EFFECT OF ITRACONAZOLE ON THE PHARMACOKINETICS OF ATORVASTATIN

Background: Itraconazole, a potent inhibitor of CYP3A4, increases the risk of skeletal muscle toxicity of some 3-hydroxy-3-methylglutaryl co enzyme A (HMG-CoA) reductase inhibitors by increasing their serum conc entrations. The aim of this study was to characterize the effect of it raconazole on the pharmacokinetics of atorvastatin, a new HMG-CoA redu ctase inhibitor that is metabolized at least in part by CYP3A4. Method s: in a randomized, double-blind, two-phase crossover study, 10 health y volunteers took 200 mg itraconazole or matched placebo orally once d aily for 4 days. On day 4, 40 mg atorvastatin was administered orally, and a further dose of 200 mg itraconazole or placebo was taken 24 hou rs after atorvastatin intake. Serum concentrations of atorvastatin aci d, atorvastatin lactone, 2-hydroxyatorvastatin acid and lactone, 4-hyd roxyatorvastatin acid and lactone, active and total HMG-CoA reductase inhibitors, itraconazole and hydroxyitraconazole were measured up to 7 2 hours. Results: Itraconazole increased the area under the concentrat ion-time curve from time zero to 72 hours [AUC(0-72)] and the eliminat ion half-life of atorvastatin acid about threefold (p < 0.001), wherea s the peak serum concentration was not significantly changed. The AUC( 0-72) of atorvastatin lactone was increased about fourfold (p < 0.001) , and the peak serum concentration and half-life were increased more t han twofold (p < 0.01). Itraconazole decreased the peak serum concentr ation and AUC(0-72) of 2-hydroxyatorvastatin acid (p < 0.01) and 2-hyd roxyatorvastatin lactone (p < 0.01). Itraconazole significantly (p < 0 .01) increased the half-life of 2hydroxyatorvastatin lactone. The AUC( 0-72) values of active and total HMG-CoA reductase inhibitors were inc reased 1.6-fold (p < 0.001) and 1.7-fold (p < 0.001), respectively. Co nclusions: Itraconazole has a significant interaction with atorvastati n. The mechanism of increased serum concentrations of atorvastatin and HMG-CoA reductase inhibitors is inhibition of CYP3A4-mediated metabol ism of atorvastatin and its metabolites by itraconazole. Concomitant u se of itraconazole and other potent inhibitors of CYP3A4 with atorvast atin should be avoided or the dose of atorvastatin should be reduced a ccordingly.