Plasma concentrations of active lovastatin acid are markedly increased by gemfibrozil but not by bezafibrate

Background Concomitant use of fibrates with statins has been associated with an increased risk of myopathy, but the underlying mechanism of this adverse reaction remains unclear. Our aim was to study the effects of bezafibrate and gemfibrozil on the pharmacokinetics of lovastatin. Methods This was a randomized, double‐blind, 3‐phase crossover study. Eleven healthy volunteers took 400 mg/day bezafibrate, 1200 mg/day gemfibrozil, or placebo for 3 days. On day 3, each subject ingested a single 40 mg dose of lovastatin. Plasma concentrations of lovastatin, lovastatin acid, gemfibrozil, and bezafibrate were measured up to 24 hours. Results Gemfibrozil markedly increased the plasma concentrations of lovastatin acid, without affecting those of the parent lovastatin compared with placebo. During the gemfibrozil phase, the mean area under the plasma concentration–time curve from 0 to 24 hours [AUC(0–24)] of lovastatin acid was 280% (range, 131% to 1184%; P < .001) and the peak plasma concentration (Cmax) was 280% (range, 123% to 1042%; P < .05) of the corresponding value during the placebo phase. Bezafibrate had no statistically significant effect on the AUC(0–24) or Cmax of lovastatin or lovastatin acid compared with placebo. Conclusions Gemfibrozil markedly increases plasma concentrations of lovastatin acid, but bezafibrate does not. The increased risk of myopathy observed during concomitant treatment with statins and fibrates may be partially of a pharmacokinetic origin. The risk of developing myopathy during concomitant therapy with lovastatin and a fibrate may be smaller with bezafibrate than with gemfibrozil. Clinical Pharmacology & Therapeutics (2001) 69, 340–345; doi: 10.1067/mcp.2001.115542