Pharmacokinetic interaction between simvastatin and fenofibrate with staggered and simultaneous dosing: Does it matter?

Simvastatin and fenofibrate are frequently co-prescribed at staggered intervals for the treatment of dyslipidemia. Since a drug-drug interaction has been reported when the two drugs are given simultaneously, it is of clinical interest to know whether the interaction differs between simultaneous and staggered combinations. A study, assessing the impact of both combinations on the interaction, was conducted with 7-day treatment regimens using simvastatin 40 mg and fenofibrate 145 mg: (A) simvastatin only (evening), (B) simvastatin and fenofibrate (both in evening), and (C) simvastatin (evening) and fenofibrate (morning). Eighty-five healthy subjects received the respective treatments in a randomized, 3-way cross-over study. The pharmacokinetics of simvastatin and the active metabolite simvastatin acid were determined. There was a limited reduction in the AUC0-24h of simvastatin acid of 21 and 29% for simultaneous and staggered combination, respectively. The geometric mean AUC0-24h ratio of simvastatin acid for the two combined dosing regimens (B/C) and 90% confidence interval were 111% (102-121). The interaction apparently had no impact on lipid markers. The findings imply that the observed pharmacokinetic interaction is unlikely clinically relevant, and support the combined use of simvastatin and fenofibrate not only given at staggered interval but also given simultaneously.