Effect of lopinavir/ritonavir on the pharmacokinetics of selexipag an oral prostacyclin receptor agonist and its active metabolite in healthy subjects

Br J Clin Pharmacol. 2015 Oct;80(4):670-7. doi: 10.1111/bcp.12650. Epub 2015 Jun 12.


Aims: 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.

Keywords: drug-drug interaction; lopinavir/ritonavir; pharmacokinetics; selexipag.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetamides / adverse effects
  • Acetamides / blood
  • Acetamides / metabolism*
  • Acetamides / pharmacokinetics*
  • Acetates / blood
  • Acetates / pharmacokinetics*
  • Adult
  • Antihypertensive Agents / adverse effects
  • Antihypertensive Agents / blood
  • Antihypertensive Agents / pharmacokinetics
  • Cross-Over Studies
  • Cytochrome P-450 CYP3A Inhibitors / pharmacology
  • Drug Combinations
  • Drug Interactions
  • Healthy Volunteers
  • Humans
  • Lopinavir / pharmacology*
  • Male
  • Middle Aged
  • Pyrazines / adverse effects
  • Pyrazines / blood
  • Pyrazines / metabolism*
  • Pyrazines / pharmacokinetics*
  • Ritonavir / pharmacology*
  • Young Adult


  • Acetamides
  • Acetates
  • Antihypertensive Agents
  • Cytochrome P-450 CYP3A Inhibitors
  • Drug Combinations
  • Pyrazines
  • lopinavir-ritonavir drug combination
  • Lopinavir
  • selexipag
  • (4-((5,6-diphenylpyrazin-2-yl)(isopropyl)amino)butoxy)acetic acid
  • Ritonavir