Development of 4-Pyridoxic Acid PBPK Model to Support Biomarker- Informed Evaluation of OAT1/3 Inhibition and Effect of Chronic Kidney Disease

Shawn pei feng Tan, Marie‐emilie Willemin, Jan Snoeys, Hong Shen, Amin Rostami‐hodjegan, Daniel Scotcher, Aleksandra Galetin

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Monitoring endogenous biomarkers is increasingly used to evaluate transporter-mediated drug-drug interactions (DDIs) in early drug development and may be applied to elucidate changes in transporter activity in disease. 4-pyridoxic acid (PDA) has been identified as the most sensitive plasma endogenous biomarker of renal organic anion transporters (OAT1/3). Increase in PDA baseline concentrations was observed after administration of probenecid, a strong clinical inhibitor of OAT1/3 and also in chronic kidney disease (CKD) patients. The aim of this study was to develop and verify a physiologically-based pharmacokinetic (PBPK) model of PDA, to predict the magnitude of probenecid DDI and predict the CKD-related changes in PDA baseline. PBPK model for PDA was first developed in healthy population, building on from previous population pharmacokinetic modelling, and incorporating a mechanistic kidney model to consider OAT1/3-mediated renal secretion. Probenecid PBPK model was adapted from the Simcyp database and re-verified to capture its dose-dependent pharmacokinetics (n=9 studies). The PBPK model successfully predicted the PDA plasma concentrations, area under the curve and renal clearance in healthy subjects at baseline and after single/multiple probenecid doses. Prospective simulations in severe CKD predicted successfully the increase in PDA plasma concentration relative to healthy (within two-fold of observed data) after accounting for 60% increase to fraction unbound in plasma and additional 50% decline in OAT1/3 activity beyond the decrease in glomerular filtration rate. The verified PDA PBPK model supports future robust evaluation of OAT1/3 DDI in drug development and increases our confidence in predicting exposure and renal secretion in CKD patients.
Original languageEnglish
JournalClinical Pharmacology & Therapeutics
Early online date24 Aug 2023
Publication statusE-pub ahead of print - 24 Aug 2023


  • Drug-drug interaction
  • Endogenous Biomarker
  • Chronic Kidney Disease
  • Physiologically-based Pharmacokinetic Modelling
  • Organic Anion Transporters


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