RT Journal Article
SR Electronic
T1 Lack of relevant pharmacokinetic and pharmacodynamic interactions between the new dual endothelin receptor antagonist macitentan and warfarin in healthy subjects
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP P950
VO 40
IS Suppl 56
A1 Patricia Sidharta
A1 Hartmut Dietrich
A1 Jasper Dingemanse
YR 2012
UL http://erj.ersjournals.com/content/40/Suppl_56/P950.abstract
AB Macitentan, a new, potent, dual endothelin receptor antagonist (ERA), is a potential treatment for pulmonary arterial hypertension (PAH). In this study (AC-055-105), the effect of macitentan on the pharmacokinetics (PK) and pharmacodynamics (PD) of a single dose of warfarin was investigated in 14 healthy male subjects. Subjects received treatment sequence A/B or B/A separated by a 2-week washout. Treatment A: macitentan for 8 days (loading dose of 30 mg, thereafter 10 mg o.d.). On Day 4, a single dose of 25 mg warfarin was given with macitentan. Treatment B: A single dose of 25 mg warfarin on Day 1. Blood samples were assessed for warfarin PK (R- and S-warfarin) and PD (INR and Factor VII). Plasma trough levels of macitentan and its active metabolite, ACT-132577, were determined. Twelve subjects were included in the PK/PD analysis. The plasma concentration-time profiles of R- and S-Warfarin (Figure 1) and PD parameters of INR and Factor VII were comparable between treatments. Warfarin did not impact the trough levels of macitentan and ACT-132577. Both treatments were well tolerated. Based on these results, no dose correction of macitentan or warfarin is needed when using these drugs together.Figure: Plasma concentration-time profile of R- and S-warfarin with and without macitentan (mean ± SD, n=12).