SIMVASTATIN BUT NOT PRAVASTATIN IS VERY SUSCEPTIBLE TO INTERACTION WITH THE CYP3A4 INHIBITOR ITRACONAZOLE

Background: Itraconazole increases the risk of skeletal muscle toxicit y of some 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in hibitors by increasing their serum concentrations. We studied possible interactions of itraconazole with simvastatin and pravastatin. Method s: Two randomized, double-blind, two-phase crossover studies were perf ormed with use of an identical design, one with simvastatin (study I) and one with pravastatin (study II). In both studies, 10 healthy volun teers received either 200 mg itraconazole or placebo orally once a day for 4 days. On day 4, each subject ingested a single 40 mg dose of si mvastatin (study I) or pravastatin (study II). Serum concentrations of simvastatin, simvastatin acid, pravastatin, HMG-CoA reductase inhibit ors, itraconazole, and hydroxyitraconazole were determined. Results: I n study I, itraconazole increased the peak serum concentrations (C-max ) and the areas under the serum concentration-time curve [AUC(0-infini ty)] of simvastatin and simvastatin acid at least tenfold (p < 0.001). The C-max and AUC(0-infinity) of total simvastatin acid (naive simvas tatin acid plus that derived by hydrolysis of the lactone) were increa sed 17-fold and 19-fold (P < 0.001), respectively, and the half-life ( t(1/2)) was increased by 25% (p < 0.05). The AUC(0-infinity) of HMG-Co A reductase inhibitors was increased fivefold (p < 0.001) and the C-ma x and t(1/2) were increased threefold (p < 0.001). In study II, itraco nazole slightly increased the AUC(0-infinity) and C-max of pravastatin , but the changes were statistically nonsignificant (p = 0.052 and 0.1 72, respectively). The t(1/2) was not altered. The AUC(0-infinity) and C-max of HMG-CoA reductase inhibitors were increased less than twofol d (p < 0.05 and p = 0.063, respectively) by itraconazole. There were n o differences in the serum concentrations of itraconazole and hydroxyi traconazole between studies I and II. Conclusions: Itraconazole greatl y increased serum concentrations of simvastatin, simvastatin acid, and HMG-CoA reductase inhibitors, probably by inhibiting CYP3A-mediated m etabolism, but it had only a minor effect on pravastatin. Concomitant use of potent inhibitors of CYP3A with simvastatin should be avoided o r its dosage should be greatly reduced.