The effects of human CYP2C8 genotype and fluvoxamine on the pharmacokinetics of rosiglitazone in healthy subjects

Abstract

Aims: To determine the effect of CYP2C8 genotype and of fluvoxamine on the pharmacokinetics of rosiglitazone.

Methods: Twenty-three healthy subjects with the following genotypes were included in a two-phase, open-label, cross-over trial: CYP2C8*3/ *3 (n = 3), CYP2C8*1/ *3 (n = 10) and CYP2C8*1/ *1 (n = 10). In Phase A, the subjects were given 4 mg rosiglitazone as a single oral dose. In Phase B, the subjects were treated with multiple oral doses of 50 mg fluvoxamine maleate for 3 days prior to the single oral administration of 4 mg rosiglitazone. Plasma concentrations of rosiglitazone and relative amounts of N-desmethylrosiglitazone were measured in both phases for 24 h after drug administration.

Results: The pharmacokinetics of rosiglitazone and N-desmethylrosiglitazone were not significantly different between the CYP2C8 genotypic groups. Fluvoxamine caused a statistically significant (P = 0.0066) increase in the AUC(0-infinity) of rosiglitazone, with a geometric mean ratio of 1.21 [95% confidence interval (CI) 1.06-1.39]. The elimination half-life (t(1/2)) was also significantly higher (P = 0.0203) with a geometric mean ratio of 1.38 [95% CI 1.06-1.79]. The coadministration of fluvoxamine had no influence on the pharmacokinetics of N-desmethylrosiglitazone.

Conclusion: The importance of the CYP2C8*3 mutation in the in vivo metabolism of rosiglitazone could not be confirmed. Fluvoxamine increased the AUC(0-infinity) and t(1/2) of rosiglitazone moderately and hence may be a weak inhibitor of CYP2C8.

Figure 1

Phase A, plasma drug concentration–time curves in subjects with the CYP2C8*3/ *3 (n = 3), CYP2C8*1/ *1 (n = 10) and CYP2C8*1/ *3 (n = 10) genotypes after a single oral dose of 4-mg rosiglitazone

Figure 2

Phase B, plasma drug concentration–time curves in subjects with the CYP2C8*3/ *3 (n = 2), CYP2C8*1/ *1 (n = 10) and CYP2C8*1/ *3 (n = 9) genotypes after a single oral dose of 4-mg rosiglitazone and coadministration of fluvoxamine

Figure 3

The area under the rosiglitazone concentration–time curves (AUC_0–∞) for each subject in Phase A (▪, baseline) and Phase B (with fluvoxamine, □)