PII-004 - EVALUATING THE UTILITY OF ENDOGENOUS OCT2 AND MATE1/2-K BIOMARKERS FOR EARLY DDI ASSESSMENT IN ONCOLOGY PHASE 1 STUDIES

R. Nishii¹, Y. Xue², R. Huo³, J. Chen¹, H. Shen³, Y. Chen², K. Ogasawara²; ¹Bristol Myers Squibb, Summit, NJ, USA, ²Bristol Myers Squibb, NJ, USA, ³Bristol Myers Squibb, Princeton, NJ, USA.

Background: There is a growing interest and significant advance in the identification and characterization of endogenous transporter biomarkers, highlighting their potential utility for assessing transporter-mediated drug-drug interactions (DDI) in early clinical settings. Endogenous biomarkers, such as creatinine, N1-methylnicotinamide (NMN), and N1-methyladenosine (m1A), have been identified as substrates of renal cation transporters OCT2 and MATE1/2-K; however, their clinical characterization remains limited, necessitating further validation to assess their predictive DDI performance.

Methods: Creatinine, NMN and m1A levels were quantified by liquid chromatography with tandem mass spectrometry in plasma and urine samples, which were obtained from a previously conducted clinical pharmacology study (NCT04231435) to assess DDI via OCT2 and MATE1/2-K between fedratinib (inhibitor) and metformin (substrate) in healthy participants. PK analysis was conducted using a noncompartmental method to determine the area under the plasma concentration-time curve and the renal clearance (CLr) of the respective substrates.

Results: A reduction in CLr (0-12hr) for 3 endogenous substrates was observed following fedratinib administration, consistent with the decreased CLr seen in the reference probe substrate, metformin (29-38% and 40%, respectively). m1A and NMN exhibited positive moderate correlations with metformin CLr changes (correlation coefficients r = 0.751 and 0.629, respectively); NMN had a better fit to the identity line with considerable diurnal and intrasubject variations. Poor correlation (r = 0.428) was observed for creatinine, suggesting lower sensitivity likely due to the limited contribution of transporter-mediated renal tubular secretion. We further conducted a simulation exercise evaluating various sampling schedules (5-11 samples over 24 hours, based on internal oncology Phase1 study protocols) and demonstrated minimal impact from reduced sampling (eg, 3 samples over 6 hours) on CLr changes.

Conclusion: Our study demonstrated the predictive capabilities of m1A and NMN in renal cation transporter inhibition as endogenous biomarkers, and potential applicability of integrating the early DDI assessments by endogenous biomarkers into future oncology Phase 1 studies.