Objective: To determine the effects of itraconazole, a potent inhibitor of CYP3A4, on the pharmacokinetics of cerivastatin, a competitive 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor.
Methods: A randomized, double-blind, cross-over study design with two phases, which were separated by a washout period of 4 weeks, was used. In each phase ten healthy volunteers took 200 mg itraconazole or matched placebo orally once daily for 4 days according to a randomization schedule. On day 4, 0.3 mg cerivastatin was administered orally. Serum concentrations of cerivastatin, its major metabolites, active and total HMG-CoA reductase inhibitors, itraconazole and hydroxyitraconazole were measured up to 24 h.
Results: Itraconazole increased the area under the concentration-time curve from time zero to infinity (AUC(0-infinity)) of the parent cerivastatin by 15% (P < 0.05). The mean peak serum concentration (Cmax) of cerivastatin lactone was increased 1.8-fold (range 1.1-fold to 2.4-fold, P < 0.001) and the AUC(0-24h) 2.6-fold (range 2.0-fold to 3.6-fold, P < 0.001) by itraconazole. The elimination half-life (t1/2) of cerivastatin lactone was increased 3.2-fold (P < 0.001). Itraconazole decreased the AUC(0-24h) of the active M-1 metabolite of cerivastatin by 28% (P < 0.05), whereas the AUC(0- 24h) of the more active metabolite, M-23, was increased by 36% (P < 0.05). The AUC(0-24h) and t1/2 of active HMG-CoA reductase inhibitors were increased by 27% (P < 0.05) and 40% (P < 0.05), respectively, by itraconazole.
Conclusions: Itraconazole has a modest interaction with cerivastatin. Inhibition of the CYP3A4-mediated M-1 metabolic pathway leads to elevated serum concentrations of cerivastatin, cerivastatin lactone and metabolite M-23, resulting in increased concentrations of active HMG-CoA reductase inhibitors.