The Role of Coproporphyrins As Endogenous Biomarkers for Organic Anion Transporting Polypeptide 1B Inhibition-Progress from 2016 to 2023.
Drug Metab Dispos
; 51(8): 950-961, 2023 Aug.
Article
en En
| MEDLINE
| ID: mdl-37407093
ABSTRACT
Since the initial clinical study investigating coproporphyrins I and III (CP-I and CP-III) as endogenous biomarkers for organic anion transporting polypeptide (OATP) inhibition drug-drug interactions (DDIs) published in 2016, significant progress has been made in confirming the usefulness of the CPs, particularly CP-I, as biomarkers in assessing OATP functions. CP-I exhibits selectivity toward 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. Physiologically based pharmacokinetic 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 minireview summarized the validation paths of coproporphyrins I and III (CP-I and CP-III) as biomarkers of organic anion transporting polypeptide 1B (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.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Coproporfirinas
/
Transportadores de Anión Orgánico
Tipo de estudio:
Prognostic_studies
/
Risk_factors_studies
Límite:
Humans
Idioma:
En
Año:
2023
Tipo del documento:
Article