Clinical Pharmacokinetics and Pharmacodynamics of the Endothelin Receptor Antagonist Macitentan

Sidharta, Patricia N.; Treiber, Alexander; Dingemanse, Jasper

doi:10.1007/s40262-015-0255-5

Cited by 41 publications

(37 citation statements)

References 87 publications

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“…Further phase 1 studies did not reveal relevant differences in PK warranting dose adjustments for race, sex, or age . Furthermore, dedicated drug–drug studies in healthy subjects indicated no or limited potential for drug interactions …”

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confidence: 97%

“…16 Furthermore, dedicated drug-drug studies in healthy subjects indicated no or limited potential for drug interactions. 17,18 During the SERAPHIN clinical trial, C trough values of macitentan and ACT-132577 were obtained at steady state following administration of macitentan at different doses (ie, 3 and 10 mg) to provide indirect information about daily exposure. This approach was considered appropriate based on the linear relationship between C trough and exposure found in healthy subjects.…”

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confidence: 99%

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

Issac

Dingemanse

Sidharta

2017

The Journal of Clinical Pharma

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Macitentan is a worldwide approved dual endothelin receptor antagonist that has demonstrated efficacy in the treatment of pulmonary arterial hypertension (PAH) in a phase 3 clinical trial, SERAPHIN, at a dose of 10 mg once daily. During this trial, trough plasma concentrations (C ) of macitentan and its active metabolite, ACT-132577, were obtained at steady state in 242 patients, indicating that mean C of both analytes was about 2-fold higher in PAH patients than in healthy subjects. To further investigate the pharmacokinetics (PK) of macitentan and its active metabolite, ACT-132577, a 24-hour PK profile was recorded at steady state in 20 PAH patients in the open-label extension of SERAPHIN. A cross-study comparison showed that although C in PAH patients is higher when compared with a historical reference group of healthy subjects, with geometric mean ratios of 1.45 and 1.36 for macitentan and ACT-132577, respectively, this does not translate to a significant difference in exposure expressed as maximum plasma concentration (C ) or area under the plasma concentration-time curve over a dosing interval (AUC ). Geometric mean ratios for C and AUC were 1.08 and 1.22, respectively, for macitentan and 1.24 and 1.31, respectively, for ACT-132577. Therefore, overall exposure at steady state to macitentan and ACT-132577 in PAH patients is considered similar to that in healthy subjects.

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confidence: 97%

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confidence: 99%

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

Issac

Dingemanse

Sidharta

2017

The Journal of Clinical Pharma

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“…Hence, when the pH of human plasma is higher, a higher ratio of macitentan is deprotonated. Furthermore, macitentan is highly bound to plasma proteins (>99%) (Sidharta et al, ). A higher pH and binding to proteins increase the solubility of macitentan.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, macitentan is highly bound to plasma proteins (>99%) (Sidharta et al, 2015). A higher pH and binding to proteins increase the solubility of macitentan.…”

Section: Matrix Effects and Extraction Recoverymentioning

confidence: 99%

“…Ambrisentan and sitaxentan are more selective than macitentan and mainly block the ET A receptor (Barst et al, ; Hynynen & Khalil, ). Macitentan is not selective and blocks both ET A and ET B receptors (Sidharta, Treiber, & Dingemanse, ). A selective ERA may be more beneficial to reducing vasoconstriction than a nonselective ERA (Barst et al, ).…”

Section: Introductionmentioning

confidence: 99%

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Simultaneous quantification of ambrisentan, macitentan and sitaxentan in human plasma using UPLC–MS/MS

Velde

Bahmany

Hitzerd

et al. 2020

Biomedical Chromatography

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Endothelin receptor antagonists (ERAs) such as, ambrisentan, macitentan and sitaxentan are primarily used for the treatment of pulmonary arterial hypertension. Considering the rise in endothelin in pre‐eclampsia, ERAs may also be useful in its treatment. To evaluate the pharmacokinetics of ERAs, a rapid ultra‐performance liquid chromatography tandem mass spectrometry method was developed and validated to determine the concentration of ambrisentan, macitentan and sitaxentan in human plasma. Plasma samples were treated with methanol to induce protein precipitation. A chromatographic separation was performed on a C18 column using a gradient of methanol–water containing 0.1% formic acid and 0.013% ammonium acetate and a flow rate of 0.5 ml/min. Multiple reaction monitoring was used for quantification. This method was validated in a linear range of 20.28–2028 μg/l for ambrisentan, 4.052–405.2 μg/l for macitentan and 205.4–10 270 μg/l for sitaxentan. The method was successfully validated according to US Food and Drug Administration guidelines to determine the concentrations of macitentan, ambrisentan and sitaxentan in human plasma. This method is now being used for study samples and clinical patient samples.

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Bioequivalence and the food effect of macitentan/tadalafil 10/20 fixed‐dose combination tablets versus the use of single‐component tablets in healthy subjects

Ford,

Sabet,

Natarajan

et al. 2024

Pharmacology Res & Perspec

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The primary aim was to demonstrate bioequivalence between the 10/20 mg fixed‐dose combination (FDC) of macitentan/tadalafil in a single tablet and the free combination of both drugs, and to evaluate the food effect on the 10/20 mg FDC in healthy participants. In this single‐center, randomized, open‐label, 3‐way crossover, single‐dose Phase 1 study in healthy adult participants, macitentan/tadalafil was administered as a 10/20 mg FDC formulation and compared with the free combination of macitentan and tadalafil. The food effect on the FDC was also evaluated. Pharmacokinetic sampling (216 h) was conducted. The 90% confidence intervals (CIs) for the geometric mean ratios of maximum observed plasma analyte concentration (Cmax) and area under the plasma analyte concentration–time curves (AUCs) for Treatment A (FDC, fasted) versus C (free combination, fasted) were within bioequivalence limits demonstrating that the FDC formulation can be considered bioequivalent to the free combination. The 90% CIs for the geometric mean ratios of Cmax and AUC for Treatment B (FDC, fed) versus A (FDC, fasted) were contained within bioequivalence limits demonstrating that there was no food effect. The administration of the 10/20 mg FDC was generally safe and well tolerated in healthy participants. This study demonstrated bioequivalence between the FDC of macitentan/tadalafil (10/20 mg) in a single tablet and the free combination of both drugs in healthy participants, and that the FDC can be taken without regard to food, similarly to the individual components. The FDC was generally safe and well tolerated.

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Clinical Pharmacokinetics and Pharmacodynamics of the Endothelin Receptor Antagonist Macitentan

Cited by 41 publications

References 87 publications

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

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

Simultaneous quantification of ambrisentan, macitentan and sitaxentan in human plasma using UPLC–MS/MS

Bioequivalence and the food effect of macitentan/tadalafil 10/20 fixed‐dose combination tablets versus the use of single‐component tablets in healthy subjects

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