title: Physiologically-Based Pharmacokinetic Modeling of Macitentan: Prediction of Drug-Drug Interactions.
abstract: BACKGROUND
  Macitentan is a novel dual endothelin receptor antagonist for the treatment of pulmonary arterial hypertension (PAH). It is metabolized by cytochrome P450 (CYP) enzymes, mainly CYP3A4, to its active metabolite ACT-132577.
  
  
  METHODS
  A physiological-based pharmacokinetic (PBPK) model was developed by combining observations from clinical studies and physicochemical parameters as well as absorption, distribution, metabolism and excretion parameters determined in vitro.
  
  
  RESULTS
  The model predicted the observed pharmacokinetics of macitentan and its active metabolite ACT-132577 after single and multiple dosing. It performed well in recovering the observed effect of the CYP3A4 inhibitors ketoconazole and cyclosporine, and the CYP3A4 inducer rifampicin, as well as in predicting interactions with S-warfarin and sildenafil. The model was robust enough to allow prospective predictions of macitentan-drug combinations not studied, including an alternative dosing regimen of ketoconazole and nine other CYP3A4-interacting drugs. Among these were the HIV drugs ritonavir and saquinavir, which were included because HIV infection is a known risk factor for the development of PAH.
  
  
  CONCLUSIONS
  This example of the application of PBPK modeling to predict drug-drug interactions was used to support the labeling of macitentan (Opsumit).
authors.affiliation: Preclinical Pharmacokinetics and Metabolism, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland. ruben.de-kanter@actelion.com.
authors.forename: Ruben
authors.identifier: http://orcid.org/0000-0001-7503-9776
authors.initials: R
authors.lastname: de Kanter
authors.affiliation: Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland.
authors.forename: Patricia N
authors.initials: PN
authors.lastname: Sidharta
authors.affiliation: Preclinical Pharmacokinetics and Metabolism, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Delahaye
authors.affiliation: Preclinical Pharmacokinetics and Metabolism, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland.
authors.forename: Carmela
authors.initials: C
authors.lastname: Gnerre
authors.affiliation: Preclinical Pharmacokinetics and Metabolism, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland.
authors.forename: Jerome
authors.initials: J
authors.lastname: Segrestaa
authors.affiliation: Preformulation and Preclinical Galenics, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Buchmann
authors.affiliation: Preclinical Pharmacokinetics and Metabolism, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland.
authors.forename: Christopher
authors.initials: C
authors.lastname: Kohl
authors.affiliation: Preclinical Pharmacokinetics and Metabolism, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Treiber
mesh_terms: D000328:Adult; D016572:Cyclosporine / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology; D004347:Drug Interactions; D065130:Endothelin A Receptor Antagonists / Q000493:pharmacokinetics*; D065131:Endothelin B Receptor Antagonists / Q000493:pharmacokinetics*; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D008954:Models, Biological; D011743:Pyrimidines / Q000097:blood / Q000493:pharmacokinetics*; D012293:Rifampin / Q000494:pharmacology; D000068677:Sildenafil Citrate / Q000494:pharmacology; D013449:Sulfonamides / Q000097:blood / Q000493:pharmacokinetics*; D014859:Warfarin / Q000494:pharmacology
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D011743:Pyrimidines; D013449:Sulfonamides; D014859:Warfarin; D016572:Cyclosporine; D000068677:Sildenafil Citrate; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C572762:aprocitentan; D007654:Ketoconazole; D012293:Rifampin; C533860:macitentan