¹Service de Néphrologie and Service de Pharmacologie-Toxicologie, Centre Hospitalier Universitaire, LimogesService de Pharmacologie and Service de Néphrologie, Centre Hospitalier Universitaire, Reims.

Correspondence: Yannick Le Meur, MD, PhD, Service de Néphrologie, Centre Hospitalier Universitaire Dupuytren, 87042 Limoges, France. E-mail: Yann.Lemeur@chu-limoges.fr

^*This study was funded by the Limousin Regional Council, Limoges University Hospital, and Wyeth Lederle, France.

Received 9 May 2005; Accepted 27 March 2006.

Abstract

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 (C_max) and trough level (C₀) values were measured.

Results: Significantly lower AUC/dose, C_max/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.