TIP-001 - A CLINICAL STUDY OF NOVEL BCRP AND ESTABLISHED OATP BIOMARKERS FOR PREDICTING DRUG-DRUG INTERACTIONS.

A. Riselli¹, S. Yee¹, K. Trumbach¹, C. Brett¹, J. Chun¹, X. Liang², R. Liu², R. Huo³, W. Chen³, Y. Xue³, L. Zhang⁴, X. Yang⁴, Y. Lai², H. Shen³, Q. Liu⁴, S. Huang⁴, K. Giacomini¹; ¹University of California, San Francisco, ²Gilead Sciences Inc, ³Bristol Myers Squibb, ⁴U.S. Food and Drug Administration.

Background: Breast Cancer Resistance Protein (BCRP) and Organic Anion Transporting Polypeptide 1B (OATP1B) are key transporters in drug-drug interaction (DDI) assessment. While several OATP1B biomarkers are well-established in humans, BCRP lacks clinically validated biomarkers. This clinical study aims to evaluate endogenous substrates of BCRP as biomarkers of transporter activity. Together with OATP1B biomarkers, these BCRP substrates will be evaluated in a clinical DDI study in which eltrombopag, an inhibitor of BCRP and OATP1B, is administered to modulate transporter activity. Rosuvastatin, a substrate of both transporters, is administered as a control.

Methods: Biomarker Selection: Four BCRP biomarker candidates (4-hydroxychlorothalonil, 3,5-dichloro-2,6-dihydroxybenzoic acid, 3-bromo-5-chloro-2,6-dihydroxybenzoic acid, and riboflavin) identified in metabolomic genomewide association studies [1,2] and Bcrp knockout models [3,4] will be evaluated. Established OATP1B biomarkers coproporphyrin-I and -III (CP-I, CP-III), hexadecanedioate (HDA), and tetradecanedioate (TDA) will also be measured.

Clinical Study: An open-label, fixed-sequence crossover study was recently completed in 11 healthy subjects. Initially, rosuvastatin (10 mg tablet) was administered. After a washout period, participants received 5 doses of eltrombopag (75 mg tablet), with the final dose co-administered with rosuvastatin (10 mg tablet). Plasma samples were collected pre-dose and up to 72 hours post-dose.

Sample Analysis: Drug and biomarker plasma concentrations will be quantified using LC-MS. Pharmacokinetic (PK) parameters will be derived through non-compartmental analysis. Statistical analysis of rosuvastatin PK and biomarkers before and after eltrombopag administration will be conducted using a paired t-test, with significance set at P < 0.05.

References:
1. Long T, et al. Nat Genet. 2017.
2. Yin X, et al. Nat Commun. 2022
3. Zhang Y, et al. Drug Metab Dispos. 2023.
4. Ganguly S, et al. PLoS One. 2021

NOVELTY OF

Design: To date, no BCRP biomarkers have been evaluated clinically. This is the first study designed to validate BCRP biomarker candidates in a clinical DDI study. Additionally, we seek to apply these biomarkers and previously established OATP1B biomarkers to elucidate the mechanism of a multi-transporter, multi-tissue DDI.