A Pilot Study to Assess the Suitability of Riboflavin as A Surrogate Marker of Breast Cancer Resistance Protein (BCRP) in Healthy Participants

Hong Shen; Runlan Huo; Yueping Zhang; Linna Wang; Nian Tong; Weiqi Chen; Andrew J Paris; Kofi Mensah; Min Chen; Yongjun Xue; Wenying Li; Michael Sinz

doi:10.1124/jpet.123.002015

A Pilot Study to Assess the Suitability of Riboflavin as A Surrogate Marker of Breast Cancer Resistance Protein (BCRP) in Healthy Participants

J Pharmacol Exp Ther. 2024 Jan 31:JPET-AR-2023-002015. doi: 10.1124/jpet.123.002015. Online ahead of print.

Authors

Hong Shen¹, Runlan Huo², Yueping Zhang³, Linna Wang², Nian Tong⁴, Weiqi Chen², Andrew J Paris², Kofi Mensah², Min Chen², Yongjun Xue², Wenying Li⁵, Michael Sinz⁶

Affiliations

¹ Drug Metabolism and Pharmacokinetics, Bristol Myers Squibb, United States Hong.Shen1@bms.com.
² Bristol Myers Squibb, United States.
³ Bristol-Myers Squibb, United States.
⁴ Clinical Pharmacology and Drug Metabolism, Bristol Myers Squibb, United States.
⁵ Biotransformation, Bristol-Myers Squibb, United States.
⁶ Metabolism and Pharmacokinetics, Biocon - Bristol Myers Squibb Research Center, India.

PMID: 38296646
DOI: 10.1124/jpet.123.002015

Abstract

We recently showed that riboflavin is a selected substrate of BCRP over P-gp and demonstrated its prediction performance in preclinical DDI studies. The aim of this study was to investigate the suitability of riboflavin to assess BCRP inhibition in humans. First, we assessed the substrate potential of riboflavin towards other major drug transporters using established transfected cell systems. Riboflavin is a substrate for OAT1, OAT3, and MATE2-K with uptake ratios ranging from 2.69 to 11.6 but riboflavin is not a substrate of OATP1B1, OATP1B3, OCT2, and MATE1. The effects of BMS-986371, a potent in vitro inhibitor of BCRP (IC ₅₀ 0.40 µM), on the pharmacokinetics of riboflavin, isobutyryl carnitine, and arginine were then examined in healthy male adults (N = 14 or 16) following oral administration of methotrexate (MTX) (7.5 mg) and enteric coated (EC) sulfasalazine (SSZ) (1,000 mg) alone or in combination with BMS-986371 (150 mg). Oral administration of BMS-986371 increased the AUCs of rosuvastatin and immediate-release (IR) SSZ to 1.38- and 1.51-fold , respectively, and significantly increased AUC(0-4h), AUC(0-24h), and C _max of riboflavin by 1.25-, 1.14-, and 1.11-fold (P-values of 0.003, 0.009, and 0.025, respectively) compared to the MTX/SSZ EC alone group. In contrast, BMS-986371 did not significantly influence the AUC(0-24h) and C _max values of isobutyryl carnitine and arginine (0.96- to 1.07-fold, respectively; P > 0.05). Overall, these data indicate that plasma riboflavin is a promising biomarker of BCRP that may offer a possibility to assess drug candidate as a BCRP modulator in early drug development. Significance Statement Endogenous compounds that serve as biomarkers for clinical inhibition of BCRP are not currently available. This study provides the initial evidence that riboflavin is a promising BCRP biomarker in humans. For the first time, the value of leveraging the substrate of BCRP with acceptable prediction performance in clinical studies is shown. Additional clinical investigations with known BCRP inhibitors are needed to fully validate and showcase the utility of this biomarker.

Keywords: Transporter-mediated drug/metabolite disposition; drug-drug interactions; transporters.