title: Pharmacokinetics of the dipeptidyl peptidase 4 inhibitor saxagliptin in rats, dogs, and monkeys and clinical projections.
abstract: Saxagliptin is a potent, selective, reversible dipeptidyl peptidase 4 (DPP4) inhibitor specifically designed for extended inhibition of the DPP4 enzyme and is currently under development for the treatment of type-2 diabetes. The pharmacokinetics of saxagliptin were evaluated in rats, dogs, and monkeys and used to predict its human pharmacokinetics. Saxagliptin was rapidly absorbed and had good bioavailability (50-75%) in the species tested. The plasma clearance of saxagliptin was higher in rats (115 ml/min/kg) than in dogs (9.3 ml/min/kg) and monkeys (14.5 ml/min/kg) and was predicted to be low to moderate in humans. The plasma elimination half-life was between 2.1 and 4.4 h in rats, dogs, and monkeys, and both metabolism and renal excretion contributed to the overall elimination. The primary metabolic clearance pathway involved the formation of a significant circulating, pharmacologically active hydroxylated metabolite, M2. The volume of distribution values observed in rats, dogs, and monkeys (1.3-5.2 l/kg) and predicted for humans (2.7 l/kg) were greater than those for total body water, indicating extravascular distribution. The in vitro serum protein binding was low (< or =30%) in rats, dogs, monkeys, and humans. After intra-arterial administration of saxagliptin to Sprague-Dawley and Zucker diabetic fatty rats, higher levels of saxagliptin and M2 were observed in the intestine (a proposed major site of drug action) relative to that in plasma. Saxagliptin has prolonged pharmacodynamic properties relative to its plasma pharmacokinetic profile, presumably due to additional contributions from M2, distribution of saxagliptin and M2 to the intestinal tissue, and prolonged dissociation of both saxagliptin and M2 from DPP4.
authors.affiliation: Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Research and Development, Princeton, NJ 08543-4000, USA. aberra.fura@bms.com
authors.forename: Aberra
authors.initials: A
authors.lastname: Fura
authors.forename: Ashish
authors.initials: A
authors.lastname: Khanna
authors.forename: Viral
authors.initials: V
authors.lastname: Vyas
authors.forename: Barry
authors.initials: B
authors.lastname: Koplowitz
authors.forename: Shu-Ying
authors.initials: SY
authors.lastname: Chang
authors.forename: Christian
authors.initials: C
authors.lastname: Caporuscio
authors.forename: David W
authors.initials: DW
authors.lastname: Boulton
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Christopher
authors.forename: Kristina D
authors.initials: KD
authors.lastname: Chadwick
authors.forename: Lawrence G
authors.initials: LG
authors.lastname: Hamann
authors.forename: W Griffith
authors.initials: WG
authors.lastname: Humphreys
authors.forename: Mark
authors.initials: M
authors.lastname: Kirby
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000818:Animals; D001682:Biological Availability; D004151:Dipeptides / Q000493:pharmacokinetics*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000493:pharmacokinetics*; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D006207:Half-Life; D000882:Haplorhini; D006801:Humans; D008657:Metabolic Clearance Rate; D008862:Microsomes, Liver / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D013045:Species Specificity
chemical_list: D004151:Dipeptides; D054873:Dipeptidyl-Peptidase IV Inhibitors; C502994:saxagliptin; D000218:Adamantane