Development of the second-generation PBPK model to quantify OATP1B, P-gp, BCRP transporter and CYP3A4 enzyme activity changes for Chinese ESRD patients
Authors: Wu Yujie , Kong Weijie , Liang Hao , Liu Dongyang 
Published: February 2025

Objectives: Physiologically based pharmacokinetic (PBPK) modeling is widely accepted for predicting pharmacokinetics (PK) in chronic kidney disease (CKD) patients to support drug development and precision medicine. However, PBPK model has not been established for nonrenal clearance pathways of end-stage renal disease (ESRD) patients due to the scarcity of clinical data. In this study, we aim to develop PBPK models for CYP3A4, OATP1B, P-gp and BCRP pathways using a microdose cocktail clinical PK data in Chinese ESRD patients. Methods: PK data of healthy volunteers (HVs, n=14) and ESRD patients (n=10) undergoing dialysis in a single dosing study of microdose cocktail (including midazolam, dabigatran etexilate, pitavastatin, rosuvastatin and atorvastatin) was used to construct the PBPK model. Drug models were adopted from SimCYP compound library (V22) or published literature [1, 2], and subsequently validated by PK data from HVs at therapeutic dose or microdose, pharmacogenomic studies, and drug-drug interaction studies. The Chinese ESRD population model was constructed based on our 1st-generation PBPK model for Chinese severe CKD patients [3], with recalibration of hematocrit, α1‐acid glycoprotein, serum albumin, and serum creatinine according to clinical data. After aligning demographic information including age, gender, and genotype to the corresponding clinical trial study designs, the back-calculation method was utilized to estimate systematic changes of CYP3A4 enzyme and transporters in ESRD populations. The predictive performance of each model was assessed based on the criterion of two-fold range of the predicted/observed ratio. Results: The predicted AUC0-last and Cmax for all drugs in HVs were within two-fold of observed values. Particularly, 15.4% of predicted AUC0-last and 23.1% of predicted Cmax fell within the range of 0.8 to 1.25-fold, indicating the reliability of drug models. Using the validated drug model, back-calculation method was utilized to estimate the functional changes of CYP3A4 enzyme and transporters in ESRD patients. The AUCRPre/Obs value ranged between 0.8 and 1.25, together with the similar predicted PK profile (mean and 90% prediction interval) were used as criteria. The final result suggested an 85% reduction in hepatic OATP1B activity and a 45% reduction in intestine P-gp activity, whereas alterations in CYP3A4 activity were negligible. Furthermore, ileum BCRP activity increased to 201% of HVs baseline value, which is consistent with previous studies. The second-generation PBPK model for Chinese ESRD patients was established accordingly. Conclusions: In this study, we uncovered the quantitative changes in activity for OATP1B, P-gp, BCRP transporter and CYP3A4 enzyme in Chinese ESRD patients and constructed the second-generation Chinese PBPK models for ESRD patients. Our study provides basis for the drug development and precision medicine for substrates eliminated by OATP1B, P-gp, BCRP and/or CYP3A4 in ESRD patients.Citations: [1] SIA J E V, LAI X, WU X, et al. Physiologically-based pharmacokinetic modeling to predict drug-drug interactions of dabigatran etexilate and rivaroxaban in the Chinese older adults [J]. Eur J Pharm Sci, 2023, 182: 106376.[2] TAN M L, ZHAO P, ZHANG L, et al. Use of Physiologically Based Pharmacokinetic Modeling to Evaluate the Effect of Chronic Kidney Disease on the Disposition of Hepatic CYP2C8 and OATP1B Drug Substrates [J]. Clin Pharmacol Ther, 2019, 105(3): 719-29.[3] CUI C, LI X, LIANG H, et al. Physiologically based pharmacokinetic model of renally cleared antibacterial drugs in Chinese renal impairment patients [J]. Biopharm Drug Dispos, 2021, 42(1): 24-34.