CYP3A53 influences sirolimus oral clearance in de novo and stable renal transplant recipients

Background The low and highly variable oral bioavailability of the immunosuppressant sirolimus is thought to result partly from genetic polymorphism of the CYP3A5 gene. Methods This study aimed to evaluate the contribution of the CYP3A5 single‐nucleotide polymorphism A6986G to the interindividual variability of sirolimus pharmacokinetics in 47 renal transplant patients at steady state, 21 of whom were also followed up for the first 3 months after transplantation. The patients were administered sirolimus, mycophenolate mofetil, and corticosteroids but no calcineurin inhibitor. They were genotyped for CYP3A5*3 by use of real‐time quantitative polymerase chain reaction based on the 5′‐nuclease allelic discrimination assay. Full sirolimus blood concentration profiles were measured at steady state (3 months after transplantation or more) in all patients, as well as at weeks 1 and 2 and month 1 in 21 of these patients, by use of liquid chromatography–tandem mass spectrometry. The sirolimus area under the concentration‐time curve (AUC) was calculated via the standard noncompartmental approach. Maximal concentration (Cmax) and trough level (C0) values were measured. Results Significantly lower AUC/dose, Cmax/dose, and C0/dose values were found at steady state (n = 47) in individuals carrying at least 1 CYP3A5*1 allele (n = 6) than in *3/*3 patients (26.6 ± 15.7 versus 51.1 ± 21.1 [P = .008], 4.8 ± 3.3 versus 7.7 ± 3.3 [P = .02], and 1.5 ± 0.8 versus 3.0 ± 1.5 [P = .01], respectively), as well as during all posttransplant periods in the subgroup of 21 patients who were followed up for the first 3 months after transplantation (n = 21) (P < .05 always). Patients with the CYP3A5*1/*1 and *1/*3 genotypes required a significantly higher sirolimus daily dose to achieve the same blood concentration at steady state as *3/*3 patients. In patients followed up for the first 3 months after transplantation, C0 levels within the target range were only achieved after 1 to 3 months of repeated dosing and dose adjustment in both genotypic groups. Conclusion These results confirm that sirolimus metabolic activity and oral clearance are significantly decreased in patients who are homozygous for the CYP3A5*3 single‐nucleotide polymorphism and suggest that the determination of this polymorphism could be useful for a priori dose adjustment of sirolimus, given the long half‐life of this drug. Clinical Pharmacology & Therapeutics (2006) 80, 51–60; doi:10.1016/j.clpt.2006.03.012