A microdose cocktail containing midazolam, dabigatran etexilate, pitavastatin, rosuvastatin, and atorvastatin has been established to allow simultaneous assessment of a perpetrator impact on the most common drug metabolizing enzyme, cytochrome P450 (CYP)3A, and the major transporters organic anion-transporting polypeptides (OATP)1B, breast cancer resistance protein (BCRP), and MDR1 P-glycoprotein (P-gp). The clinical utility of these microdose cocktail probe substrates was qualified by conducting clinical drug interaction studies with three inhibitors with different in vitro inhibitory profiles (rifampin, itraconazole, and clarithromycin). Generally, the pharmacokinetic profiles of the probe substrates, in the absence and presence of the inhibitors, were comparable to their reported corresponding pharmacological doses, and/or in agreement with theoretical expectations. The exception was dabigatran, which resulted in an approximately twofold higher magnitude for microdose compared to conventional dosing, and, thus, can be used to flag a worst-case scenario for P-gp. Broader application of the microdose cocktail will facilitate a more comprehensive understanding of the roles of drug transporters in drug disposition and drug interactions.

GPR40 mediates free fatty acid–induced insulin secretion in beta cells. We investigated the safety, pharmacokinetics, and glucose response of MK‐8666, a partial GPR40 agonist, after once‐daily multiple dosing in type 2 diabetes patients. This double‐blind, multisite, parallel‐group study randomized 63 patients (placebo, n = 18; 50 mg, n = 9; 150 mg, n = 18; 500 mg, n = 18) for 14‐day treatment. The results showed no serious adverse effects or treatment‐related hypoglycemia. One patient (150‐mg group) showed mild‐to‐moderate transaminitis at the end of dosing. Median MK‐8666 Tmax was 2.0–2.5 h and mean apparent terminal half‐life was 22–32 h. On Day 15, MK‐8666 reduced fasting plasma glucose by 54.1 mg/dL (500 mg), 36.0 mg/dL (150 mg), and 30.8 mg/dL (50 mg) more than placebo, consistent with translational pharmacokinetic/pharmacodynamic model predictions. Maximal efficacy for longer‐term assessment is projected at 500 mg based on exposure–response analysis. In conclusion, MK‐8666 was generally well tolerated with robust glucose‐lowering efficacy.