C. Kyrklund et al., Plasma concentrations of active lovastatin acid are markedly increased by gemfibrozil but not by bezafibrate, CLIN PHARM, 69(5), 2001, pp. 340-345
Background: Concomitant use of fibrates with statins has been associated wi
th an increased risk of myopathy, but the underlying mechanism of this adve
rse reaction remains unclear. Our aim was to study the effects of bezafibra
te and gemfibrozil on the pharmacokinetics of lovastatin.
Methods: This was a randomized, double-blind, 3-phase crossover study. Elev
en 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, gemfi
brozil, and bezafibrate were measured up to 24 hours.
Results: Gemfibrozil markedly increased the plasma concentrations of lovast
atin acid, without affecting those of the parent lovastatin compared with p
lacebo. During the gemfibrozil phase, the mean area under the plasma concen
tration-time curve from 0 to 24 hours [AUC(0-24)] of lovastatin acid was 28
0% (range, 131% to 1184%; P < .001) and the peak plasma concentration (C-ma
x) was 280% (range, 123% to 1042%; P < .05) of the corresponding value duri
ng the placebo phase. Bezafibrate had no statistically significant effect o
n the AUC(0-24) or C-max of lovastatin or lovastatin acid compared with pla
cebo.
Conclusions: Gemfibrozil markedly increases plasma concentrations of lovast
atin acid, but bezafibrate does not. The increased risk of myopathy observe
d during concomitant treatment with statins and fibrates may be partially o
f a pharmacokinetic origin, The risk of developing myopathy during concomit
ant therapy with lovastatin and a fibrate may be smaller with bezafibrate t
han with gemfibrozil.