Abstract: Evaluation of transporter‐mediated drug–drug interactions (DDI) with endogenous biomarkers, coupled with physiologically‐based pharmacokinetic modeling (PBPK) is envisioned to replace or reduce dedicated DDI clinical trials with clinical probe substrates. The current study developed a PBPK model of adefovir (OAT1 clinical probe) by incorporating experimental measurements of adefovir passive diffusion and OAT1‐mediated transport in a mechanistic kidney model for in vitro–in vivo extrapolation of its secretion and renal clearance. The adefovir model was verified with clinical data from nine studies (188 subjects) investigating a range of adefovir intravenous and adefovir‐dipivoxil oral doses in White, Japanese, and Chinese populations with healthy renal function. A previously verified probenecid model, incorporating in vivo OAT1/3 inhibitory constant estimated using OAT1/3 endogenous biomarker (4‐pyridoxic acid) clinical data, was utilized. The ratio of adefovir maximal plasma concentrations (CmaxR) and area under the curve (AUCR) after mid‐to‐high single oral doses of probenecid was predicted within the stringent Guest criterion. With the lowest probenecid dose (0.5 g), adefovir AUCR and CmaxR were slightly overpredicted but still within a 1.5‐fold error. Application of the adefovir model to patients with severe chronic kidney disease (CKD) accounted for our previously recommended additional 50% decrease in OAT1 activity beyond the decline of glomerular filtration rate. The model successfully predicted 3‐fold higher adefovir Cmax and 6‐fold higher AUC in patients with severe CKD relative to healthy individuals. This study reinforces the role of PBPK modeling to predict transporter‐mediated DDI (coupled with biomarker‐informed approach to optimize in vivo inhibitory constant) and the effect of renal impairment on OAT1/3 drugs in lieu of clinical studies.
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