Establishing Clinically Relevant Specifications for Carbamazepine Tablets Using Physiologically Based Pharmacokinetic Modeling

Abstract

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_a). Additionally, the sensitivity of T_max, C_max, 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_{60 min} ≥ 80% meanwhile 50% ≤ Q_{15 min} ≤ 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.

Keywords: in vitro-in vivo relationship; carbamazepine tablets; clinically relevant drug product specification; physiologically based pharmacokinetic modeling; virtual bioequivalence.