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Effect of renal impairment on the pharmacokinetics and safety of dorzagliatin, a novel dual‐acting glucokinase activator

Dorzagliatin is a novel allosteric glucokinase activator targeting both pancreatic and hepatic glucokinase currently under clinical investigation for treatment of type 2 diabetes (T2D). This study aimed to investigate the effect of renal impairment (RI) on dorzagliatin’s pharmacokinetics (PKs) and s...

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Autores principales: Miao, Jia, Fu, Ping, Ren, Shuang, Hu, Chao, Wang, Ying, Jiao, Chengfeng, Li, Ping, zhao, Yu, Tang, Cui, Qian, Yuli, Yang, Rong, Dong, Yanli, Rong, Jing, Wang, Yaohui, Jin, Xiaowei, Sun, Yu, Chen, Li
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8841463/
https://www.ncbi.nlm.nih.gov/pubmed/34706161
http://dx.doi.org/10.1111/cts.13174
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author Miao, Jia
Fu, Ping
Ren, Shuang
Hu, Chao
Wang, Ying
Jiao, Chengfeng
Li, Ping
zhao, Yu
Tang, Cui
Qian, Yuli
Yang, Rong
Dong, Yanli
Rong, Jing
Wang, Yaohui
Jin, Xiaowei
Sun, Yu
Chen, Li
author_facet Miao, Jia
Fu, Ping
Ren, Shuang
Hu, Chao
Wang, Ying
Jiao, Chengfeng
Li, Ping
zhao, Yu
Tang, Cui
Qian, Yuli
Yang, Rong
Dong, Yanli
Rong, Jing
Wang, Yaohui
Jin, Xiaowei
Sun, Yu
Chen, Li
author_sort Miao, Jia
collection PubMed
description Dorzagliatin is a novel allosteric glucokinase activator targeting both pancreatic and hepatic glucokinase currently under clinical investigation for treatment of type 2 diabetes (T2D). This study aimed to investigate the effect of renal impairment (RI) on dorzagliatin’s pharmacokinetics (PKs) and safety, and to guide appropriate clinical dosing in patients with diabetic kidney disease, including end‐stage renal disease (ESRD). Based on the results from physiologically‐based pharmacokinetic modeling, the predicted outcome of RI on dorzagliatin PK property would be minimum that the plasma exposure area under concentration (AUC) of dorzagliatin in patients with ESRD would increase at about 30% with minimal change in peak concentration (C(max)) comparing to those in healthy volunteers (HVs). To definitively confirm the prediction, a two‐part RI study was designed and conducted based on regulatory guidance starting with the patients with ESRD matched with HVs. Results of the RI study showed minimum difference between patients with ESRD and HVs with respect to dorzagliatin exposure with geometric mean ratio of ESRD to HV at 0.81 for C(max) and 1.11 for AUC. The elimination half‐life, volume of distribution, and systemic clearance for dorzagliatin were similar between the two groups. Dorzagliatin was well‐tolerated in patients with ESRD during the study. Therefore, RI showed no significant impact on dorzagliatin PK, suggesting that dorzagliatin can be readily used in patients with T2D at all stages of RI without need for dose adjustment.
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spelling pubmed-88414632022-02-22 Effect of renal impairment on the pharmacokinetics and safety of dorzagliatin, a novel dual‐acting glucokinase activator Miao, Jia Fu, Ping Ren, Shuang Hu, Chao Wang, Ying Jiao, Chengfeng Li, Ping zhao, Yu Tang, Cui Qian, Yuli Yang, Rong Dong, Yanli Rong, Jing Wang, Yaohui Jin, Xiaowei Sun, Yu Chen, Li Clin Transl Sci Research Dorzagliatin is a novel allosteric glucokinase activator targeting both pancreatic and hepatic glucokinase currently under clinical investigation for treatment of type 2 diabetes (T2D). This study aimed to investigate the effect of renal impairment (RI) on dorzagliatin’s pharmacokinetics (PKs) and safety, and to guide appropriate clinical dosing in patients with diabetic kidney disease, including end‐stage renal disease (ESRD). Based on the results from physiologically‐based pharmacokinetic modeling, the predicted outcome of RI on dorzagliatin PK property would be minimum that the plasma exposure area under concentration (AUC) of dorzagliatin in patients with ESRD would increase at about 30% with minimal change in peak concentration (C(max)) comparing to those in healthy volunteers (HVs). To definitively confirm the prediction, a two‐part RI study was designed and conducted based on regulatory guidance starting with the patients with ESRD matched with HVs. Results of the RI study showed minimum difference between patients with ESRD and HVs with respect to dorzagliatin exposure with geometric mean ratio of ESRD to HV at 0.81 for C(max) and 1.11 for AUC. The elimination half‐life, volume of distribution, and systemic clearance for dorzagliatin were similar between the two groups. Dorzagliatin was well‐tolerated in patients with ESRD during the study. Therefore, RI showed no significant impact on dorzagliatin PK, suggesting that dorzagliatin can be readily used in patients with T2D at all stages of RI without need for dose adjustment. John Wiley and Sons Inc. 2021-11-11 2022-02 /pmc/articles/PMC8841463/ /pubmed/34706161 http://dx.doi.org/10.1111/cts.13174 Text en © 2021 Hua medicine (Shangai) Ltd. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Research
Miao, Jia
Fu, Ping
Ren, Shuang
Hu, Chao
Wang, Ying
Jiao, Chengfeng
Li, Ping
zhao, Yu
Tang, Cui
Qian, Yuli
Yang, Rong
Dong, Yanli
Rong, Jing
Wang, Yaohui
Jin, Xiaowei
Sun, Yu
Chen, Li
Effect of renal impairment on the pharmacokinetics and safety of dorzagliatin, a novel dual‐acting glucokinase activator
title Effect of renal impairment on the pharmacokinetics and safety of dorzagliatin, a novel dual‐acting glucokinase activator
title_full Effect of renal impairment on the pharmacokinetics and safety of dorzagliatin, a novel dual‐acting glucokinase activator
title_fullStr Effect of renal impairment on the pharmacokinetics and safety of dorzagliatin, a novel dual‐acting glucokinase activator
title_full_unstemmed Effect of renal impairment on the pharmacokinetics and safety of dorzagliatin, a novel dual‐acting glucokinase activator
title_short Effect of renal impairment on the pharmacokinetics and safety of dorzagliatin, a novel dual‐acting glucokinase activator
title_sort effect of renal impairment on the pharmacokinetics and safety of dorzagliatin, a novel dual‐acting glucokinase activator
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8841463/
https://www.ncbi.nlm.nih.gov/pubmed/34706161
http://dx.doi.org/10.1111/cts.13174
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