A pharmacokinetic drug–drug interaction study between selexipag and midazolam, a CYP3A4 substrate, in healthy male subjects

• Published in: European journal of clinical pharmacology Vol. 73; no. 9; pp. 1121 - 1128
• Main Authors: Juif, Pierre-Eric, Boehler, Margaux, Donazzolo, Yves, Bruderer, Shirin, Dingemanse, Jasper
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.09.2017; Springer Nature B.V
• Subjects: Acetamides - adverse effects; Acetamides - blood; Acetamides - pharmacokinetics; Acetamides - pharmacology; Adult; Antihypertensive Agents - adverse effects; Antihypertensive Agents - blood; Antihypertensive Agents - pharmacokinetics; Antihypertensive Agents - pharmacology; Area Under Curve; Biomedical and Life Sciences; Biomedicine; Cross-Over Studies; Cytochrome P-450 CYP3A - metabolism; Drug interaction; Drug Interactions; Half-Life; Healthy Volunteers; Humans; Intestine; Liver; Male; Midazolam; Midazolam - adverse effects; Midazolam - blood; Midazolam - pharmacokinetics; Midazolam - pharmacology; Pharmacokinetics; Pharmacokinetics and Disposition; Pharmacology; Pharmacology/Toxicology; Prescription drugs; Pyrazines - adverse effects; Pyrazines - blood; Pyrazines - pharmacokinetics; Pyrazines - pharmacology; Titration; Young Adult; Midazolam; Pharmacokinetics; CYP3A4; Drug interactions; Selexipag
• ISSN: 0031-6970; 1432-1041; 1432-1041
• DOI: 10.1007/s00228-017-2282-7

Purpose In vitro data showed that selexipag and its active metabolite (ACT-333679) have an inductive effect on CYP3A4, CYP2B6, and CYP2C9 at concentrations approximately 100-fold higher than the maximum plasma concentration ( C max ) measured under steady-state conditions. In order to confirm in vivo the lack of induction at the enterocyte level, we assessed the effect of selexipag on midazolam, a substrate of hepatic and intestinal CYP3A4. Methods This study was conducted according to an open-label, randomized, two-way crossover design. A total of 20 subjects received a single oral dose of 7.5 mg midazolam alone (treatment A) or on top of steady-state selexipag (treatment B). Selexipag was administered twice daily using an up-titration scheme consisting of three steps: 400, 600, 1000, and 1600 μg with increments every fourth day. A 24-h pharmacokinetic profile was performed following midazolam administration, and bioequivalence criteria were investigated on an exploratory basis. Results The C max of midazolam and 1-hydroxymidazolam was decreased by approximately 20 and 14%, respectively, following treatment B compared to A. The time to reach C max for midazolam and 1-hydroxymidazolam was similar between treatments. The terminal half-life was reduced in treatment B compared to A for both midazolam (16%) and 1-hydroxymidazolam (20%). Exposure (area under the curve) to midazolam and 1-hydroxymidazolam was similar between treatments, and the 90% confidence intervals of geometric mean ratios were within the bioequivalence interval. Treatment with midazolam, selexipag, and the combination was safe and well tolerated. Conclusion Exposure to midazolam and 1-hydroxymidazolam was not affected by treatment with selexipag.