PT-001 - UTILITY OF A PANEL OF ENDOGENOUS BIOMARKERS TO PREDICT DRUG-DRUG INTERACTIONS AND INTERINDIVIDUAL VARIABILITY INVOLVING ORGANIC ANION TRANSPORTERS 1 AND 3 ACTIVITY.

A. Thakur¹, D. Singh², M. Paine², B. Prasad²; ¹Department of Pharmaceutical Sciences, Washington State University, Spokane, WA, USA, ²Department of Pharmaceutical Sciences, Washington State University, Spokane, WA, USA.

Background: Endogenous compounds like pyridoxic acid, kynurenic acid, and taurine have shown promise as biomarkers of renal organic anion transporter 1 (OAT1) and OAT3 to predict drug-drug interactions (DDIs). However, these biomarkers are confounded by low selectivity and sensitivity, high interindividual variability, disease state, and other factors, limiting their utility to predict transport function.

Methods: We identified and validated putative OAT1/3 biomarkers using a novel metabolomics-based biomarker discovery approach.1 We then utilized a panel of the top six putative biomarkers as predictor of OAT1/3-mediated interindividual variability in renal clearance (CLR) of OAT1/3 substrate furosemide. Putative biomarkers were identified by untargeted metabolomics analysis of human plasma and urine samples obtained from a completed clinical pharmacokinetic DDI study (n=16 healthy adults; NCT05365451) involving oral furosemide (5 mg) and probenecid (1000 mg, OAT1/3 inhibitor). Involvement of individual transporters was mechanistically confirmed by in vitro uptake assays using OAT1 or OAT3 over-expressing cells, followed by clinical validation involving pharmacokinetic analysis (0-24 h) of plasma and urine samples (n=4 participants).

Results: Probenecid increased plasma AUC0-24h of the 23 biomarkers (m/z range: 160.1332-427.1974) by ~2.5-fold (range: 1.4- to 4.1-fold), with a corresponding decrease in CLR of 62% (range: 38-78%). Based on intraindividual ( < 30%) and interindividual ( < 50%) variability in baseline plasma concentrations, lack of diurnal variation, AUC ratio (> 2-fold), and CLR ratio ( < 0.5), top six biomarkers were selected for the panel. The fold change in furosemide concentrations in pooled plasma (n=16) correlated significantly with average fold change in biomarker panel (r = 0.5, p-value < 0.05), highlighting that OAT1/3-mediated interindividual variability in the probenecid-furosemide interaction can be predicted by a panel of OAT1/3 biomarkers.

Conclusion: Extension of this approach using weighted values of individual biomarkers in the panel is currently ongoing. Once validated, the biomarker panel can be used to assess DDIs and interindividual variability in OAT1/3 transport function in pediatric and other specific populations.
Ref:
1. Thakur et al. ASPET 2024 Annual Meeting Abstract (DMD) 389, 433.