A Clinical Drug-Drug Interaction Study Assessing a Novel Drug Transporter Phenotyping Cocktail With Adefovir, Sitagliptin, Metformin, Pitavastatin, and Digoxin.

Abstract

A new probe drug cocktail containing substrates of important drug transporters was tested for mutual interactions in a clinical trial. The cocktail consisted of (predominant transporter; primary phenotyping metric): 10mg adefovir-dipivoxil (OAT1; renal clearance (CLR )), 100mg sitagliptin (OAT3; CLR ), 500mg metformin (several renal transporters; CLR ), 2mg pitavastatin (OATP1B1; clearance/F), and 0.5mg digoxin (intestinal P-gp, renal P-gp, and OATP4C1; peak plasma concentration (Cmax ) and CLR ). Using a randomized six-period, open change-over design, single oral doses were administrated either concomitantly or separately to 24 healthy male and female volunteers. Phenotyping metrics were evaluated by noncompartmental analysis and compared between periods by the standard average bioequivalence approach (boundaries for ratios 0.80-1.25). Primary metrics supported the absence of relevant interactions, whereas secondary metrics suggested that mainly adefovir was a victim of minor drug-drug interactions (DDIs). All drugs were well tolerated. This cocktail may be another useful tool to assess transporter-based DDIs invivo.