Pyridoxic Acid as Endogenous Biomarker of Renal Organic Anion Transporter Activity: Population Variability and Mechanistic Modeling to Predict Drug-Drug Interactions.

Abstract

Pyridoxic acid (PDA) was suggested as a potential endogenous biomarker to assess in vivo renal organic anion transporter (OAT) 1 and 3 activity. Here, we first investigated the population variability in the plasma baseline levels of PDA using data from five independent studies (conducted/supported by Pfizer), and subsequently developed mechanistic physiologically based pharmacokinetic (PBPK) model to assess its effectiveness in biomarker-informed drug-drug interaction (DDI) predictions. Meta-analysis suggested that the inter-individual variability in PDA plasma concentration was ~40% across all five studies (n = 71 subjects). While sex-dependent differences were not evident, the baseline plasma PDA levels were significantly higher (38%, p < 0.05) in White males compared to Japanese males. Correspondingly, the amount of PDA excreted in urine and renal clearance were significantly higher (p < 0.05) in Japanese males (1.5- and 2.2-fold, respectively), compared to White males. A PBPK model considering relative activity factor-based scaling of in vitro transport data indicated > 80% contribution by OAT3 to the renal clearance of PDA. The baseline plasma concentrations across multiple studies were recovered by the model; and using in vitro inhibition potency data, the model predicted effect of OAT inhibitors (probenecid, ritlecitinib and tafamidis) on PDA pharmacokinetics. Furthermore, DDIs with OAT3 object drug, furosemide, were well-predicted by the biomarker-informed PBPK model. PDA data and the modeling approach indicated lack of clinically-relevant OAT inhibition with ritlecitinib and tafamidis. Overall, this study presents PDA as a reliable biomarker to assess OAT3-mediated renal DDIs with moderate inter-subject and inter-study variability.