PI-077 - DEVELOPMENT AND VERIFICATION OF A PYRIDOXIC ACID PBPK MODEL TO EVALUATE BIOMARKER INFORMED ORGANIC ANION TRANSPORTERS (OAT) 1 AND 3 INHIBITION.

S. Tan¹, M. Willemin², J. Snoeys², H. Shen³, A. Rostami-Hodjegan^1,4, D. Scotcher¹, A. Galetin¹; ¹University of Manchester, Manchester, United Kingdom, ²Janssen Pharmaceuticals, Beerse, Belgium, ³Bristol Myers Squibb, Princeton, NJ, USA, ⁴Certara UK Limited (Simcyp Division), Sheffield, United Kingdom.

Background: Monitoring the levels of endogenous biomarkers in early clinical trials is increasingly used to evaluate transporter-mediated drug-drug interactions (DDIs). Pyridoxic acid (PDA) has been identified as the most sensitive plasma endogenous biomarker of renal OAT1/3 transporters in humans. The aim of this study was to develop and verify a physiologically-based pharmacokinetic (PBPK) model of PDA by leveraging published clinical DDI data with probenecid, a strong clinical OAT1/3 inhibitor.

Methods: PBPK model for PDA was developed using Simcyp V21. PDA biosynthesis rate and non-renal clearance were based on previous population pharmacokinetic modelling [1]. A top-down estimate of OAT1/3-mediated intrinsic clearance and experimentally measured passive diffusion clearance were used in the mechanistic kidney model. Probenecid PBPK model was adapted from the Simcyp database, modified, and re-verified to capture dose-dependent pharmacokinetics of probenecid (n = 5 studies).

Results: See Figure 1.

Conclusion: The PDA PBPK model successfully predicted the extent of change in PDA concentrations and renal clearance after a DDI with either single or multiple doses of probenecid, highlighting its robustness. The verified PDA PBPK model is aimed to support future robust evaluation of the clinical relevance of OAT1/3 inhibition in drug development.

[1] Ahmad, A. et al. Population Pharmacokinetic Modeling and Simulation to Support Qualification of Pyridoxic Acid as Endogenous Biomarker of OAT1/3 Renal Transporters. CPT. Pharmacometrics Syst. Pharmacol. 10, 467-77 (2021).
[2] Shen, H. et al. Evidence for the Validity of Pyridoxic Acid (PDA) as a Plasma-Based Endogenous Probe for OAT1 and OAT3 Function in Healthy Subjects. J. Pharmacol. Exp. Ther. 368, 136-45 (2019).
[3] Willemin, M.E. et al. Clinical Investigation on Endogenous Biomarkers to Predict Strong OAT-Mediated Drug-Drug Interactions. Clin. Pharmacokinet. 60, 1187-99 (2021).

Figure 1. Predicted PDA plasma concentrations before and after a DDI with (A) 1.0 g single oral dose and (B) 0.5 g four times daily oral dose of probenecid. The solid line represents the predicted mean PDA plasma concentration. The symbols and error bars represent the mean ± standard deviation of observed PDA plasma concentrations from published clinical studies after single [2] and multiple probenecid doses [3]. Pre-and post-DDI phases are represented by the black and blue line/symbols, respectively. Predicted ratios of the area under the curve (post-DDI/pre-DDI) were within 1.5-fold of the observed data in both scenarios. The predicted percentage inhibition of PDA renal clearance was 63% and 79% after single and multiple dosing of probenecid, versus the observed values of 71% and 83%, respectively.