Rosiglitazone Has No Clinically Significant Effect on Nifedipine Pharmacokinetics

• Published in: Journal of clinical pharmacology 1999-11, Vol.39 (11), p.1189-1194
• Main Authors: Harris, Robert Z., Inglis, Anne Marie L., Miller, Ann K., Thompson, Kathleen A., Finnerty, Dana, Patterson, Scott, Jorkasky, Diane K., Freed, Martin I.
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Biological and medical sciences; Calcium Channel Blockers - adverse effects; Calcium Channel Blockers - blood; Calcium Channel Blockers - pharmacokinetics; Cross-Over Studies; Dose-Response Relationship, Drug; Drug Interactions; Enzyme Inhibitors - pharmacology; Hormones. Endocrine system; Humans; Hypoglycemic Agents - adverse effects; Hypoglycemic Agents - blood; Hypoglycemic Agents - pharmacology; Male; Medical sciences; Nifedipine - adverse effects; Nifedipine - blood; Nifedipine - pharmacokinetics; Pharmacology. Drug treatments; Thiazoles - administration & dosage; Thiazoles - adverse effects; Thiazoles - pharmacology; Thiazolidinediones; Time Factors
• ISSN: 0091-2700; 1552-4604
• DOI: 10.1177/009127009903901112

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 (AUC0‐∞;) was 13% lower than that after administration of nifedipine alone. This difference in nifedipine AUC0‐∞; 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.