Interactions between simvastatin and troglitazone or pioglitazone in healthy subjects

Two a randomized, two-period crossover studies were conducted to evaluate t he effects of repeat oral dosing of troglitazone (Study I) and pioglitazone (Study II) on the pharmacokinetics of plasma HMG-CoA reductase inhibitors following multiple oral doses of simvastatin and of simvastatin on the plas ma pharmacokinetics of troglitazone (Study I) in healthy subjects. In both studies, each subject received two treatments. Treatment A consisted of onc e-daily oral doses of troglitazone 400 mg (Study I) or pioglitazone 45 mg ( Study II) for 24 days with coadministration of once-daily doses of simvasta tin 40 mg (Study I) or 80 mg (Study II on Days 25 through 24, Treatment B c onsisted of once-daily oral doses of simvastatin 40 mg (Study I) or 80 mg ( Study II)for 10 days. In Study I, the area under the plasma concentration-t ime profiles (AUC)and maximum plasma concentrations (C-max) of HMG-CoA redu ctase inhibitors in subjects who received both troglitazone and simvastatin were decreased modestly (by similar to 30% for C-max and similar to 40% fo r AUC), but time to reach C-max (t(max)) did not change, as compared with t hose who received simvastatin alone. Simvastatin, administered orally as a 40 mg tablet daily for 10 days, did not affect the AUC or t(max) (p > 0.5) but caused a small but clinically insignificant increase (similar to 25%) i n C-max for troglitazone. In Study II, pioglitazone, at the highest approve d dose for clinical use, did not significantly alter any of the pharmacokin etic parameters (AUC, C-max, and t(max)) of simvastatin HMG-CoA reductase i nhibitory activity. For all treatment regimens, side effects were mild and transient, suggesting that coadministration of simvastatin with either trog litazone or pioglitazone was well tolerated. The modest effect of troglitaz one an simvastatin pharmacokinetics is in agreement with the suggestion tha t troglitazone is an inducer of CYP3A. The insignificant effect of simvasta tin on troglitazone pharmacokinetics is consistent with the conclusion that simvastatin is not a significant inhibitor for drug-metabolizing enzymes. The lack of pharmacokinetic effect of pioglitazone on simvastatin supports the expectation that this combination may be used safely. (C) 2001 the Amer ican College of Clinical Pharmacology.