title: Effect of lopinavir/ritonavir on the pharmacokinetics of selexipag an oral prostacyclin receptor agonist and its active metabolite in healthy subjects.
abstract: OBJECTIVE
  This study investigated the effect of a fixed dose combination of lopinavir/ritonavir on the pharmacokinetics (PK) of selexipag and its active metabolite ACT-333679.
  
  
  METHODS
  This was an open label, randomized, single centre, two way, crossover study. Twenty healthy male subjects were treated with a single dose of 400 µg selexipag alone and in combination with multiple doses of lopinavir/ritonavir (400/100 mg) twice daily.
  
  
  RESULTS
  The results showed that lopinavir/ritonavir approximately doubled the exposure to selexipag. The area under the plasma concentration-time curve from time zero to infinity (AUC(0,∞) and the maximum plasma concentration (Cmax) of selexipag were 2.2- and 2.1-fold higher, respectively, than under selexipag alone, with a 90% confidence interval (CI) of the geometric mean ratio (GMR) of 1.9, 2.7 and 1.7, 2.6, respectively. For ACT-333679, the clinically more relevant component of selexipag, systemic exposure was increased by 8% (GMR of AUC(0,∞) 1.1, 90% CI 0.9, 1.3), when lopinavir/ritonavir was co-administered with selexipag. The most frequently reported adverse event (AE) was headache. A single dose of selexipag, administered either alone or together with multiple doses of lopinavir/ritonavir, was safe and well tolerated.
  
  
  CONCLUSIONS
  Lopinavir/ritonavir does not affect the PK parameters of selexipag and ACT-333679 to a clinically relevant extent. Therefore, adaptation of the selexipag dose is not required when co-administered with inhibitors of the organic anion-transporting polypeptide (OATP) 1B1/ 1B3, P-glycoprotein (P-gp) and/or CYP3A4.
authors: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil.
authors: Priska
authors: P
authors: Kaufmann
authors: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil.
authors: Séverine
authors: S
authors: Niglis
authors: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil.
authors: Shirin
authors: S
authors: Bruderer
authors: Department of Preclinical Pharmacokinetics and Metabolism, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors: Jérôme
authors: J
authors: Segrestaa
authors: Department of Preclinical Pharmacokinetics and Metabolism, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors: Päivi
authors: P
authors: Äänismaa
authors: Clinical Research Services Kiel GmbH, Kiel, Germany.
authors: Atef
authors: A
authors: Halabi
authors: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil.
authors: Jasper
authors: J
authors: Dingemanse
mesh_terms: D000081:Acetamides / Q000009:adverse effects / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*; D000085:Acetates / Q000097:blood / Q000493:pharmacokinetics*; D000328:Adult; D000959:Antihypertensive Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000494:pharmacology; D004338:Drug Combinations; D004347:Drug Interactions; D064368:Healthy Volunteers; D006801:Humans; D061466:Lopinavir / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D011719:Pyrazines / Q000009:adverse effects / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D000081:Acetamides; D000085:Acetates; D000959:Antihypertensive Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D004338:Drug Combinations; D011719:Pyrazines; C558899:lopinavir-ritonavir drug combination; D061466:Lopinavir; C523468:selexipag; C531934:(4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid; D019438:Ritonavir
keywords: drug-drug interaction; lopinavir/ritonavir; pharmacokinetics; selexipag