Novel Mechanistic PBPK Model to Predict Renal Clearance in Varying Stages of CKD by Incorporating Tubular Adaptation and Dynamic Passive Reabsorption

Chronic kidney disease (CKD) has significant effects on renal clearance (CLr) of drugs. Physiologically‐based pharmacokinetic (PBPK) models have been used to predict CKD effects on transporter‐mediated renal active secretion and CLr for hydrophilic nonpermeable compounds. However, no studies have shown systematic PBPK modeling of renal passive reabsorption or CLr for hydrophobic permeable drugs in CKD. The goal of this study was to expand our previously developed and verified mechanistic kidney model to develop a universal model to predict changes in CLr in CKD for permeable and nonpermeable drugs that accounts for the dramatic nonlinear effect of CKD on renal passive reabsorption of permeable drugs. The developed model incorporates physiologically‐based tubular changes of reduced water reabsorption/increased tubular flow rate per remaining functional nephron in CKD. The final adaptive kidney model successfully (absolute fold error (AFE) all