Pharmacokinetics and Pharmacodynamics of KR-66223, a Novel DPP-4 Inhibitor

被引:1
作者
Song, Jin Sook [1 ]
Lee, Kyeong-Ryoon [1 ]
Kwon, Hyun Jin [1 ]
Dal Rhee, Sang
Kim, Min Sun [1 ]
Choi, Sung Hum [1 ]
Lee, Sung-Hack [3 ]
Song, Im Sook [2 ]
Ahn, Jin Hee
Ahn, Sung Hoon [1 ]
Bae, Myung Ae [1 ]
机构
[1] Korea Res Inst Chem Technol, Drug Discovery Platform Technol Team, Bioorgan Sci Div, Taejon 305600, South Korea
[2] Inje Univ, Coll Med, Res Ctr, Dept Pharmacol & Pharmacogen, Pusan, South Korea
[3] LG Life Sci R&D, Drug Metab & Pharmacokinet Dept, Taejon, South Korea
关键词
dipeptidyl peptidase-4 inhibitors; KR-66223; pharmacokinetics; pharmacodynamics; allometric scalling; DIPEPTIDYL-PEPTIDASE-IV; CELLS;
D O I
10.2133/dmpk.DMPK-11-RG-095
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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.
引用
收藏
页码:216 / 222
页数:7
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