Population pharmacokinetic analysis of dutogliptin, a selective dipeptidyl peptidase-4 inhibitor

摘要

Dutogliptin is a selective dipeptidyl peptidase-4 inhibitor shown to be efficacious and safe in patients with type 2 diabetes mellitus (T2DM). Population pharmacokinetic (PK) analysis of dutogliptin was performed based on data collected in 561 healthy subjects and patients with T2DM enrolled in Phase I and II studies to assess sources of variability and support dosing rationale. The effect of extrinsic (formulations, fed/fasting conditions, potential drug-drug interaction with metformin) and intrinsic (baseline characteristics, markers of renal function, renal impairment category, and disease status) covariates was evaluated using non-linear mixed effect modeling. Plasma concentrations of dutogliptin were best fitted with a two-compartment model with a first-order rate constant of absorption (Ka) and a lag time. No differences were observed between healthy subjects and patients with T2DM. Apparent clearance (CL/F) and terminal elimination half-life of dutogliptin were 176L/h and 12.2hours, respectively. Typical CL/F values in patients with mild and moderate renal impairment were 121 and 79L/h, respectively. No drug-drug interaction was observed with metformin. These results suggest that a reduction in dosing from 400 to 200mg daily is warranted in T2DM patients with moderate renal impairment. No dose adjustments were deemed necessary for other evaluated patient characteristics and coadministration with metformin.