Effect of lopinavir/ritonavir on the pharmacokinetics of selexipag an oral prostacyclin receptor agonist and its active metabolite in healthy subjects. (12th June 2015)

• Record Type: Journal Article
• Authors: Kaufmann, Priska; Niglis, Séverine; Bruderer, Shirin; Segrestaa, Jérôme; Äänismaa, Päivi; Halabi, Atef; Dingemanse, Jasper
• Is Part Of: British journal of clinical pharmacology. Volume 80:Number 4(2015:Oct.)
• Page Start: 670
• Page End: 677
• Publication Date: 2015-06-12
• Subjects: Pharmacology -- Periodicals; Drugs -- Periodicals; 615.1
• DOI: 10.1111/bcp.12650
• Languages: English
• ISSNs: 0306-5251

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bcp12650-sec-0001" sec-type="section"> <title>Aims</title> <p>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.</p> </sec> <sec id="bcp12650-sec-0002" sec-type="section"> <title>Methods</title> <p>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.</p> </sec> <sec id="bcp12650-sec-0003" sec-type="section"> <title>Results</title> <p>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 (<italic>C</italic><sub>max</sub>) 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.</p> <p>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.</p> </sec> <sec id="bcp12650-sec-0004" sec-type="section"> <title>Conclusions</title> <p>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.</p> </sec> </abstract>