Kikuchi, Ryota, Chothe, Paresh, Chu, Xiaoyan, Huth, Felix, Ishida, Kazuya, Ishiguro, Naoki, Jiang, Rosa, Shen, Hong, Stahl, Simone, Varma, Manthena, Willemin, Marie-Emilie and Morse, Bridget (2023) Use of Endogenous Biomarkers to Guide OATP1B Drug-Drug Interaction Risk Assessment: Evaluation by the Pharmaceutical Industry. Clinical Pharmacology & Therapeutics. ISSN 0009-92361532-6535

Abstract

Drug-drug interactions (DDIs) involving hepatic organic anion transporting polypeptides 1B1/1B3 (OATP1B) can be substantial and clinically relevant, however challenges remain for predicting these DDIs using in vitro inhibition data. Emerging evidence suggests the use of endogenous biomarkers, particularly coproporphyrin-I (CP-I), as selective markers of in vivo OATP1B activity. The present work under the International Consortium for Innovation and Quality in Pharmaceutical Development was aimed primarily at establishing the relationship between changes in CP-I exposure and substrate drug exposure following clinical OATP1B inhibition. Additionally, we evaluated static models to predict changes in exposure of CP-I, as a selective OATP1B endogenous substrate. Literature and proprietary data related to clinical OATP1B biomarkers along with pertinent in vitro and clinical DDI information were collected to identify clinical DDIs via primarily OATP1B inhibition and assess the relationship between substrate drug and CP-I exposure changes. Significant correlations were observed between CP-I area-under-the-curve ratio (AUCR) or maximum concentration ratio (CmaxR) and AUCR of substrate drugs. CP-I AUCR and CmaxR of <1.25 was associated with negative OATP1B-mediated DDIs (AUCR <1.25) with no false negative predictions observed while applying both criteria. CP-I AUCR of <1.5 and CmaxR of <2 was associated with OATP1B-mediated DDIs with AUCR <2. A correlation was identified between CP-I exposure changes and OATP1B1 static DDI predictions. Recommendations for collecting and interpreting CP-I data are described, including a decision tree for guiding DDI risk assessment. Measurement of CP-I is considered sufficient for evaluation of in vivo OATP1B inhibition potential.

Item Type:	Article
Keywords:	Transporter, OATP1B, biomarker, coproporphyrine
Date Deposited:	27 Oct 2023 00:45
Last Modified:	27 Oct 2023 00:45
URI:	https://oak.novartis.com/id/eprint/49840