Single-Dose Pharmacokinetics, Safety, and Tolerability of Macitentan, a New Dual Endothelin Receptor Antagonist, in Subjects With Severe Renal Function Impairment

Sidharta, Patricia N.; Lindegger, Nicolas; Ulč, Ivan; Giersbergen, Paul van; Dingemanse, Jasper

doi:10.1378/chest.1387371

Cited by 3 publications

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“…In preclinical and clinical studies macitentan showed (1) sustained receptor binding [1], high potency, and tissue penetration properties [2], (2) excellent pharmacokinetic (PK) properties [3,4,5], (3) low potential for interaction with other drugs at the level of cytochrome P450 enzymes and organic anion-transporting polypeptide transporters [6,7], and (4) no need for dose adjustment in patients with hepatic or renal impairment [8,9]. …”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of Macitentan in Caucasian and Japanese Subjects: The Influence of Ethnicity and Sex

et al. 2013

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Background/Aims: Macitentan is a novel dual endothelin receptor antagonist with sustained receptor binding in clinical development for pulmonary arterial hypertension. The present study compared the pharmacokinetics and safety of macitentan in healthy Caucasian and Japanese subjects and explored the potential sex differences. Methods: In this single-center, open-label, phase I study 10 healthy subjects of each ethnic origin with a male/female ratio of 1:1 in each group were administered a single oral 10-mg dose of macitentan. Blood samples were taken to determine plasma levels of macitentan and its pharmacologically active metabolite, ACT-132577, and safety and tolerability were monitored using standard assessments. Results: For both macitentan and its metabolite, values for C_max were similar but a shorter half-life was determined in Japanese subjects resulting in an exposure to both compounds being approximately 15% lower in Japanese when compared to Caucasian subjects. The exposure to macitentan was similar in Japanese males and females whereas Caucasian females had an approximately 25% higher exposure than Caucasian males. In both ethnic groups, females had an approximately 15% higher exposure to ACT-132577 than male subjects. Macitentan was well tolerated in both ethnic groups. There were no clinically significant differences in adverse event profile, clinical laboratory, electrocardiographic parameters, and vital signs between both groups. Conclusion: The data suggest that the minor differences in pharmacokinetics between the two groups are not clinically relevant and no dose adjustment of macitentan based on Japanese ethnic origin or sex is necessary.

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Section: Introductionmentioning

confidence: 99%

Pharmacokinetics of Macitentan in Caucasian and Japanese Subjects: The Influence of Ethnicity and Sex

et al. 2013

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Investigation of the Effects of Ketoconazole on the Pharmacokinetics of Macitentan, a Novel Dual Endothelin Receptor Antagonist, in Healthy Subjects

et al. 2013

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Efficacy, safety and clinical pharmacology of macitentan in comparison to other endothelin receptor antagonists in the treatment of pulmonary arterial hypertension

Dingemanse

Sidharta

Maddrey

et al. 2013

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The large Phase III study (SERAPHIN) tested macitentan in more than 700 PAH patients and has provided unique long-term outcome data for this ERA, not available for other members of this class. The effect on a composite clinically relevant morbidity/mortality end point was highly significant at a 10 mg/day dose. The safety profile of macitentan appears to be superior with respect to hepatic safety and edema/fluid retention than bosentan and ambrisentan, respectively, and is similar when considering decrease in hemoglobin concentration. The drug has a low propensity for drug-drug interactions and has one circulating pharmacologically active metabolite. The pharmacokinetics of macitentan in patients with renal or hepatic impairment does not require dose adjustments. Based on its characteristics, macitentan is an important addition to the therapeutic armamentarium in the long-term treatment of PAH. Its potential use in other disorders is under investigation.

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Single-Dose Pharmacokinetics, Safety, and Tolerability of Macitentan, a New Dual Endothelin Receptor Antagonist, in Subjects With Severe Renal Function Impairment

Cited by 3 publications

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Pharmacokinetics of Macitentan in Caucasian and Japanese Subjects: The Influence of Ethnicity and Sex

Pharmacokinetics of Macitentan in Caucasian and Japanese Subjects: The Influence of Ethnicity and Sex

Investigation of the Effects of Ketoconazole on the Pharmacokinetics of Macitentan, a Novel Dual Endothelin Receptor Antagonist, in Healthy Subjects

Efficacy, safety and clinical pharmacology of macitentan in comparison to other endothelin receptor antagonists in the treatment of pulmonary arterial hypertension

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