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

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.

• Authors: Shawn Pei Feng Tan, Marie-Emilie Willemin, Jan Snoeys, Hong Shen, Amin Rostami-Hodjegan, Daniel Scotcher, Aleksandra Galetin
• Journal: Clinical pharmacology and therapeutics (Clin Pharmacol Ther) Vol. 114 Issue 6 Pg. 1243-1253 (Dec 2023) ISSN: 1532-6535 [Electronic] United States
• PMID: 37620246 (Publication Type: Journal Article)
• Copyright: © 2023 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

Chemical References

• Pyridoxic Acid
• Probenecid
• Biomarkers

Topics

• Humans
• Pyridoxic Acid
• Probenecid (pharmacology)
• Renal Insufficiency, Chronic (drug therapy)
• Kidney
• Drug Interactions
• Biomarkers
• Models, Biological