DIFFERENT EFFECTS OF ITRACONAZOLE ON THE PHARMACOKINETICS OF FLUVASTATIN AND LOVASTATIN

Aims The effects of itraconazole on the pharmacokinetics of fluvastati n and lovastatin, two inhibitors of HMG-CoA reductase with different p harmacokinetic properties, were studied. Methods Two separate randomiz ed, placebo-controlled, cross-over studies, each involving 10 healthy volunteers, were carried out. The general design was identical in both studies. The subjects took either 100 mg itraconazole or matched plac ebo orally once daily for 4 days. On day 4, 40 mg fluvastatin or 40 mg lovastatin was administered orally. Plasma concentrations of fluvasta tin, lovastatin, lovastatin acid, itraconazole and hydroxyitraconazole were determined up to 24 h. ml(-1). Results Itraconazole had no signi ficant effect on the C-max (190+/-124 ng ml(-1) vs 197 +/- 189 ng ml(- 1) (mean+/-s.d.)) or total AUC (368 +/- 153ng ml(-1) h vs 324 +/- 155 ng ml(-1) h) of fluvastatin compared with placebo. However, the t(1/2, z) of fluvastatin was slightly prolonged by itraconazole (2.8 +/- 0.49 h vs 2.4 +/- 0.51 h; P<0.05). The C-max of lovastatin was increased a bout 15-fold (P<0.01) and the total AUC more than 15-fold (P<0.01) by itraconazole. Similarly, the C-max and total AUC of lovastatin acid we re increased about 12-fold (95% CI, 5.3 to 17.7-fold; P<0.01) and 15-f old (95% CI, 4.6 to 26.2-fold; P<0.01) by itraconazole, respectively. The t(1/2,z) oOf lovastatin averaged 3.7 +/- 3.8 h and that oflovastat in acid 4.7 +/- 4.0 h during the itraconazole phase; these variables c ould not be determined in all subjects during the placebo phase. Concl usions Itraconazole, even at a small dosage of 100 mg daily, greatly e levated plasma concentrations oflovastatin and its active metabolite, lovastatin acid. Lovastatin should therefore not be used concomitantly with itraconazole and other potent CYP3A4 inhibitors, or the dosage o f lovastatin should be greatly reduced while using a CYP3A4 inhibitor. In contrast, fluvastatin concentrations were not significantly increa sed by itraconazole, indicating that fluvastatin has much less potenti al than lovastatin for clinically significant interactions with itraco nazole and other CYP3A4 inhibitors.