HD-6277, a selective GPR40 agonist, enhances glucose-stimulated insulin secretion and improves hyperglycemia. We have investigated the accuracy of the in-vivo correlation between rat and human to predict the total systemic clearance (CL), the volume of distribution at steady state (Vss), and the half-life (t1/2) using simple allometric scaling techniques. We compared the in vivo pharmacokinetic parameters of HD-6277 in rat, monkey and dog, following single oral administrations by gavage. Human liver microsome was used to confirm metabolic stability in human. The monkey showed the lowest Tmax of 0.67 h and the rat, the highest value of 4 h. A 1.5- to 6-fold greater dose-normalized Cmax was observed in the dog compared to the other species. The dog showed the highest dose-normalized AUC, which was 1.5- to 3 fold greater than that for the rat and monkey both of which by approximation, recorded the lowest value. The Cl/F increased across species from 0.02 L/h for rat to 0.38 L/h for dog. The rat showed the lowest VD/F of 0.06 L and the dog, the highest VD/F of 0.82 L. The calculated extraction ratios were 0.02, 0.12 and 0.38 for rat, monkey and dog, respectively. The rat showed the lowest terminal half-life of 2.4 h and the monkey, the highest value of 5.62 h. The simple allometric human VD/F and Cl/F were 2.515 L and 1.325 L/h. Overall, a species-specific difference was observed for Cl/F with this parameter increasing across species from rat to dog. We will use this allometric scaling to determine the clinical dose.

Prediction of drug metabolism and in vivo pharmacokinetics of HD-6277 (a Novel GPR40 Agonist) in human