Prediction of pharmacokinetics and pharmacodynamics of trelagliptin and omarigliptin in healthy humans and in patients with renal impairment using physiologically based pharmacokinetic combined DPP-4 occupancy modeling

被引：6

作者：

Wu, Chunnuan ^{[1
]}

Liu, Huining ^{[2
]}

Yu, Shuang ^{[2
]}

Ren, Congcong ^{[3
]}

Zhang, Jie ^{[1
,5
]}

Wang, Guopeng ^{[4
,6
]}

Li, Bole ^{[1
,5
]}

Liu, Yang ^{[2
,7
]}

机构：

[1] Tianjin Med Univ Canc Inst & Hosp, Natl Clin Res Ctr Canc, Tianjins Clin Res Ctr Canc, Key Lab Canc Prevent & Therapy, Tianjin 300060, Peoples R China

[2] Beijing Univ Chinese Med, Sch Chinese Mat Med, Beijing 100102, Peoples R China

[3] Liaocheng Peoples Hosp, Dept Pharm, Liaocheng 252000, Peoples R China

[4] Zhongcai Hlth Beijing Biol Technol Dev Co Ltd, Beijing 101500, Peoples R China

[5] Tianjin Med Univ Canc Inst & Hosp, 45 Binshuidao, Tianjin 300060, Peoples R China

[6] Zhongcai Hlth Beijing Biol Technol Dev Co Ltd, Xingsheng South Rd, Beijing 101520, Peoples R China

[7] Beijing Univ Chinese Med, Sch Chinese Mat Med, Sunshine South St, Beijing 102488, Peoples R China

来源：

BIOMEDICINE & PHARMACOTHERAPY | 2022年 / 153卷

基金：

中国国家自然科学基金;

关键词：

Trelagliptin; Omarigliptin; Renal impairment simulation; DPP-4; occupancy; PBPK-DO model; DIPEPTIDYL PEPTIDASE-4 INHIBITOR; TYPE-2; DIABETES-MELLITUS; 1ST; EFFICACY; MK-3102; SAFETY;

D O I：

10.1016/j.biopha.2022.113509

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Background: This study aimed to build a mathematical model of physiologically based pharmacokinetic combined DPP-4 occupancy (PBPK-DO) in humans to provide some recommendations for dosing adjustment in patients with renal impairment. Methods: The PBPK-DO model was built using physicochemical and biochemical properties and binding kinetics data of TRE and OMA, and then validated by the clinically observed pharmacokinetics (PK) and pharmacodynamics (PD). Finally, the model was applied to determine dose adjustment in patients with renal impairment. Results: The predicted PK and DPP-4 occupancy matched well with the clinically observed data, and all absolute average-folding errors (AAFEs) were within 2. The simulations showed that TRE and OMA were both suggested to only support dose reduction by half in patients with severe renal impairment based on this PBPK-DO model, which is different from the commendations only in terms of their AUC0-336 changes. These simulation results were in good agreement with clinical recommendations about dosage adjustment in patients. Conclusion: The present PBPK-DO model can simultaneously predict PK and PD of TRE and OMA in humans and also provide valuable recommendations for dosing adjustment in renal impairment patients, which cannot be achieved by alone depending on PK change.

引用

页数：11

共 31 条

[1] Effects of Age, Sex, and Obesity on the Single-Dose Pharmacokinetics of Omarigliptin in Healthy Subjects [J].