Development, Verification, and Application of a Chinese Pediatric Physiologically Based Pharmacokinetic Model: Emphasis on CYP Metabolism and Renal Elimination.

Physiologically based pharmacokinetics (PBPK) models are increasingly being used in pediatric drug development and with the conduct of clinical studies in specific countries, the development of such models to describe both age and ethnicity related differences is a logical step forward. This study described the development, verification, and application of a Chinese pediatric PBPK (p-PBPK) model. Chinese pediatric physiological systems parameters and clinical data was derived from public databases and the literature, the PBPK model was assembled so that demographic and physiological outputs such as height, cardiac output, and liver size with age represented the Chinese pediatric population. The model was tested using two drugs predominately metabolized by CYP3A4 (fentanyl and midazolam), one dual CYP3A4/CYP2C9 substrate (ruxolitinib), two by other CYPs (efavirenz and theophylline), and two by renal elimination (ceftazidime and vancomycin). Overall, 79% of all pharmacokinetic parameters were predicted within 0.8 to 1.25-fold, and 100% within 0.67 to 1.5-fold of the observed data. The application of the Chinese p-PBPK model is demonstrated with two bridging scenarios, by investigating whether recommended dosing regimens for efavirenz and theophylline are suitable for Chinese pediatric subjects. Given the increased regulatory use of pediatric PBPK models in drug development, expanding these models to other ethnic groups is important. There is a need to further develop the current model across a wider range of drugs with different elimination pathways, to increase model confidence, this should involve academia, industry, model providers, and regulatory agencies.