Pharmacokinetic–Pharmacodynamic Relationships of Macitentan, a New Endothelin Receptor Antagonist, After Multiple Dosing in Healthy Korean Subjects

Ahn, Li Young; Kim, Sung Eun; Yi, Sangho; Dingemanse, Jasper; Lim, Kyoung Soo; Jang, In‐Jin; Yu, Kyung‐Sang

doi:10.1007/s40256-014-0081-4

Cited by 11 publications

(8 citation statements)

References 29 publications

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“…PK and PD of macitentan in healthy Japanese male subjects obtained in this study were similar to those reported previously in Caucasian and Korean subjects 17,18) . The results of this study indicate a lack of significant variation in PK and PD of macitentan between ethnicities.…”

Section: )supporting

confidence: 90%

<b>Tolerability, Safety, Pharmacokinetics, and Pharmacodynamics of Macitentan, a New Endothelin Receptor Antagonist, in Healthy Japanese Male Subjects </b>

Yokoyama¹,

Dingemanse

Motonori³

et al. 2016

Jpn. J. Clin. Pharmacol. Ther.

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Tolerability, safety, pharmacokinetics, and pharmacodynamics of orally administered macitentan at 3 and 10 mg once daily for 10 days were investigated in 16 healthy Japanese male subjects in a randomized, placebo-controlled, double-blind, single-center study. Plasma concentrations of macitentan were found to peak at 5 hr, with a mean terminal elimination half-life of approximately 11 hr, for both doses of macitentan. Furthermore, the active metabolite of macitentan, ACT-132577, demonstrated a longer elimination half-life(approximately 48 hr). Area under the plasma concentration-time curve(AUC)of endothelin-1 was significantly higher in the macitentan 10-mg group compared with the placebo group (exploratory p value, 0.0154). No critical issues regarding the safety and tolerability of macitentan were observed, including time-matched electrocardiographic (ECG)evaluations. The results of this study in healthy Japanese male subjects corroborate with previous studies in Caucasian and Korean subjects. In conclusion, the macitentan dose range from 3 to 10 mg had a good safety and tolerability profile in healthy Japanese male subjects, and its pharmacokinetics and pharmacodynamics were dose-dependent without ethnic differences.

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Section: )supporting

confidence: 90%

<b>Tolerability, Safety, Pharmacokinetics, and Pharmacodynamics of Macitentan, a New Endothelin Receptor Antagonist, in Healthy Japanese Male Subjects </b>

Yokoyama¹,

Dingemanse

Motonori³

et al. 2016

Jpn. J. Clin. Pharmacol. Ther.

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“…The pharmacokinetics of macitentan and ACT-132577 were further investigated in multiple-ascending dose studies in 30 healthy Korean subjects [ 68 ] and 24 Japanese subjects [ 100 ]. Doses of macitentan 3, 10, and 30 mg or placebo were studied in groups of ten Korean subjects (eight on active, two on placebo) and eight Japanese subjects (six on active, two on placebo) each.…”

Section: Pharmacokinetics In Special Populationsmentioning

confidence: 99%

Clinical Pharmacokinetics and Pharmacodynamics of the Endothelin Receptor Antagonist Macitentan

2015

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Pulmonary arterial hypertension (PAH) is a progressive disease of the lung vascular system, which leads to right-sided heart failure and ultimately death if untreated. Treatments to regulate the pulmonary vascular pressure target the prostacyclin, nitric oxide, and endothelin (ET) pathways. Macitentan, an oral, once-daily, dual ETA and ETB receptor antagonist with high affinity and sustained receptor binding is the first ET receptor antagonist to show significant reduction of the risk of morbidity and mortality in PAH patients in a large-scale phase III study with a long-term outcome. Here we present a review of the available clinical pharmacokinetic, pharmacodynamic, pharmacokinetic/pharmacodynamic relationship, and drug–drug interaction data of macitentan in healthy subjects, patients with PAH, and in special populations.

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“…The exposure to ACT-132577 was~15% higher in all women, independent of race, when compared to men [66]. Similar PK properties were observed in Korean subjects in a multiple dosing regimen with macitentan [67]. ACT-132577 Data are expressed as geometric means (and 95% CI) or for t max the median (and range).…”

Section: Pks In Healthy Subjectsmentioning

confidence: 64%

“…ET-1 levels did not further increase at a dose level of 30 mg macitentan, which supported the choice of 10 mg macitentan in further clinical studies [62]. In a study in healthy Korean subjects ET-1 plasma concentrations increased to a similar extent as in Caucasians, following multiple-dose administration of macitentan [67]. This indicates that ethnic differences probably do not impact the efficacy of macitentan.…”

Section: Pharmacodynamicsmentioning

confidence: 68%

Pharmacokinetic and pharmacodynamic evaluation of macitentan, a novel endothelin receptor antagonist for the treatment of pulmonary arterial hypertension

Sidharta

Krähenbühl

Dingemanse

2015

Expert Opinion on Drug Metabolism & Toxicology

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Up to date, macitentan is the only registered treatment for PAH that significantly reduced morbidity and mortality as a combined endpoint in a long-term event-driven study. The safety profile of macitentan is favorable with respect to hepatic safety and edema/fluid retention and may be better than that of other ET receptor antagonists such as bosentan and ambrisentan. The PK profile supports a once-a-day dosing regimen. Macitentan has limited interactions with other drugs. Based on these characteristics macitentan is an important new addition to the treatment of PAH.

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Pharmacokinetic–Pharmacodynamic Relationships of Macitentan, a New Endothelin Receptor Antagonist, After Multiple Dosing in Healthy Korean Subjects

Abstract: Multiple oral doses of 3, 10, and 30 mg of macitentan were well tolerated in healthy Korean subjects, and its pharmacokinetics correlated positively with ET-1 concentrations.

Cited by 11 publications

References 29 publications

<b>Tolerability, Safety, Pharmacokinetics, and Pharmacodynamics of Macitentan, a New Endothelin Receptor Antagonist, in Healthy Japanese Male Subjects </b>

<b>Tolerability, Safety, Pharmacokinetics, and Pharmacodynamics of Macitentan, a New Endothelin Receptor Antagonist, in Healthy Japanese Male Subjects </b>

Clinical Pharmacokinetics and Pharmacodynamics of the Endothelin Receptor Antagonist Macitentan

Pharmacokinetic and pharmacodynamic evaluation of macitentan, a novel endothelin receptor antagonist for the treatment of pulmonary arterial hypertension

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