Development and Validation of a Chinese Obesity-Specific Physiological Database for PBPK Modeling.

OBJECTIVES

To develop and validate a physiologically based pharmacokinetic (PBPK) population model for the Chinese obese population.

METHODS

A Chinese adult population database was established in PK-Sim through recalibration of the East Asian population database, using newly collected anatomical and physiological data from Chinese adults. All three drugs (dexmedetomidine, omeprazole, and propofol) possessing Chinese obese population PK data were selected, with their PBPK models then developed and validated using matched clinical data. These models with the fixed drug-specific parameters were applied to the Chinese adult database to simulate drug concentrations, with results compared with the built-in East Asian database. Then, physiological parameters were adjusted using real-world and literature data from Chinese patients with obesity to establish a Chinese obese adult database. Similarly, drug concentrations in this population were simulated and compared with the simulation results based on the published White obese population database.

RESULTS

The predicted Cmax and AUClast values were within 0.5-2 fold of the observed values, demonstrating all drug models were validated. The Chinese adult database showed superior accuracy to the East Asian database (90% versus 75% of AUClast and 80% versus 70% of Cmax within 0.8-1.25 fold). Similarly, the Chinese obese database outperformed the White obese database (83% versus 33% for AUClast and 33% versus 0% for Cmax within 0.8-1.25 fold).

CONCLUSIONS

The validated drug models, combined with the Chinese adult and obese adult databases, reliably predicted drug concentrations in Chinese adults and adults with obesity, outperforming the East Asian population database and White obese population database.