A pharmacokinetic drug-drug interaction study between selexipag and midazolam, a CYP3A4 substrate, in healthy male subjects.
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 ) measured under steady-state conditions. In order to confirm in vivo t...
| Published in: | European Journal of Clinical Pharmacology Vol. 73; no. 9; pp. 1121 - 1129 |
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| Main Authors: | , , , , |
| Format: | research tables/charts randomized controlled trial Journal Article |
| Published: |
Springer Nature
Sep2017
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| Online Access: | View this record in EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=124504645&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 124504645 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00316970 NP9 jtl: European Journal of Clinical Pharmacology issn: 00316970 maglogo: N pubinfo: dt: Sep2017 vid: 73 iid: 9 pid: 237 pub: Springer Nature place: New York, New York artinfo: ui: 124504645 124504645 144059743 124504645 10.1007/s00228-017-2282-7 124504645 ppf: 1121 ppct: 8 formats: fmt: @attributes: type: P tig: atl: A pharmacokinetic drug-drug interaction study between selexipag and midazolam, a CYP3A4 substrate, in healthy male subjects. aug: au: Juif, Pierre-Eric Boehler, Margaux Donazzolo, Yves Bruderer, Shirin Dingemanse, Jasper affil: Department of Clinical Pharmacology , Actelion Pharmaceuticals Ltd. , Gewerbestrasse 16 4123 Allschwil Switzerland sug: subj: Midazolam Pharmacokinetics Drug Interactions Prostaglandins I Cytochrome P-450 Enzyme System Human Male Health Data Collection Randomized Controlled Trials Receptors, Cell Surface Patient Safety Data Analysis Software Drug Therapy, Combination Funding Source Male ab: 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 ) 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 of midazolam and 1-hydroxymidazolam was decreased by approximately 20 and 14%, respectively, following treatment B compared to A. The time to reach C 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. pubtype: Academic Journal doctype: research tables/charts randomized controlled trial Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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