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Investigation of the Effect of Macitentan on the Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Male Subjects

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Abstract

Background and Objectives

Macitentan is a novel dual endothelin receptor antagonist recently approved for the treatment of pulmonary arterial hypertension (PAH). Warfarin, an anticoagulant often prescribed to patients with PAH, has a narrow therapeutic index and is prone to potential interactions with drugs. This study assessed the effects of macitentan on the pharmacokinetics and pharmacodynamics of single-dose warfarin in healthy subjects.

Methods

This was a randomised, open-label, single-centre, two-way crossover (treatment A followed by treatment B, or vice versa), phase I study in 14 healthy male subjects. Treatment A was a loading dose of macitentan 30 mg on Day 1 followed by 10 mg once daily for 8 days, with a single 25 mg dose of warfarin on Day 4. Treatment B was a single dose of warfarin on Day 1. Blood samples were assessed for warfarin pharmacokinetics (R- and S-warfarin) and pharmacodynamics [international normalised ratio (INR) and factor VII]. Plasma trough concentrations of macitentan and its active metabolite (ACT-132577) and the safety and tolerability of each treatment were also assessed.

Results

Plasma concentrations of R- and S-warfarin were similar in both treatment periods. Warfarin did not affect the mean trough plasma concentrations of macitentan or ACT-132577. Macitentan did not affect the pharmacodynamics of warfarin; the mean INR and factor VII activity versus time profiles were similar with and without macitentan.

Conclusions

The absence of effect of macitentan on the pharmacokinetics and pharmacodynamics of a single dose of warfarin suggests that both drugs can be concomitantly administered without need for dose adjustment.

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Acknowledgments

Medical writing assistance was provided by Rose Doyle, PhD (Elements Communications Ltd, Westerham, UK) and funded by Actelion Pharmaceuticals Ltd.

Conflict of interest

P.N. Sidharta and J. Dingemanse are employees of Actelion Pharmaceuticals Ltd, Allschwil, Switzerland. H. Dietrich was the principal investigator in this study and ClinPharmCologne received funding from Actelion Pharmaceuticals Ltd to conduct the trial.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, Allschwil, Switzerland

    Patricia N. Sidharta & Jasper Dingemanse

  2. ClinPharmCologne, MEDA Manufacturing GmbH, Cologne, Germany

    Hartmut Dietrich

Authors
  1. Patricia N. Sidharta
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  2. Hartmut Dietrich
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  3. Jasper Dingemanse
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Correspondence to Jasper Dingemanse.

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Sidharta, P.N., Dietrich, H. & Dingemanse, J. Investigation of the Effect of Macitentan on the Pharmacokinetics and Pharmacodynamics of Warfarin in Healthy Male Subjects. Clin Drug Investig 34, 545–552 (2014). https://doi.org/10.1007/s40261-014-0207-0

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  • DOI: https://doi.org/10.1007/s40261-014-0207-0

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