Pharmacokinetics of Macitentan in Patients With Pulmonary Arterial Hypertension and Comparison With Healthy Subjects

Issac, Milena; Dingemanse, Jasper; Sidharta, Patricia N.

doi:10.1002/jcph.888

Cited by 5 publications

(6 citation statements)

References 21 publications

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“…According to our literature survey, there was only one pharmacokinetic study in PAH patients and the values obtained were 289 ± 42 ng/mL ( C max ), 8.0 (6.0–9.0) h ( t max ) and 4879 ± 48 ng h/mL (AUC). The results obtained from a pharmacokinetic study were well correlated with the study (Issac et al, ) mentioned above.…”

Section: Resultssupporting

confidence: 84%

“…The best recovery from plasma was obtained with diethyl ether. In the literature, several studies determined the pharmacokinetics of macitentan in PAH patients (Issac, Dingemanse, & Sidharta, ) and healthy volunteers (Ahn et al, ; Kummer et al, ; Sidharta, van Giersbergen, & Dingemanse, ; Yu et al, ). According to our literature survey, there was only one pharmacokinetic study in PAH patients and the values obtained were 289 ± 42 ng/mL ( C max ), 8.0 (6.0–9.0) h ( t max ) and 4879 ± 48 ng h/mL (AUC).…”

Section: Resultsmentioning

confidence: 99%

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A novel, rapid and sensitive UPLC–MS/MS method for the determination of macitentan in patients with pulmonary arterial hypertension

Albayrak

Alptug

Uçar

et al. 2019

Biomedical Chromatography

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Macitentan is an endothelin receptor antagonist commonly used in the treatment of pulmonary arterial hypertension (PAH). A novel, rapid, simple and sensitive UPLC–MS/MS method was developed and validated for pharmacokinetic study and the determination of macitentan in PAH patients. Macitentan and bosentan, which are used as internal standards, were detected using atmospheric pressure chemical ionization in positive ion and multiple reaction monitoring mode by monitoring the mass transitions m/z 589.1 → 203.3 and 552.6 → 311.5, respectively. Chromatographic separation was performed on a reverse‐phase C18 column (5 μm, 4.6 × 150 mm) with an isocratic mobile phase, which consisted of water containing 0.2% acetic acid–acetonitrile (90:10, v/v) at a flow rate of 1 mL/min. Retention times were 1.97 and 1.72 min for macitentan and IS, respectively. The calibration curve with high correlation coefficient (0.9996) was linear in the range 1–500 ng/mL. The lower limit of quantitation and average recovery values were determined as 1 ng/mL and 89.8%, respectively. This method is the first UPLC–MS/MS method developed and validated for the determination of macitentan from human plasma. The developed analytical method was fully validated for linearity, selectivity, specificity, accuracy, precision, sensitivity, stability, matrix effect and recovery according to US Food and Drug Administration guidelines. The developed method was applied successfully for pharmacokinetic study and the determination of macitentan in PAH patients.

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Section: Resultssupporting

confidence: 84%

Section: Resultsmentioning

confidence: 99%

A novel, rapid and sensitive UPLC–MS/MS method for the determination of macitentan in patients with pulmonary arterial hypertension

Albayrak

Alptug

Uçar

et al. 2019

Biomedical Chromatography

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“…Despite these limitations our studies show that there is no pharmacokinetic interaction between macitentan and the BCRP substrates, rosuvastatin and riociguat, in healthy subjects. Given that the pharmacokinetic profile of macitentan in healthy subjects is similar to that in PAH patients, the results presented here can be extrapolated to PAH [34]. Our results also suggest that macitentan can be used in combination with other BCRP substrates.…”

Section: Discussionsupporting

confidence: 52%

Effect of Macitentan on the Pharmacokinetics of the Breast Cancer Resistance Protein Substrates, Rosuvastatin and Riociguat, in Healthy Male Subjects

et al. 2019

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BackgroundMacitentan is a clinically approved endothelin receptor antagonist for the treatment of pulmonary arterial hypertension (PAH). Increasing use of combination drug therapy in PAH means that it is important to recognize potential drug–drug interactions (DDIs) that could affect the efficacy and safety of macitentan in patients with PAH.ObjectiveTwo Phase 1 studies were conducted to investigate the effect of macitentan at steady-state on the pharmacokinetics of the breast cancer resistance protein (BCRP) substrates, rosuvastatin and riociguat in healthy male subjects. Another objective was to determine the safety and tolerability of concomitant administration of rosuvastatin or riociguat with macitentan.MethodsHealthy male subjects received a single oral dose of rosuvastatin 10 mg (n = 20) or riociguat 1 mg (n = 20) on Day 1 (reference treatment). A loading oral dose of macitentan 30 mg was administered on Day 5 followed by macitentan 10 mg once-daily from Day 6 to Day 15 (riociguat study) or Day 6 to Day 16 (rosuvastatin study). A concomitant oral dose of rosuvastatin 10 mg or riociguat 1 mg was administered on Day 10 (test treatment). Pharmacokinetics were evaluated for 96 h after treatment on Day 1 and for 144 h (riociguat study) or 168 h (rosuvastatin study) after treatment on Day 10. To compare the reference and test treatments, the geometric mean ratio was calculated for the maximum plasma concentration (Cmax), the area under the plasma concentration-time curve (AUC) from zero (pre-dose) to time of the last measured concentration above the limit of quantification (AUC0–t), the AUC from zero to infinity (AUC0–∞) and the terminal elimination half-life (t½) of rosuvastatin, riociguat and riociguat’s metabolite, M1. The difference in the time to reach maximum plasma concentration (tmax) was determined by the Wilcoxon test. Trough levels of macitentan and its metabolite, ACT-132577, were measured and safety was monitored throughout.ResultsNinety percent confidence intervals of the geometric mean ratios were within the bioequivalence criteria of 0.80–1.25. There was no significant difference between test and reference tmax. Rosuvastatin or riociguat did not affect the steady-state concentrations of macitentan and ACT-132577. The adverse event profile was consistent with the known safety profiles of the drugs.ConclusionsMacitentan 10 mg did not affect the pharmacokinetics of BCRP substrates, rosuvastatin or riociguat in healthy male subjects.EudraCT numbers: 2017–003095–31 and 2017–003502–41.

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“…Although the trough plasma concentration of macitentan and its active metabolite was about two-fold higher in PAH patients from the SERAPHIN trial than in healthy people, this did not translate to a significant difference in exposure expressed as maximum plasma concentration (Cmax) or area under the plasma concentration–time curve (AUC) over a dosing interval. 44…”

Section: Macitentan: Clinical Evidencementioning

confidence: 99%

“…Although the trough plasma concentration of macitentan and its active metabolite was about twofold higher in PAH patients from the SERAPHIN trial than in healthy people, this did not translate to a significant difference in exposure expressed as maximum plasma concentration (Cmax) or area under the plasma concentration-time curve (AUC) over a dosing interval. 44 Dosage and (contra) indications Macitentan (10 mg once daily orally) was approved in 2013 by the United States Food and Drug Administration (US FDA) and European Medicines Agency for the treatment of PAH to delay disease progression and to reduce hospitalizations (US, https://opsumit.com/opsumit-pre scribing-information.pdf) and for the long-term treatment of adults with PAH functioning in New York Heart Association class II-III (Europe, https://www.actelion.com/documents/en -rebranded/our-products/opsumit-smpc.pdf), in monotherapy or in combination therapy.…”

Section: Hemodynamicsmentioning

confidence: 99%

Treatment of pulmonary arterial hypertension with the dual endothelin receptor antagonist macitentan: clinical evidence and experience

Belge

Delcroix

2019

Ther Adv Respir Dis

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Macitentan (10 mg once daily orally), a dual endothelin receptor antagonist (ERA) developed by modifying the structure of bosentan to increase the efficacity and safety, is approved for the treatment of pulmonary arterial hypertension (PAH). The pivotal SERAPHIN trial, (a landmark trial in the history of PAH trials because of the large number of included patients, the long-term follow up and the first trial with morbidity/mortality as the primary endpoint) showed a reduction of the risk of a morbidity or mortality event by 45% over the treatment time compared with placebo. The positive effect on the primary endpoint was observed whether or not the patient was already on PAH therapy. There has been no direct comparison between macitentan and other ERAs, which were approved based on improved exercise capacity, but preclinical and clinical data suggest better pharmacological and safety profiles. Further analyses of the SERAPHIN trial investigated the predictive value of different indices and events on long-term outcome and mortality. The efficacy in children, the long-term effects and safety of macitentan and its place in combination therapy compared with other ERAs are still under investigation. This review presents the preclinical evidence of superiority of macitentan compared with other ERAs, and the available clinical trial data. The place of macitentan in the therapeutic algorithm for PAH treatment, post-marketing experience and future perspectives are discussed.

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Pharmacokinetics of Macitentan in Patients With Pulmonary Arterial Hypertension and Comparison With Healthy Subjects

Cited by 5 publications

References 21 publications

A novel, rapid and sensitive UPLC–MS/MS method for the determination of macitentan in patients with pulmonary arterial hypertension

A novel, rapid and sensitive UPLC–MS/MS method for the determination of macitentan in patients with pulmonary arterial hypertension

Effect of Macitentan on the Pharmacokinetics of the Breast Cancer Resistance Protein Substrates, Rosuvastatin and Riociguat, in Healthy Male Subjects

Treatment of pulmonary arterial hypertension with the dual endothelin receptor antagonist macitentan: clinical evidence and experience

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