PMID- 34045960 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20210530 IS - 1663-9812 (Print) IS - 1663-9812 (Electronic) IS - 1663-9812 (Linking) VI - 12 DP - 2021 TI - Development of a Virtual Chinese Pediatric Population Physiological Model Targeting Specific Metabolism and Kidney Elimination Pathways. PG - 648697 LID - 10.3389/fphar.2021.648697 [doi] LID - 648697 AB - Background: Physiologically based pharmacokinetic (PBPK) modeling and simulating may be a powerful tool in predicting drug behaviors in specific populations. It is a mathematical model that relates the pharmacokinetic (PK) profile of a compound with human anatomical characteristics, physiological characteristics, and biochemical parameters. Predictions using PBPK models offer a promising way to guide drug development and can be used to optimize clinical dosing regimens. However, PK data of new drugs in the pediatric population are too limited to guide clinical therapy, which may lead to frequent adverse events or insufficient efficacy for pediatric patients, particularly in neonates and infants. Objective: The objective of this study was to establish a virtual Chinese pediatric population based on the physiological parameters of Chinese children that could be utilized in PBPK models. Methods: A Chinese pediatric PBPK model was developed in Simcyp Simulator by collecting published Chinese pediatric physiological and anthropometric data to use as system parameters. This pediatric population model was then evaluated in the Chinese pediatric population by predicting the pharmacokinetic characteristics of four probe drugs: theophylline (major CYP1A2 substrate), fentanyl (major CYP3A4 substrate), vancomycin, and ceftazidime (renal-eliminated). Results: The predicted maximum concentration (C(max)), area under the curve of concentration-time (AUC), and clearance (CL) for theophylline (CYP1A2 metabolism pathway) and fentanyl (CYP3A4 metabolism pathway) were within two folds of the observed data. For drugs mainly eliminated by renal clearance (vancomycin and ceftazidime) in the Chinese pediatric population, the ratio of prediction to observation for major PK parameters was within a 2-fold error range. Conclusion: The model is a supplement to the previous Chinese population PBPK model. We anticipate the model to be a better representative of the pediatric Chinese population for drugs PK, offering greater clinical precision for medication given to the pediatric population, ultimately advancing clinical development of pediatric drugs. We can refine this model further by collecting more physiological parameters of Chinese children. CI - Copyright (c) 2021 Yao, Liu, Tu, Li, Lei, Hou, Yu, Cui, Dong, Salem, Li and Liu. FAU - Yao, Xueting AU - Yao X AD - Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China. FAU - Liu, Xuanlin AU - Liu X AD - Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China. AD - School of Pharmaceutical Sciences, Tsinghua University, Beijing, China. FAU - Tu, Siqi AU - Tu S AD - Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China. AD - School of Pharmaceutical Sciences, Peking University Health Science Center, Peking University, Beijing, China. FAU - Li, Xiaobei AU - Li X AD - Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China. AD - School of Pharmaceutical Sciences, Peking University Health Science Center, Peking University, Beijing, China. FAU - Lei, Zihan AU - Lei Z AD - Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China. AD - School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China. FAU - Hou, Zhe AU - Hou Z AD - Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China. AD - School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China. FAU - Yu, Zhiheng AU - Yu Z AD - Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China. FAU - Cui, Cheng AU - Cui C AD - Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China. FAU - Dong, Zhongqi AU - Dong Z AD - Janssen China R&D Center, Shanghai, China. FAU - Salem, Farzaneh AU - Salem F AD - Certara UK Limited, Simcyp Division, Sheffield, United Kingdom. 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 - Liu, Dongyang AU - Liu D AD - Drug Clinical Trial Center, Peking University Third Hospital, Beijing, China. LA - eng PT - Journal Article DEP - 20210511 PL - Switzerland TA - Front Pharmacol JT - Frontiers in pharmacology JID - 101548923 PMC - PMC8145459 OTO - NOTNLM OT - CYP1A2 OT - CYP3A4 OT - Chinese pediatric population OT - PBPK OT - pharmacokinetics OT - renal elimination COIS- Author FS was employed by the company Certara UK Limited. Author ZD was employed by company Janssen China R&D Center. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2021/05/29 06:00 MHDA- 2021/05/29 06:01 PMCR- 2021/05/11 CRDT- 2021/05/28 07:23 PHST- 2021/01/01 00:00 [received] PHST- 2021/03/23 00:00 [accepted] PHST- 2021/05/28 07:23 [entrez] PHST- 2021/05/29 06:00 [pubmed] PHST- 2021/05/29 06:01 [medline] PHST- 2021/05/11 00:00 [pmc-release] AID - 648697 [pii] AID - 10.3389/fphar.2021.648697 [doi] PST - epublish SO - Front Pharmacol. 2021 May 11;12:648697. doi: 10.3389/fphar.2021.648697. eCollection 2021.