Rosiglitazone has no clinically significant effect on nifedipine pharmacokinetics.
To examine the effects of repeat oral dosing of rosiglitazone on the pharmacokinetics 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 administered on day 14. Plasma nifedipine concentrations were determined over the 24-hour period following administration of the nifedipine doses. Lack of effect was defined as the demonstration that the 90% CI was contained entirely within a symmetrical 30% range either side of unity on the loge-scale. Following rosiglitazone + nifedipine administration, the area under the nifedipine concentration-time curve from time zero to infinity (AUC(0-infinity)) was 13% lower than that after administration of nifedipine alone. This difference in nifedipine AUC(0-infinity) was not deemed to be clinically 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 concentration (point estimate: 0.99; 90% CI: 0.73, 1.34) or time to peak concentration compared with nifedipine alone. Rosiglitazone coadministration produced 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 well 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 nifedipine pharmacokinetics suggests that rosiglitazone is an extremely weak inducer of CYP3A4, a characteristic that distinguishes rosiglitazone from troglitazone.
Harris
R Z
RZ
SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA.
Inglis
A M
AM
Miller
A K
AK
Thompson
K A
KA
Finnerty
D
D
Patterson
S
S
Jorkasky
D K
DK
Freed
M I
MI
D000293:Adolescent; D000328:Adult; D002121:Calcium Channel Blockers / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000097:blood / Q000494:pharmacology*; D008297:Male; D009543:Nifedipine / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000077154:Rosiglitazone; D013844:Thiazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D045162:Thiazolidinediones; D013997:Time Factors
D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D013844:Thiazoles; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D009543:Nifedipine