title: Pharmacokinetics and pharmacodynamics of KR-66223, a novel DPP-4 inhibitor.
abstract: KR-66223 is a novel dipeptidyl peptidase-4 (DPP-4) inhibitor that is under development for the treatment of type 2 diabetes. We studied the pharmacokinetic and pharmacodynamic characteristics of KR-66223 in rats, monkeys, and dogs to predict PK/PD profiles in humans. KR-66223 exhibited a moderate volume of distribution (0.3-1.8 L/kg), moderate systemic clearance (1-1.76 L/h/kg), long half-life (>3 h), and low oral bioavailability (below 2.5% in all tested species). The EC(50)s for DPP-4 inhibition as calculated by the E(max) model was below 4.25 ng/mL across all species, confirming KR-66223 as a potent DPP-4 inhibitor. In vitro plasma protein binding suggested that it was available (69-89%), correlating with its volume of distribution in animals. Using allometric scaling and the E(max) model, human systemic clearance, volume of the central compartment, volume of the peripheral compartment, and EC₅₀ for DPP-4 inhibition were predicted to be 0.31 L/h/kg, 0.1 L/kg, 2.4 L/kg, and 3 ng/mL, respectively. These results can serve as a valuable foundation for future clinical trials.
authors.affiliation: Drug Discovery Platform Technology Team, Division of Bio-organic Science, Korea Research Institute of Chemical Technology, Daejeon.
authors.forename: Jin Sook
authors.initials: JS
authors.lastname: Song
authors.forename: Kyeong-Ryoon
authors.initials: KR
authors.lastname: Lee
authors.forename: Hyun Jin
authors.initials: HJ
authors.lastname: Kwon
authors.forename: Sang Dal
authors.initials: SD
authors.lastname: Rhee
authors.forename: Min Sun
authors.initials: MS
authors.lastname: Kim
authors.forename: Sung Hum
authors.initials: SH
authors.lastname: Choi
authors.forename: Sung-Hack
authors.initials: SH
authors.lastname: Lee
authors.forename: Im Sook
authors.initials: IS
authors.lastname: Song
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Ahn
authors.forename: Sung Hoon
authors.initials: SH
authors.lastname: Ahn
authors.forename: Myung Ae
authors.initials: MA
authors.lastname: Bae
mesh_terms: D000818:Animals; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000493:pharmacokinetics*; D004285:Dogs; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D053778:Thiazolidines / Q000493:pharmacokinetics* / Q000494:pharmacology*; D014633:Valine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; C561086:KR 66223; D053778:Thiazolidines; D018819:Dipeptidyl Peptidase 4; D014633:Valine