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Dose-Dependent Inhibition of OATP1B by Rifampicin in Healthy Volunteers: Comprehensive Evaluation of Candidate

Daiki Mori1, Emi Kimoto2, Brian Rago2

  • 1Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan.

Clinical Pharmacology and Therapeutics
|October 20, 2019
PubMed

Insights

New endogenous biomarkers were identified to improve drug-drug interaction risk assessment for organic anion transporting polypeptide 1B (OATP1B) inhibitors. These biomarkers offer better sensitivity and dynamic range than current methods in early clinical trials.

Area of Science:

  • Pharmacology
  • Biochemistry
  • Clinical Pharmacology

Background:

  • Drug-drug interactions (DDIs) pose significant risks in clinical practice.
  • Organic anion transporting polypeptide 1B (OATP1B) is crucial for the disposition of many drugs.
  • Accurate assessment of OATP1B-mediated DDIs is essential for drug safety.

Purpose of the Study:

  • To identify novel endogenous biomarkers for assessing OATP1B-mediated DDIs.
  • To evaluate the sensitivity and dynamic range of potential biomarkers.
  • To determine the suitability of endogenous compounds as biomarkers for OATP1B inhibition.

Main Methods:

  • Eight healthy subjects received rifampicin (an OATP1B inhibitor) at escalating doses (150, 300, 600 mg).
  • A probe drug cocktail including atorvastatin, pitavastatin, rosuvastatin, and valsartan was administered.
  • Plasma concentrations of endogenous compounds and probe drugs were analyzed to calculate area under the curve ratios (AUCR) and inhibition constants.

Main Results:

  • Four endogenous compounds (direct bilirubin, glycochenodeoxycholate-3-glucuronide, glycochenodeoxycholate-3-sulfate, hexadecanedioate) showed good sensitivity and dynamic range.
  • These compounds correlated well with probe drug exposure (AUC0-24h).
  • Nonlinear regression analysis provided estimates for rifampicin's inhibition constant, supporting biomarker suitability.

Conclusions:

  • Direct bilirubin, glycochenodeoxycholate conjugates, and hexadecanedioate are promising endogenous biomarkers for OATP1B.
  • These biomarkers can enhance early clinical trial DDI risk assessment.
  • They complement existing OATP1B biomarker strategies and agency guidelines.

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