Different effects of itraconazole on the pharmacokinetics of fluvastatin and lovastatin.
OBJECTIVE
The effects of itraconazole on the pharmacokinetics of fluvastatin and lovastatin, two inhibitors of HMG-CoA reductase with different pharmacokinetic properties, were studied.


METHODS
Two separate randomized, 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 placebo orally once daily for 4 days. On day 4, 40 mg fluvastatin or 40 mg lovastatin was administered orally. Plasma concentrations of fluvastatin, lovastatin, lovastatin acid, itraconazole and hydroxyitraconazole were determined up to 24 h.


RESULTS
Itraconazole had no significant effect on the Cmax (190 +/- 124 ng ml(-1) vs 197 +/- 189 ng ml(-1) (mean +/- s.d.)) or total AUC (368 +/- 153 ng ml(-1) h vs 324 +/- 155 ng ml(-1) h) of fluvastatin compared with placebo. However, the t1/2,z of fluvastatin was slightly prolonged by itraconazole (2.8 +/- 0.49 h vs 2.4 +/- 0.51 h; P < 0.05). The Cmax of lovastatin was increased about 15-fold (P < 0.01) and the total AUC more than 15-fold (P < 0.01) by itraconazole. Similarly, the Cmax and total AUC of lovastatin acid were increased about 12-fold (95% CI, 5.3 to 17.7-fold; P < 0.01) and 15-fold (95% CI, 4.6 to 26.2-fold; P < 0.01) by itraconazole, respectively. The t1/2,z of lovastatin averaged 3.7 +/- 3.8 h and that of lovastatin acid 4.7 +/- 4.0 h during the itraconazole phase; these variables could not be determined in all subjects during the placebo phase.


CONCLUSIONS
Itraconazole, even at a small dosage of 100 mg daily, greatly elevated plasma concentrations of lovastatin and its active metabolite, lovastatin acid. Lovastatin should therefore not be used concomitantly with itraconazole and other potent CYP3A4 inhibitors, or the dosage of lovastatin should be greatly reduced while using a CYP3A4 inhibitor. In contrast, fluvastatin concentrations were not significantly increased by itraconazole, indicating that fluvastatin has much less potential than lovastatin for clinically significant interactions with itraconazole and other CYP3A4 inhibitors.
Kivistö
K T
KT
Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital, Finland.
Kantola
T
T
Neuvonen
P J
PJ
D000284:Administration, Oral; D000328:Adult; D000924:Anticholesteremic Agents / Q000493:pharmacokinetics*; D000935:Antifungal Agents / Q000494:pharmacology*; D018592:Cross-Over Studies; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004311:Double-Blind Method; D004344:Drug Incompatibility; D004347:Drug Interactions; D005229:Fatty Acids, Monounsaturated / Q000009:adverse effects / Q000493:pharmacokinetics*; D005260:Female; D000077340:Fluvastatin; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000493:pharmacokinetics*; D017964:Itraconazole / Q000494:pharmacology*; D008148:Lovastatin / Q000009:adverse effects / Q000493:pharmacokinetics*; D008297:Male
D000924:Anticholesteremic Agents; D000935:Antifungal Agents; D005229:Fatty Acids, Monounsaturated; D007211:Indoles; D017964:Itraconazole; D000077340:Fluvastatin; D003577:Cytochrome P-450 Enzyme System; D008148:Lovastatin