Pierre-Eric Juif1, Margaux Boehler2, Yves Donazzolo3, Shirin Bruderer2, Jasper Dingemanse2. 1. Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, 4123, Allschwil, Switzerland. pierre-eric.juif@actelion.com. 2. Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, 4123, Allschwil, Switzerland. 3. Eurofins Optimed, 1 rue des Essarts, 38610, Gieres, France.
Abstract
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.
RCT Entities:
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.
Entities:
Keywords:
CYP3A4; Drug interactions; Midazolam; Pharmacokinetics; Selexipag
Authors: Mary F Paine; Heather L Hart; Shana S Ludington; Robert L Haining; Allan E Rettie; Darryl C Zeldin Journal: Drug Metab Dispos Date: 2006-02-07 Impact factor: 3.922