Rational assessment of the interaction profile of cerivastatin supports its low propensity for drug interactions

Abstract

Pharmacokinetic drug-drug interactions influence drug efficacy, tolerability, and compliance. Such interactions are both more common and of more clinical relevance than often appreciated. The US Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products have recently issued guidelines setting out in vitro and in vivo investigations to be conducted during drug development. These guidelines reflect the increasing interest of public health authorities in this topic. Cerivastatin is a novel, potent HMG-CoA reductase inhibitor that effectively reduces serum cholesterol levels at low daily doses. It is completely absorbed after oral administration, undergoes moderate first-pass metabolism and high plasma protein binding, and is cleared exclusively via hepatic cytochrome P450 (CYP). Unlike other drugs of its class, cerivastatin has a dual metabolic pathway, with the involvement of more than one CYP isozyme. Metabolites are cleared via both biliary and renal excretion. On the basis of this pharmacokinetic profile and a knowledge of the target population, the formal in vivo interaction programme for cerivastatin investigated many important potential cerivastatin drug-drug interactions. Cerivastatin appears to lack clinically relevant interactions with digoxin, warfarin, antacid, cimetidine, nifedipine, omeprazole, erythromycin and itraconazole.