PMID- 37078371
OWN - NLM
STAT- MEDLINE
DCOM- 20230717
LR  - 20231116
IS  - 2163-8306 (Electronic)
IS  - 2163-8306 (Linking)
VI  - 12
IP  - 7
DP  - 2023 Jul
TI  - Development of a PBPK model to quantitatively understand absorption and 
      disposition mechanism and support future clinical trials for PB-201.
PG  - 941-952
LID - 10.1002/psp4.12964 [doi]
AB  - PB-201 is the second glucokinase activator in the world to enter the phase III 
      clinical trials for the treatment of type 2 diabetes mellitus (T2DM). Combined 
      with the efficacy advantages and the friendly absorption, distribution, 
      metabolism, and excretion characteristics, the indication population of PB-201 
      will be broad. Because the liver is the primary organ for PB-201 elimination, and 
      the elderly account for 20% of patients with T2DM, it is essential to estimate 
      PB-201 exposure in specific populations to understand the pharmacokinetic 
      characteristics and avoid hypoglycemia. Despite the limited contribution of 
      CYP3A4 to PB-201 metabolism in vivo, the dual effects of nonspecific 
      inhibitors/inducers on PB-201 (substrate for CYP3A4 and CYP2C9 isoenzymes) 
      exposure under fasted and fed states also need to be evaluated to understand 
      potential risks of combination therapy. To grasp the unknown information, the 
      physiologically-based pharmacokinetic (PBPK) model was first developed and the 
      influence of internal and external factors on PB-201 exposure was evaluated. 
      Results are shown that the predictive performance of the mechanistic PBPK model 
      meets the predefined criteria, and can accurately capture the absorption and 
      disposition characteristics. Impaired liver function and age-induced changes in 
      physiological factors may significantly increase the exposure under fasted state 
      by 36%-158% and 48%-82%, respectively. The nonspecific inhibitor (fluconazole) 
      and inducer (rifampicin) may separately increase/decrease PB-201 systemic 
      exposure by 44% and 58% under fasted state, and by 78% and 47% under fed state. 
      Therefore, the influence of internal and external factors on PB-201 exposure 
      deserves attention, and the precision dose can be informed in future clinical 
      studies based on the predicted results.
CI  - (c) 2023 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by 
      Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and 
      Therapeutics.
FAU - Zhang, Miao
AU  - Zhang M
AUID- ORCID: 0000-0002-6132-133X
AD  - Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China.
AD  - Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical 
      Sciences, University at Buffalo, The State University of New York, Buffalo, New 
      York, USA.
FAU - Lei, Zihan
AU  - Lei Z
AD  - Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China.
FAU - Yu, Ziheng
AU  - Yu Z
AD  - Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China.
AD  - Department of Obstetrics and Gynecology, Peking University Third Hospital, 
      Beijing, China.
FAU - Yao, Xueting
AU  - Yao X
AD  - Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China.
FAU - Li, Haiyan
AU  - Li H
AD  - Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China.
AD  - Department of Cardiology and Institute of Vascular Medicine, Peking University 
      Third Hospital, Beijing, China.
FAU - Xu, Min
AU  - Xu M
AD  - PegBio Co., Ltd., Suzhou, Jiangsu, China.
FAU - Liu, Dongyang
AU  - Liu D
AUID- ORCID: 0000-0002-0608-8192
AD  - Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China.
LA  - eng
PT  - Journal Article
DEP - 20230420
PL  - United States
TA  - CPT Pharmacometrics Syst Pharmacol
JT  - CPT: pharmacometrics & systems pharmacology
JID - 101580011
RN  - EC 1.14.14.1 (Cytochrome P-450 CYP3A)
RN  - VJT6J7R4TR (Rifampin)
SB  - IM
MH  - Humans
MH  - Aged
MH  - *Diabetes Mellitus, Type 2/drug therapy
MH  - Cytochrome P-450 CYP3A/metabolism
MH  - Drug Interactions
MH  - Computer Simulation
MH  - Rifampin/pharmacokinetics
MH  - Models, Biological
PMC - PMC10349193
COIS- M.X. is employed by PegBio Co., Ltd. All other authors declared no competing 
      interests for this work.
EDAT- 2023/04/20 06:42
MHDA- 2023/07/17 06:42
PMCR- 2023/04/20
CRDT- 2023/04/20 05:23
PHST- 2023/03/11 00:00 [revised]
PHST- 2022/10/30 00:00 [received]
PHST- 2023/03/18 00:00 [accepted]
PHST- 2023/07/17 06:42 [medline]
PHST- 2023/04/20 06:42 [pubmed]
PHST- 2023/04/20 05:23 [entrez]
PHST- 2023/04/20 00:00 [pmc-release]
AID - PSP412964 [pii]
AID - 10.1002/psp4.12964 [doi]
PST - ppublish
SO  - CPT Pharmacometrics Syst Pharmacol. 2023 Jul;12(7):941-952. doi: 
      10.1002/psp4.12964. Epub 2023 Apr 20.