Preliminary physiologically based pharmacokinetic modeling of renally cleared drugs in Chinese pregnant women

Abstract

AimThe aim of this study was to build and verify a preliminary physiologically based pharmacokinetic (PBPK) model of Chinese pregnant women. The model was used to predict maternal pharmacokinetics (PK) of 6 predominantly renally cleared drugs.MethodBased on SimCYP Caucasian pregnancy population dataset, the preliminary Chinese pregnant population was built by updating several key parameters and equations according to physiological parameters of Chinese (or Japanese) pregnant women. Drug‐specific parameters of 6 renally cleared drugs were validated through PBPK modeling of Caucasian non‐pregnant, Caucasian pregnant and Chinese non‐pregnant population. The preliminary PBPK model of Chinese pregnant population was then developed by integrating the preliminary Chinese pregnant population and the drug‐specific parameters. This model was verified by comparing the predicted maternal PK of these 6 drugs with the observed in vivo data from the literature.ResultsThe preliminary Chinese pregnant population PBPK model successfully predicted the PK of 6 target drugs for different pregnancy stages. The predicted plasma concentrations time profiles fitted the observed data well, and most predicted PK parameters were within 2‐fold of observed data. Conclusions: The preliminary Chinese pregnant population PBPK model provided a useful tool to predict the maternal PK of 6 predominantly renally cleared drugs in Chinese pregnant women.

PBPK Modeling Approach to Predict the Behavior of Drugs Cleared by Kidney in Pregnant Subjects and Fetus

“…In addition, these models have other limitations as the exchange between the amniotic fluid and the fetus is not considered. Pregnancy PBPK model for renally eliminated drugs was also enhanced recently to account for ethnic differences by including specific details for Chinese pregnant populations [57]. Ongoing research regarding placental tissue structure and the consequences on fetal exposure will support enhancement of PBPK model for pregnancy applications [58,59].…”

Computational Approaches in Preclinical Studies on Drug Discovery and Development

“…The second type consists of drug-related parameters, such as the plasma ratio, organ/blood partition coefficient, and permeability (Nestorov, 2003 ). Recently, PBPK models have been widely constructed to predict drug-related parameters (Chow et al, 2016 ; Pathak et al, 2019 ; Song et al, 2020 ). For example, Chow et al used a physiologically based model to predict drug solubility and effective permeability (Chow et al, 2016 ) to examine the potential impact of excipients on oral drug absorption.…”

Dosage Adjustment for Ceftazidime in Pediatric Patients With Renal Impairment Using Physiologically Based Pharmacokinetic Modeling

“…The fraction unbound in plasma (Fup) value and the blood-to-plasma concentration ratio (Rbp) were obtained from previous studies. 10,30 Model Verification Simulations were conducted using consistent clinical study conditions as reported in actual clinical trials, including demographic data and dosing regimens. The fold error of PK parameters, such as the area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C max ) derived from the ratio of the observed and predicted in vivo values, and visual checks of the plasma concentration profiles were used to assess the predictive performance of the model.…”