and non-expressers. CYP3A5 expressers have decreased dose-adjusted tacrolimus C₀ when compared to non-expressers. Dose-adjusted C₀ of tacrolimus increases in a time-dependent manner in both groups.