Xinyue Zhang, Hao Xue, Jialei Xu, Ke Ren, Fangyi Qian, Yifan Zhang, Jingru Dou, Kai Shen, Xiao Zhu, Xiaoqiang Xiang, Qingfeng He
{"title":"儿童Henagliflozin给药的生理药代动力学和经验药效学建模:对中国患者的临床见解。","authors":"Xinyue Zhang, Hao Xue, Jialei Xu, Ke Ren, Fangyi Qian, Yifan Zhang, Jingru Dou, Kai Shen, Xiao Zhu, Xiaoqiang Xiang, Qingfeng He","doi":"10.1155/pedi/8857248","DOIUrl":null,"url":null,"abstract":"<p><p><b>Objective:</b> This study aimed to present a quantitative modeling and simulation approach for oral henagliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor primarily metabolized by uridine diphosphate-glucuronosyltransferase (UGT) enzymes. <b>Methods:</b> A physiologically-based pharmacokinetic (PBPK) model for henagliflozin was developed using in vitro metabolism and clinical pharmacokinetic (PK) data, with validation across multiple contexts, including healthy adults, and hepatic impairment populations. Additionally, empirical pharmacodynamic (PD) modeling was employed to optimize pediatric dosing based on exposure-response relationships for urinary glucose excretion (UGE). Predicting henagliflozin exposure in pediatric patients poses challenges due to UGT enzyme ontogeny and the scarcity of clinical PK data in younger age groups. Using twofold acceptance criteria, model-predicted and observed drug exposures and PK parameters (area under the curve and peak concentration) were compared in diverse scenarios, including monotherapy in healthy adults (single/multiple doses), hepatic impairment, and extrapolation to pediatric age groups. <b>Results:</b> The PBPK model accurately captured observed exposures within a twofold range in both adults and adolescents, supporting the model's predictive utility. The verified PBPK and empirical PD models informed dosing recommendations in pediatric populations aged 1 month to 18 years, achieving henagliflozin exposures comparable to those in adult patients receiving a 5-10 mg dose. <b>Conclusion:</b> This study shows that PBPK and PD modeling effectively guide pediatric dosing of henagliflozin, reducing trial reliance and supporting real-world validation.</p>","PeriodicalId":19797,"journal":{"name":"Pediatric Diabetes","volume":"2025 ","pages":"8857248"},"PeriodicalIF":5.6000,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12352996/pdf/","citationCount":"0","resultStr":"{\"title\":\"Physiologically-Based Pharmacokinetics and Empirical Pharmacodynamic Modeling for Pediatric Henagliflozin Dosing: Clinical Insights for Chinese Patients.\",\"authors\":\"Xinyue Zhang, Hao Xue, Jialei Xu, Ke Ren, Fangyi Qian, Yifan Zhang, Jingru Dou, Kai Shen, Xiao Zhu, Xiaoqiang Xiang, Qingfeng He\",\"doi\":\"10.1155/pedi/8857248\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p><b>Objective:</b> This study aimed to present a quantitative modeling and simulation approach for oral henagliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor primarily metabolized by uridine diphosphate-glucuronosyltransferase (UGT) enzymes. <b>Methods:</b> A physiologically-based pharmacokinetic (PBPK) model for henagliflozin was developed using in vitro metabolism and clinical pharmacokinetic (PK) data, with validation across multiple contexts, including healthy adults, and hepatic impairment populations. Additionally, empirical pharmacodynamic (PD) modeling was employed to optimize pediatric dosing based on exposure-response relationships for urinary glucose excretion (UGE). Predicting henagliflozin exposure in pediatric patients poses challenges due to UGT enzyme ontogeny and the scarcity of clinical PK data in younger age groups. Using twofold acceptance criteria, model-predicted and observed drug exposures and PK parameters (area under the curve and peak concentration) were compared in diverse scenarios, including monotherapy in healthy adults (single/multiple doses), hepatic impairment, and extrapolation to pediatric age groups. <b>Results:</b> The PBPK model accurately captured observed exposures within a twofold range in both adults and adolescents, supporting the model's predictive utility. The verified PBPK and empirical PD models informed dosing recommendations in pediatric populations aged 1 month to 18 years, achieving henagliflozin exposures comparable to those in adult patients receiving a 5-10 mg dose. <b>Conclusion:</b> This study shows that PBPK and PD modeling effectively guide pediatric dosing of henagliflozin, reducing trial reliance and supporting real-world validation.</p>\",\"PeriodicalId\":19797,\"journal\":{\"name\":\"Pediatric Diabetes\",\"volume\":\"2025 \",\"pages\":\"8857248\"},\"PeriodicalIF\":5.6000,\"publicationDate\":\"2025-08-07\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12352996/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Pediatric Diabetes\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1155/pedi/8857248\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q2\",\"JCRName\":\"ENDOCRINOLOGY & METABOLISM\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pediatric Diabetes","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1155/pedi/8857248","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
Physiologically-Based Pharmacokinetics and Empirical Pharmacodynamic Modeling for Pediatric Henagliflozin Dosing: Clinical Insights for Chinese Patients.
Objective: This study aimed to present a quantitative modeling and simulation approach for oral henagliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor primarily metabolized by uridine diphosphate-glucuronosyltransferase (UGT) enzymes. Methods: A physiologically-based pharmacokinetic (PBPK) model for henagliflozin was developed using in vitro metabolism and clinical pharmacokinetic (PK) data, with validation across multiple contexts, including healthy adults, and hepatic impairment populations. Additionally, empirical pharmacodynamic (PD) modeling was employed to optimize pediatric dosing based on exposure-response relationships for urinary glucose excretion (UGE). Predicting henagliflozin exposure in pediatric patients poses challenges due to UGT enzyme ontogeny and the scarcity of clinical PK data in younger age groups. Using twofold acceptance criteria, model-predicted and observed drug exposures and PK parameters (area under the curve and peak concentration) were compared in diverse scenarios, including monotherapy in healthy adults (single/multiple doses), hepatic impairment, and extrapolation to pediatric age groups. Results: The PBPK model accurately captured observed exposures within a twofold range in both adults and adolescents, supporting the model's predictive utility. The verified PBPK and empirical PD models informed dosing recommendations in pediatric populations aged 1 month to 18 years, achieving henagliflozin exposures comparable to those in adult patients receiving a 5-10 mg dose. Conclusion: This study shows that PBPK and PD modeling effectively guide pediatric dosing of henagliflozin, reducing trial reliance and supporting real-world validation.
期刊介绍:
Pediatric Diabetes is a bi-monthly journal devoted to disseminating new knowledge relating to the epidemiology, etiology, pathogenesis, management, complications and prevention of diabetes in childhood and adolescence. The aim of the journal is to become the leading vehicle for international dissemination of research and practice relating to diabetes in youth. Papers are considered for publication based on the rigor of scientific approach, novelty, and importance for understanding mechanisms involved in the epidemiology and etiology of this disease, especially its molecular, biochemical and physiological aspects. Work relating to the clinical presentation, course, management and outcome of diabetes, including its physical and emotional sequelae, is considered. In vitro studies using animal or human tissues, whole animal and clinical studies in humans are also considered. The journal reviews full-length papers, preliminary communications with important new information, clinical reports, and reviews of major topics. Invited editorials, commentaries, and perspectives are a regular feature. The editors, based in the USA, Europe, and Australasia, maintain regular communications to assure rapid turnaround time of submitted manuscripts.