title: Population pharmacokinetic analysis of dutogliptin, a selective dipeptidyl peptidase-4 inhibitor.
abstract: 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 176 L/h and 12.2 hours, respectively. Typical CL/F values in patients with mild and moderate renal impairment were 121 and 79 L/h, respectively. No drug-drug interaction was observed with metformin. These results suggest that a reduction in dosing from 400 to 200 mg 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.
authors.affiliation: Pharsight, A Certara Company, Montreal, QC, Canada.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Marier
authors.affiliation: Pharsight, A Certara Company, Montreal, QC, Canada.
authors.forename: Mohamad-Samer
authors.initials: MS
authors.lastname: Mouksassi
authors.affiliation: Pharsight, A Certara Company, Montreal, QC, Canada.
authors.forename: Nathalie H
authors.initials: NH
authors.lastname: Gosselin
authors.affiliation: Phenomix Corporation, San Diego, CA, USA.|Ambit Biosciences Corporation, San Diego, CA, USA.
authors.forename: Jianke
authors.initials: J
authors.lastname: Li
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D016903:Drug Monitoring; D005260:Female; D006207:Half-Life; D006801:Humans; D007668:Kidney / Q000503:physiopathology; D007674:Kidney Diseases / Q000175:diagnosis / Q000503:physiopathology; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D017711:Nonlinear Dynamics; D012307:Risk Factors; D055815:Young Adult
chemical_list: D001897:Boronic Acids; D054873:Dipeptidyl-Peptidase IV Inhibitors; C552164:dutogliptin
keywords: DPP-4 inhibitor; dutogliptin; pharmacokinetics; sources of variability