Absorption, distribution, metabolism, and excretion of macitentan, a dual endothelin receptor antagonist, in humans

  title={Absorption, distribution, metabolism, and excretion of macitentan, a dual endothelin receptor antagonist, in humans},
  author={Shirin Bruderer and G{\'e}rard Hopfgartner and Michael Seiberling and J Ean H. S Wank and Patricia N. Sidharta and Alexander Treiber and Jasper Dingemanse},
  pages={901 - 910}
Macitentan is a tissue-targeting, dual endothelin receptor antagonist, currently under phase 3 investigation in pulmonary arterial hypertension. In this study the disposition and metabolism of macitentan were investigated following administration of a single oral 10 mg dose of 14C-macitentan to six healthy male subjects. The total radioactivity in matrices was determined using liquid scintillation counting. The proposed structure of metabolites was based on mass spectrometry characteristics and… 

The metabolism of the dual endothelin receptor antagonist macitentan in rat and dog

Metabolism was a prerequisite for macitentan excretion as relevant amounts of parent drug were neither detected in bile nor urine, and all metabolic pathways were present in rat and dog.

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

Macitentan metabolism is indeed affected by CYP3A4 inhibition, but the changes are not considered to be clinically significant and macitentan can be administered concomitantly with CYP2C19 isoenzyme without need for dose adjustment.

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

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.

Mass balance, pharmacokinetics and metabolism of the selective S1P1 receptor modulator ponesimod in humans

Ponesimod is an orally administered, selective S1P1 receptor modulator that blocks the egress of lymphocytes from lymphoid organs and reduces the availability of circulating effector T/B-cells and was extensively metabolised and two pharmacologically inactive metabolites were detected in the circulation.

A Population Pharmacokinetic Model of Macitentan and Its Active Metabolite Aprocitentan in Healthy Volunteers and Patients with Pulmonary Arterial Hypertension

The comprehensive population pharmacokinetic model adequately described the pharmacokinetics of macitentan and aprocitentan across different dose concentrations, regimens, and formulations.

Pharmacokinetics of the novel dual endothelin receptor antagonist macitentan in subjects with hepatic or renal impairment

Based on these observations, pharmacokinetic alterations of macitentan due to hepatic or renal function impairment are not considered clinically relevant and no dose adjustment is necessary in these patients.

Human mass balance, pharmacokinetics and metabolism of rovatirelin and identification of its metabolic enzymes in vitro

Rovatirelin was extensively metabolised to 20 metabolites, and TAMP was identified as the major metabolite in plasma and excreta among its metabolites and recombinant human cytochrome P450 3A4 and CYP3A5 displayed enzymatic activity in the assay.

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

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.

Pharmacokinetic study of ACT-132577 in rat plasma by ultra performance liquid chromatography-tandem mass spectrometry.

A sensitive and selective ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for determination of ACT-132577 in rat plasma was developed and validated and successfully applied to pharmacokinetic study of macitentan after oral and intravenous administration.



Pharmacology of Macitentan, an Orally Active Tissue-Targeting Dual Endothelin Receptor Antagonist

Macitentan, by its tissue-targeting properties and dual antagonism of ET receptors, protects against end-organ damage in diabetes and improves survival in pulmonary hypertensive rats, which makes it a new agent to treat cardiovascular disorders associated with chronic tissue ET system activation.

Comparison of the dissolution and pharmacokinetic profiles of two galenical formulations of the endothelin receptor antagonist macitentan.

  • O. KummerM. Haschke S. Krähenbühl
  • Biology, Medicine
    European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences
  • 2009

What is the Objective of the Mass Balance Study? A Retrospective Analysis of Data in Animal and Human Excretion Studies Employing Radiolabeled Drugs

Overall, mean recovery was greater in rats and dogs than in humans, and absolute recovery in humans should not be used as a major decision criteria as to whether a radiolabeled study has met its objectives.

Scope of radiological protection control measures.

[RECOMMENDATIONS of the International Commission on Radiological Protection].

  • R. SievertG. Failla
  • Physics
    Journal de radiologie, d'electrologie & archives d'electricite medicale
  • 1955
Recommendations are presented which represent concepts and practices evolved from recent discussions at formal and informal meetings of the Commission and its Committees.

Investigation of the effect of ketoconazole on the pharmacokinetics of macitentan in healthy male subjects

  • (Abstract). Br J Clin Pharmacol, 70, 730–731.
  • 2010

Safety, tolerability, pharmacokinetics, and pharmacodynamics of macitentan, an endothelin receptor antagonist, in an ascending multiple‐dose study in healthy subjects

The present results support investigation of macitentan in the management of pulmonary arterial hypertension and ET‐1‐dependent pathologies and suggest an improved liver safety profile.

Macitentan: entry-into-humans study with a new endothelin receptor antagonist

The pharmacokinetic and tolerability profile of macitentan is consistent with a once-a-day dosing regimen and warrants further investigation in clinical studies.

The 2007 Recommendations of the International Commission on Radiological Protection. ICRP publication 103.

  • J. Valentin
  • Physics, Environmental Science
    Annals of the ICRP
  • 2007
These revised Recommendations for a System of Radiological Protection formally replace the Commission's previous, 1990, Recommendations; and update, consolidate, and develop the additional guidance

Multiple - dose tolerability , safety , pharmacokinetics , and pharmacodynamics of the dual endothelin receptor antagonist ACT064992 in healthy human subjects . ( Abstract )

  • J Clin Pharmacol
  • 2008