title: Absolute bioavailability of sitagliptin, an oral dipeptidyl peptidase-4 inhibitor, in healthy volunteers.
abstract: The purpose of this study was to determine the absolute bioavailability of sitagliptin, an orally active, potent and highly selective dipeptidyl peptidase-4 inhibitor recently approved in the United States for the treatment of type 2 diabetes. The effect of a high fat meal on sitagliptin pharmacokinetics was also assessed. The study was performed in two parts. Intravenous doses (2 h infusion) of 25, 50 and 100 mg were administered double-blind to 10 (8 active, 2 placebo) subjects in a fixed-sequence manner in Part I. In Part II, 12 subjects were randomized to each of three open-label treatments: an intravenous 100 mg dose; a single oral 100 mg final market image tablet administered following a high fat meal and a single oral 100 mg final market image tablet administered fasted. Following each dose, plasma and urine were collected at pre-specified times for evaluation of sitagliptin pharmacokinetics. All doses were generally well tolerated in both parts of the study. Following rising intravenous doses of sitagliptin, AUC(0-infinity) increased dose-proportionally, indicating that plasma clearance is independent of dose over the dose range evaluated. Renal clearance of unchanged sitagliptin accounted for approximately 70% of the total plasma clearance of sitagliptin, indicating that sitagliptin is primarily cleared via renal excretion. Averaged across doses, the mean total plasma clearance was 416 ml/min. The mean absolute bioavailability of sitagliptin was 87% with a 90% CI of (81%, 93%). The AUC(0-infinity) and C(max) geometric mean ratios (fed/fasted) and 90% CIs were 1.03 (0.97, 1.11) and 0.94 (0.86, 1.03), respectively, and were contained within the bounds of (0.80, 1.25). Additionally, the high-fat meal had no significant effect on T(max) or apparent terminal t(1/2). Thus, food does not affect the pharmacokinetics of sitagliptin and therefore can be administered without regard to food.
authors.affiliation: Merck & Co Inc, Whitehouse Station, NJ 07065, USA.
authors.forename: Arthur
authors.initials: A
authors.lastname: Bergman
authors.forename: David
authors.initials: D
authors.lastname: Ebel
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.forename: Julie
authors.initials: J
authors.lastname: Stone
authors.forename: Amy
authors.initials: A
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Zeng
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: Stacy
authors.initials: S
authors.lastname: Dilzer
authors.forename: Kenneth
authors.initials: K
authors.lastname: Lasseter
authors.forename: Gary
authors.initials: G
authors.lastname: Herman
authors.forename: John
authors.initials: J
authors.lastname: Wagner
authors.forename: Rajesh
authors.initials: R
authors.lastname: Krishna
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001682:Biological Availability; D018592:Cross-Over Studies; D018819:Dipeptidyl Peptidase 4; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D011719:Pyrazines / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000068900:Sitagliptin Phosphate; D013607:Tablets; D014230:Triazoles / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D004791:Enzyme Inhibitors; D011719:Pyrazines; D013607:Tablets; D014230:Triazoles; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D000068900:Sitagliptin Phosphate