Development and Evaluation of a Physiologically Based Pharmacokinetic Model for Cipepofol Across Diverse Clinical...

Background/Objectives: Cipepofol is a novel intravenous anesthetic whose pharmacokinetics (PK) may vary with dosing regimens, sampling sites, and physiological differences across populations. However, clinical PK data remain fragmented across study settings and are limited for special populations and individualized perioperative use, highlighting the need for a mechanistic modeling framework. This study aimed to develop and evaluate a physiologically based pharmacokinetic (PBPK) model for cipepofol across diverse populations. Methods: Clinical data from nine studies were included, comprising 371 subjects and 3521 plasma concentration measurements. The model was established in healthy adults using HSK3486-101, qualified using healthy-adult data from HSK3486-111 and anesthesia induction datasets, and extrapolated to hepatic impairment, renal impairment, and elderly populations using pathophysiology-informed adjustments. Individualized external validation was further performed in adult and pediatric surgical patients using actual clinical dosing histories. Model performance was evaluated using concentration-time profiles, goodness-of-fit plots, fold error, and geometric mean fold error (GMFE) for C_max and AUC_0-t. Results: The model adequately described both arterial and venous plasma concentration-time profiles across the establishment, qualification, extrapolation, and external validation datasets. Most predicted concentrations were within two-fold of the observed values, and the overall GMFE values were 1.22 for C_max and 1.21 for AUC_0-t. Simulated exposure differences in hepatic impairment, renal impairment, and elderly subjects were generally limited, suggesting no clinically meaningful PK changes from a PK exposure perspective in these populations. The model also reproduced arterial-venous concentration differences and supported the major contributions of UGT1A9 and CYP2B6 to cipepofol clearance. Conclusions: This PBPK model provides a mechanistic framework for characterizing cipepofol disposition and may inform future model-informed dosing studies.