The cytochrome P450 3AP1 variant genotype shows correlation with the true clearance in a renal transplant population

Background. Cytochrome P₄₅₀ 3AP1 is important for the metabolism of sirolimus (SRL). Polymorphisms in the gene affect the production of the enzyme and hence possibly the pharmacokinetics of SRL. We attempt to resolve part of the observed variability in the ratio of the observed predose SRL concentrations (Cmin) relating it to the genotype as well as to the individual patient pharmacokinetic parameters.

Methods. Trough SRL blood concentrations (Cmin; n = 768) in renal transplant patients (n = 41), receiving combination SRL and cyclosporine for immune system suppression, were analyzed retrospectively. The promoter of the CYP3AP1 pseudogene was genotyped for polymorphisms. The association between the therapeutic surrogate Cmin/Dose and genotype was explored with standard methods and mixed effects models. A Bayesian method was used to resolve the patient specific pharmacokinetic parameters. The systemic clearance was regressed against the genotype, weight and sex as covariates in general additive models.

Results. A subgroup of 34 homozygotes (82.9%) and one of 7 heterozygotes (17%) were found. Mixed effects modeling of Cmin/ Dose showed a significant difference between the two subgroups in this variable (mean ± SD) (3.63 ± 1.17 [1000 x L] -1 and 2.86 ± 0.72 [1000 x L] -1, respectively; p < 0.0001) and insignificant effects for covariates weight and sex. A general additive model between individual CL and genotype resulted in a significant explanatory relationship (p < 0.05; F-test).

Conclusion. Polymorphisms in the CYP3AP1 gene appear to associate with different subpopulations of Cmin/Dose and of patient specific systemic SRL clearance. However, controlled prospective testing in much larger populations is needed to verify this result, preferably including haplotypic analysis with full pharmacokinetic population screens on the patients.