Physiologically-Based Pharmacokinetics and Empirical Pharmacodynamic Modeling for Pediatric Henagliflozin Dosing: Clinical Insights for Chinese Patients.

IF 5.6 3区 医学 Q2 ENDOCRINOLOGY & METABOLISM
Pediatric Diabetes Pub Date : 2025-08-07 eCollection Date: 2025-01-01 DOI:10.1155/pedi/8857248
Xinyue Zhang, Hao Xue, Jialei Xu, Ke Ren, Fangyi Qian, Yifan Zhang, Jingru Dou, Kai Shen, Xiao Zhu, Xiaoqiang Xiang, Qingfeng He
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Abstract

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.

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。
目的:本研究旨在建立口服henagliflozin的定量建模和模拟方法,henagliflozin是一种选择性钠-葡萄糖共转运蛋白2 (SGLT2)抑制剂,主要由尿苷二磷酸-葡萄糖醛酸转移酶(UGT)酶代谢。方法:利用体外代谢和临床药代动力学(PK)数据建立henagliflozin基于生理的药代动力学(PBPK)模型,并在多种背景下进行验证,包括健康成人和肝功能障碍人群。此外,根据尿糖排泄(UGE)的暴露-反应关系,采用经验药效学(PD)模型优化儿科给药剂量。由于UGT酶的个体发生和缺乏较年轻年龄组的临床PK数据,预测儿科患者的亨纳列净暴露存在挑战。使用双重接受标准,模型预测和观察到的药物暴露和PK参数(曲线下面积和峰值浓度)在不同情况下进行比较,包括健康成人的单药治疗(单/多剂量)、肝功能损害和儿科年龄组的外推。结果:PBPK模型准确地捕获了在成人和青少年两种范围内观察到的暴露,支持了该模型的预测效用。经过验证的PBPK和经验PD模型为1个月至18岁的儿科人群提供了剂量建议,使亨格列净暴露量与接受5-10 mg剂量的成人患者相当。结论:本研究表明,PBPK和PD模型有效地指导了亨格列净的儿科给药,减少了试验依赖并支持现实验证。
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来源期刊
Pediatric Diabetes
Pediatric Diabetes 医学-内分泌学与代谢
CiteScore
6.60
自引率
14.70%
发文量
141
审稿时长
4-8 weeks
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.
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