From discovery to translation: Endogenous substrates of OAT1 and OAT3 as clinical biomarkers for renal secretory function
The recent ICH M12 guidance on Drug Interaction Studies encourages the use of alternate approaches for predicting drug-drug interaction (DDI) potential of new chemical entities. One approach involves biomarkers, which are endogenous substrates of drug metabolizing enzymes and transporters (DMET) and can be used to assess the inhibitory potential of new chemical entities during Phase 1 clinical studies. Thus, biomarkers could potentially eliminate the need for dedicated DDI studies with exogenous probe substrates. Metabolomics, in conjunction with in vitro and/or in vivo preclinical models or clinical studies, can be used for biomarker discovery. We developed and applied a novel metabolomics-based DMET biomarker discovery (MDBD) approach to identify and qualify biomarkers of renal organic anion transporter 1 (OAT1) and OAT3. Untargeted metabolomics of pooled plasma and urine samples from a pharmacokinetic DDI study using the OAT1/3 inhibitor, probenecid, yielded 153 features identified as putative OAT1/3 biomarkers. Subsequently, in vitro transporter uptake assays using processed urine samples confirmed 57 of these features as OAT1 and/or OAT3 substrates. Finally, 23 features were clinically validated as OAT1/3 biomarkers through a detailed pharmacokinetic analysis (0-24 h) of plasma and urine samples. These biomarkers, either alone or as part of a panel, can predict OAT1/3-mediated DDIs and interindividual variability in the renal secretory clearance of organic anions across different populations, thereby enabling translational utility in clinical settings. The novel MDBD approach can be extended to discover biomarkers of other transporters and enzymes. SUMMARYUsing clinical and mechanistic in vitro approaches, 23 endogenous substrates of OAT1/3 were identified as potential clinical biomarkers of renal secretary elimination of organic anions.