Macitentan is a dual endothelin receptor antagonist under phase 3 investigation in pulmonary arterial hypertension. We investigated the effect of cyclosporine (Cs) and rifampin on the pharmacokinetics of macitentan and its metabolites ACT-132577 and ACT-373898 in healthy male subjects. In addition, in vitro studies were performed to investigate interactions between macitentan and its active metabolite ACT-132577 with human organic anion-transporting polypeptides (OATPs). The clinical study (AC-055-111) was conducted as a two-part, one-sequence, crossover study. Ten subjects in each part received multiple-dose macitentan followed by multiple-dose co-administration of Cs (part A) or rifampin (part B). In the presence of Cs, steady-state area under the plasma concentration-time profiles during a dose interval (AUC(τ)) for macitentan and ACT-373898 increased 10% and 7%, respectively, and decreased 3% for ACT-132577. Steady-state AUC(τ) of macitentan and ACT-373898 in the presence of rifampin decreased 79% and 64%, respectively. For ACT-132577, no relevant difference in AUC(τ) between the two treatments was observed. Macitentan co-administered with Cs or rifampin was well tolerated. The complementary in vitro studies demonstrated no marked differences in uptake rates of macitentan and ACT-132577 between the wild-type and OATP over-expressing cells over the concentration range tested. Concomitant treatment with Cs did not have any clinically relevant effect on the exposure to macitentan or its metabolites, at steady-state. Concomitant treatment with rifampin reduced significantly the exposure to macitentan and its metabolite ACT-373898 at steady-state but did not affect the exposure to the active metabolite ACT-132577 to a clinically relevant extent.
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http://dx.doi.org/10.1208/s12248-011-9316-3 | DOI Listing |
Clin J Gastroenterol
December 2024
Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, 514-8507, Japan.
Farm Hosp
December 2024
Servicio de Farmacia, División de Medicamentos, Hospital Clínico de Barcelona, Universidad sw Barcelona, Barcelona, España.
Objective: Improving understanding of actual pulmonary hypertension (PH) treatment adherence patterns is crucial to properly treating these patients. We aimed to primarily assess adherence to treatments used for pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) specific therapies, identify potential factors related to it and secondly describe its treatment patterns.
Methods: A 6-month observational cross-sectional study in a tertiary care hospital was conducted.
Expert Opin Drug Saf
December 2024
Department of Rheumatology, Chongqing Emergency Medical Center, Chongqing University Central Hospital, Chongqing, China.
Background: Adverse drug events (ADEs) for endothelin receptor antagonists (ERAs) and prostacyclin-related drugs (PRDs) have been reported in clinical trials, but large-scale, real-world evaluations for respiratory, thoracic, and mediastinal disorders (RTMD) remain scarce.
Methods: A pharmacovigilance analysis of the FAERS database (Q1 2004~Q2 2024) used the reporting odds ratio (ROR) method for disproportionality analysis to assess the adverse drug events (ADEs) of ERAs and PRDs in pulmonary arterial hypertension, focusing on risks related to RTMD.
Results: Reports of ADEs for ERAs (bosentan, ambrisentan, and macitentan) were 15,286, 36795, and 17,497, respectively, and for PRDs (epoprostenol, treprostinil, iloprost, and selexipag) were 5,477, 57265, 3,247, and 5,504.
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