Wang Xiaofeng, Li Longjie, Yang Hongyi, He Qingfeng, Zhu Xiao, Wang Jiajing, Sun Bo, Liu Peng, Xiang Xiaoqiang
Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fudan University, Shanghai, 201203, China.
Shanghai Center for Drug Evaluation and Inspection, Shanghai, 201210, China.
AAPS J. 2025 May 2;27(4):87. doi: 10.1208/s12248-025-01074-1.
The purpose of this study was to establish a clinically relevant specification for carbamazepine (CBZ) tablets, a classic narrow therapeutic index drug (NTID), within the Chinese population. By integrating physiologically based pharmacokinetic (PBPK) modeling with in vitro dissolution profiles and corresponding pharmacokinetic (PK) data, we developed an in vitro-in vivo relationship (IVIVR) by selecting an appropriate dissolution model, and the IVIVR model was validated using in vitro and in vivo data from external sources to ensure the reliability of the method. Parameter sensitivity analysis was used to examine how the critical parameters influence the drug's absorption fraction (F). Additionally, the sensitivity of T, C, and AUC to physiological and formulation parameters was quantitatively evaluated. Based on the validated model, we also developed and validated a virtual bioequivalence (VBE) approach. Additionally, the safety space of the dissolution (Q ≥ 80% meanwhile 50% ≤ Q ≤ 85% and the assay (95 ~ 105%) for carbamazepine tablets (100 mg) were successfully explored depending on the VBE study. This study provides a valuable reference for establishing clinically relevant specifications for NTIDs through PBPK model-informed research.
本研究的目的是为中国人群中的经典窄治疗指数药物（NTID）卡马西平（CBZ）片剂建立临床相关规格。通过将基于生理的药代动力学（PBPK）模型与体外溶出曲线及相应的药代动力学（PK）数据相结合，我们通过选择合适的溶出模型建立了体外-体内关系（IVIVR），并使用来自外部来源的体外和体内数据对IVIVR模型进行了验证，以确保该方法的可靠性。采用参数敏感性分析来研究关键参数如何影响药物的吸收分数（F）。此外，还定量评估了T、C和AUC对生理和制剂参数的敏感性。基于验证后的模型，我们还开发并验证了一种虚拟生物等效性（VBE）方法。此外，根据VBE研究，成功探索了卡马西平片（100mg）溶出度（Q≥80%，同时50%≤Q≤85%）和含量测定（95~105%）的安全范围。本研究为通过PBPK模型指导的研究建立NTIDs的临床相关规格提供了有价值的参考。
