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

• Published in: British journal of clinical pharmacology Vol. 80; no. 4; pp. 670 - 677
• Main Authors: Kaufmann, Priska, Niglis, Séverine, Bruderer, Shirin, Segrestaa, Jérôme, Äänismaa, Päivi, Halabi, Atef, Dingemanse, Jasper
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Ltd 01.10.2015
• Subjects: 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; drug–drug interaction; Healthy Volunteers; Humans; Lopinavir - pharmacology; lopinavir/ritonavir; Male; Middle Aged; pharmacokinetics; Pyrazines - adverse effects; Pyrazines - blood; Pyrazines - metabolism; Pyrazines - pharmacokinetics; Ritonavir - pharmacology; selexipag; Young Adult; lopinavir/ritonavir; pharmacokinetics; selexipag; drug-drug interaction
• ISSN: 0306-5251; 1365-2125; 1365-2125
• DOI: 10.1111/bcp.12650

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.