Influence of Rifampin-Mediated Organic Anion-Transporting Polypeptide 1B1/1B3 Inhibition on the Pharmacokinetics of Clazosentan

Clin Transl Sci. 2019 Sep;12(5):440-444. doi: 10.1111/cts.12639. Epub 2019 May 6.


Clazosentan is a selective endothelin A receptor antagonist in development for the prevention and treatment of vasospasm postsubarachnoid hemorrhage. It is a substrate of organic anion-transporting polypeptide 1B1/1B3 based on preclinical data. This randomized, double-blind, two-period, cross-over study investigated the pharmacokinetics, safety, and tolerability of an intravenous infusion of clazosentan (15 mg/hour for 3 hours) after the intravenous administration of placebo or rifampin (600 mg/100 mL in 30 minutes). A total of 14 healthy male participants were enrolled resulting in 13 completers. Clazosentan exposure was three to four times higher after organic anion-transporting polypeptide 1B1/1B3 inhibition, as reflected by the geometric mean ratio (90% confidence interval) of area under the plasma concentration-time curve from zero to infinity: 3.88 (3.24-4.65). Clearance and volume of distribution decreased to a similar extent. Elimination half-life was not affected. A similar pattern but a higher incidence and frequency of adverse events were observed when clazosentan was given with rifampin than with placebo.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Dioxanes / adverse effects
  • Dioxanes / pharmacokinetics*
  • Humans
  • Liver-Specific Organic Anion Transporter 1 / antagonists & inhibitors*
  • Liver-Specific Organic Anion Transporter 1 / metabolism
  • Male
  • Middle Aged
  • Pyridines / adverse effects
  • Pyridines / pharmacokinetics*
  • Pyrimidines / adverse effects
  • Pyrimidines / pharmacokinetics*
  • Rifampin / pharmacology*
  • Solute Carrier Organic Anion Transporter Family Member 1B3 / antagonists & inhibitors*
  • Solute Carrier Organic Anion Transporter Family Member 1B3 / metabolism
  • Sulfonamides / adverse effects
  • Sulfonamides / pharmacokinetics*
  • Tetrazoles / adverse effects
  • Tetrazoles / pharmacokinetics*


  • Dioxanes
  • Liver-Specific Organic Anion Transporter 1
  • Pyridines
  • Pyrimidines
  • SLCO1B1 protein, human
  • SLCO1B3 protein, human
  • Solute Carrier Organic Anion Transporter Family Member 1B3
  • Sulfonamides
  • Tetrazoles
  • clazosentan
  • Rifampin