Quantitative prediction of human pharmacokinetics and pharmacodynamics of imigliptin, a novel DPP-4 inhibitor, using allometric scaling, IVIVE and PK/PD modeling methods.

Abstract Purpose To predict the pharmacokinetic/pharmacodynamic (PK/PD) profiles of imigliptin, a novel DPP-4 inhibitor, in first-in-human (FIH) study based on the data from preclinical species. Methods Imigliptin was intravenously and orally administered to rats, dogs, and monkeys to assess their PK/PD properties. DPP-4 activity was the PD biomarker. PK/PD profiles of sitagliptin and alogliptin in rats and humans were obtained and digitized from literatures. PK/PD profiles of all dose levels for each drug in each species were analyzed using modeling approach. Human CL , V ss and PK profiles of imigliptin were then predicted using Allometric Scaling (AS), in vitro in vivo extrapolation (IVIVE), and the steady-state plasma drug concentration – mean residence time ( C ss - MRT ) methods. In vitro EC 50 corrected by f u and in vivo EC 50 in rats corrected by interspecies difference of sitagliptin and alogliptin were utilized separately to predict imigliptin human EC 50 . The prediction by integrating all above methods was evaluated by comparing observed and simulated PK/PD profiles in healthy subjects. Results Full PK/PD profiles in animal were summarized for imigliptin, sitagliptin and alogliptin. Imigliptin CL , V ss , and F a were predicted to be 19.1 L/h, 247 L, and 0.81 in humans, respectively. Predicted imigliptin AUCs, AUECs, and E max in humans were within 0.8–1.2 times of observed values whereas other predicted PK/PD parameters were within 0.5–1.5 times of observed values. Conclusions By integrating available preclinical and clinical data, FIH PK/PD profiles of imigliptin could be accurately predicted.