Itraconazole alters the pharmacokinetics of atorvastatin to a greater extent than either cerivastatin or pravastatin

Background 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (stat ins) are metabolized by distinct pathways that may alter the extent of drug -drug interactions. Cerivastatin is metabolized by cytochrome P450 (CYP)3A4 and CYP2C8. Atorvastatin is metabolized solely by CYP3A4, and pravastatin metabolism is not well defined. Coadministration of higher doses of these s tatins with CYP3A4 inhibitors has the potential for eliciting adverse drug- drug interactions. Objective: To determine the comparative effect of intraconazole, a potent C YP3A4 inhibitor, on the pharmacokinetics of cerivastatin, atorvastatin, and pravastatin. Methods: In this single-site, randomized, three-way crossover, open-labeled study, healthy subjects (n = 18) received single doses of cerivastatin 0.8 mg, atorvastatin 20 mg, or pravastatin 40 mg without and with itraconazole 200 mg. Pharmacokinetic parameters [AUC(0-infinity), AUC(0-tn), peak conce ntration (C-max), time to reach C-max (t(max)), and half-life (t(1/2))] wer e determined for parent statins and major metabolites. Results: Concomitant cerivastatin/itraconazole treatment produced small ele vations in the cerivastatin AUC(0-infinity), C-max, and t(1/2) (27%, 25%, a nd 19%, respectively; P < .05 versus cerivastatin alone). Itraconazole coad ministration produced similar changes in pravastatin pharmacokinetics [AUC elevated 51% (P < .05 versus pravastatin alone), 24% (C-max), and 23% (t(1/ 2)), respectively]. However, itraconazole dramatically increased atorvastat in AUC (150%), C-max (38%), and t(1/2) (30%) (P < .05). The elevation in at orvastatin AUC was significantly greater than that of cerivastatin (P < .00 5) or pravastatin (P < .005). Conclusion: Itraconazole markedly elevated atorvastatin plasma levels (2.5- fold) after 20 mg dosing, suggesting that concomitant itraconazole/atorvast atin therapy be carefully considered. Itraconazole produced modest elevatio ns in the plasma levels of cerivastatin 0.8 mg or pravastatin 40 mg (1.3-fo ld and 1.5-fold, respectively), indicating that combination treatment with itraconazole with cerivastatin or pravastatin may be preferable.