Prediction of Pharmacokinetics for CYP3A4-Metabolized Drugs in Pediatrics and Geriatrics Using Dynamic Age-Dependent Physiologically Based Pharmacokinetic Models.

Abstract

Background/Objectives: The use of medicines in pediatrics and geriatrics is widespread. However, information on pharmacokinetics of therapeutic drugs mainly comes from healthy adults, and the pharmacokinetic parameters of therapeutic drugs in other age stages, including pediatrics and geriatrics, are limited. The aim of the study was to develop a dynamic age-dependent physiologically based pharmacokinetic (PBPK) model to predict the pharmacokinetics of drugs in humans at different ages. Method: The PBPK models characterizing dynamic age-dependence were developed in adults (20-59 years old) and 1000 virtual individuals were constructed. Four CYP3A substrates, namely midazolam, fentanyl, alfentanil and sufentanil, served as model drugs. Following validation using clinic observations in adult populations, the developed PBPK models were extrapolated to other age populations, such as pediatrics and geriatrics, via replacing their physiological parameters and pharmacokinetic parameters, such as organ volume, organ blood flow, clearance, f_u,b and K_t:p. The simulations were compared with clinic observations in corresponding age populations. Midazolam served as an example, the dose transitions between adult pediatrics and adult geriatrics were visualized using the developed PBPK models. Results: Most of observed plasma concentrations fell within the 5th-95th percentile of the predicted values in the 1000 virtual individuals, and the predicted AUC_0-t and C_max were almost within between 0.5 and 2 times of the observations. The optimization of dosages in pediatrics and geriatrics were further documented. Conclusions: The developed PBPK model may be successfully used to predict the pharmacokinetics of CYP3A4-metabolized drugs in different age groups and to optimize their dosage regiments in pediatrics and geriatrics.