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

  • Clin Pharmacol Ther. 2023 Dec;114(6):1243-1253. doi: 10.1002/cpt.3029.
Shawn Pei Feng Tan  1 ,  Marie-Emilie Willemin  2 ,  Jan Snoeys  2 ,  Hong Shen  3 ,  Amin Rostami-Hodjegan  1  4 ,  Daniel Scotcher  1 ,  Aleksandra Galetin  1
Affiliations
  • 1. Centre for Applied Pharmacokinetic Research, School of Health Sciences, University of Manchester, Manchester, UK.
  • 2. Janssen Pharmaceutical Companies of Johnson & Johnson, Janssen Research & Development, Beerse, Belgium.
  • 3. Bristol Myers Squibb, Princeton, New Jersey, USA.
  • 4. Certara UK Limited (Simcyp Division), Sheffield, UK.
PMID: 37620246 DOI: 10.1002/cpt.3029
Abstract

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 patients with chronic kidney disease (CKD). 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. The PBPK model for PDA was first developed in healthy population, building on from previous population pharmacokinetic modeling, 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 2-fold of observed data) after accounting for 60% increase in 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 patients with CKD.

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