Drug-drug interaction studies in preclinical species: should metabolite(s) kinetics be studied?

Drug-drug interaction studies are important building blocks in drug development to understand the perceived risk of a purported interaction due to the differing clinical pharmacology attributes of the co-administered drugs. Two case studies are presented that justify the importance of evaluating the metabolite kinetics data along with the parent in a preclinical model. Atorvastatin and verapamil have interesting clinical pharmacology attributes in that both agents are substrates and/or inhibitors of the dual cytochrome P450 (CYP) 3A4 and P-glycoprotein (Pgp) efflux transporter interplay. As articulated by the two case studies, the presence of metabolite kinetic data (i.e., norverapamil) provided unequivocal evidence in order to tease out the actual pathway responsible for the interaction between atorvastatin and verapamil. Therefore, consideration for metabolite kinetics, wherever feasible, appears to be prudent in defining the interaction liability between the two agents in a preclinical model.