THE INFLUENCE OF ABCB1 GENOTYPE ON BLOOD SIROLIMUS CONCENTRATIONS FOLLOWING SWITCH FROM A CALCINEURIN INHIBITOR

CLINICAL IMMUNOSUPPRESSION - KIDNEY LATE

M. Moreton¹, E. Junior¹, D.W. Holt¹, I.A.M. Macphee^2
1Cardiac And Vascular Sciences: Analytical Unit, St. George's, University of London, London/UNITED KINGDOM, ²Cellular And Molecular Medicine: Renal Medicine, St. George's, University of London, London/UNITED KINGDOM

Body: Introduction: CYP3A5 genotype has been shown to have a major and the ABCB1 genotype to have a minor influence on the dose-requirement for tacrolimus. Data for sirolimus are less clear, with a likely influence of the CYP3A5 genotype and no positive reports of an association with the ABCB1 genotype. Methods: A sub-group of patients from a multi-centre randomized controlled trial of switching patients from calcineurin inhibitor therapy to sirolimus at least 6 months after renal transplantation consented to entry to a pharmacogenetic sub-study. Calcineurin inhibitor was discontinued and on the next day a loading dose of 12 mg sirolimus was given followed by 4 mg daily. The dose was then adjusted to a target blood concentration of 8-16 ng/mL. The study received ethical approval and subjects gave written informed consent. Results: Of the 47 patients recruited there were 5 CYP3A5 expressers. Associations with the ABCB1 genotype were only apparent after exclusion of the CYP3A5 expressers. The data presented are for the 42 CYP3A5 non-expressers. Median time post-transplant was 4.3 years (range 0.6-17.8); 11 were female and 31 male; median age was 44 years (range 26-71). Ethnic groups: 2 Asian, 39 Caucasian and 1 other. Values shown in the table are median (interquartile range) for dose normalized sirolimus blood concentration (ng/mL/mg/kg) on day 4 after switch to sirolimus. Exposure was significantly lower for heterozygotes at the 3435C>T SNP (Kruskal-Wallis p=0.006) and when TT homozygotes were compared to the other groups for the 1236C>T SNP (Mann-Whitney p=0.025).

SNP	CC or GG	CT or GT/GA	TT	p
1236C>T (Exon 12)	212(172-263)	186(152-271)	291(227-379)	NS
2677g>(T,A) (Exon 21)	178(154-237)	237(174-318)	224(170-266)	NS
3435C>T (Exon 26)	264(187-322)	171(148-214)	301(243-377)	0.006

Conclusion: In this small study there were some statistically significant associations between the ABCB1 genotype and sirolimus exposure early after switch from a calcineurin inhibitor that were apparent when only CYP3A5 non-expressers were included. While these data may be of interest in terms of the basic pharmacology of sirolimus there is no sufficiently clear pattern to allow the use of the ABCB1 genotype in a strategy to guide dosing.

Disclosure: All authors have declared no conflicts of interest.