Rosiglitazone has no clinically significant effect on nifedipine pharmacokinetics

To examine the effects of repeat oral dosing of rosiglitazone on the pharma cokinetics of nifedipine, a prototype CYP3A4 substrate, a randomized, open- label, crossover study was performed with two treatment phases separated by a washout period of at least 14 days. Twenty-eight healthy male volunteers received either a single 20 mg oral nifedipine dose or rosiglitazone 8 mg orally once daily for 14 days with a single 20 mg oral nifedipine dose admi nistered on day 14. Plasma nifedipine concentrations were determined over t he 24-hour period following administration of the nifedipine doses. Lack of effect was defined as the demonstration that the 90% CI was contained enti rely within a symmetrical 30% range either side of unity on the log(e)-scal e. Following rosiglitazone + nifedipine administration, the area under the nifedipine concentration-time curve from time zero to infinity (AUC((0-infi nity))) was 13% lower than that after administration of nifedipine alone. T his difference in nifedipine AUC((0-infinity)) was not deemed to be clinica lly significant since the 90% CI was contained within the protocol-defined 30% range (point estimate for ratio of geometric means 0.87; 90% CI: 0.79, 0.96). Rosiglitazone had no marked effect on nifedipine peak plasma concent ration (point estimate: 0.99; 90% CI: 0.73, 1.34) or time to peak concentra tion compared with nifedipine alone. Rosiglitazone coadministration produce d a small decrease in the mean nifedipine half-life (point estimate: -0.77; 90% CI: mean difference -1.29 h, -0.25 h). Both treatment regimens were we ll tolerated and associated with a favorable safety profile. Rosiglitazone, at the highest dose used in clinical studies, produced a small, clinically insignificant decrease in nifedipine exposure. The very small effect on ni fedipine pharmacokinetics suggests that rosiglitazone is an extremely weak inducer of CYP3A4, a characteristic that distinguishes rosiglitazone from t roglitazone. (C) 1999 the American College of Clinical Pharmacology.