The Role of Coproporphyrins as Endogenous Biomarkers for Organic Anion Transporting Polypeptide 1B Inhibition - progress from 2016 to 2023 .

Since the initial clinical study investigating CP-I and CP-III as endogenous biomarkers for OATP inhibition DDIs published in 2016, significant progress has been made in confirming the usefulness of the CPs, particularly the CP-I, as biomarkers in assessing OATP inhibition DDIs. CP-I exhibits selectivity towards OATP1B activity in human subjects with genetic variants of OATP1B1. Its sensitivity to a broad spectrum of clinical OATP1B inhibitors has been established, from weak to vigorous. Dose-dependent CP-I changes in healthy human subjects show agreement with DDI magnitudes of probe substrates by rifampin treatment. PBPK models have been established for concentration changes of plasma CP-I with OATP inhibitors, demonstrating the usefulness of supporting the quantitative translation of the effect of CP-I levels into the DDI risk assessment of potential OATP inhibitors. As plasma CP-I's sensitivity, specificity, and selectivity have been validated in humans, monitoring CP-I levels in single and multiple clinical phase I dose escalation studies is recommended for early assessment of DDI risks and understanding the full dose-response of an investigational drug to OATP inhibitions. A decision tree is proposed to preclude the need to conduct a dedicated DDI study by administering a probe substrate drug to human subjects. Significance Statement The mini-review summarized the validation paths of CP-I and CP-III as biomarkers of OATP1B inhibition in humans for their selectivity, specificity, and sensitivity. The utility of monitoring CP-I to assess drug-drug interactions of OATP1B inhibition in early drug development is proposed. Changes in plasma CP-I in phase I dose range studies can be used to frame plans for late-stage development and facilitate the mechanistic understanding of complex drug-drug interactions.