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Impact of the Selective Orexin‐1 Receptor Antagonist ACT‐539313 on the Pharmacokinetics of the CYP3A Probe Drug Midazolam in Healthy Male Subjects
Author(s) -
Berger Benjamin,
Kaufmann Priska,
Koch Annelize,
Dingemanse Jasper
Publication year - 2020
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.1588
Subject(s) - midazolam , pharmacokinetics , cyp3a , pharmacology , antagonist , medicine , concomitant , chemistry , anesthesia , endocrinology , cytochrome p450 , receptor , metabolism , sedation
ACT‐539313 is a potent and selective orexin‐1 receptor antagonist. CYP3A is the major cytochrome P450 (CYP) enzyme involved in the metabolism and clearance of ACT‐539313 in man. The main objective of this study was to investigate the effect of ACT‐539313 on the pharmacokinetics of orally administered midazolam. Thereby, this single‐center, open‐label, fixed‐sequence study investigated the CYP3A interaction potential of ACT‐539313 following single‐ (on day 2) and repeated‐dose (on day 11) twice‐daily administration of 200 mg ACT‐539313. Exposure to midazolam was higher during concomitant administration of single as well as after repeated doses of ACT‐539313 over 10 days compared to midazolam alone (day 1). In the presence of ACT‐539313, the geometric mean ratio of the maximum plasma concentration and the area under the plasma concentration–time curve from time 0 to 24 hours increased by 1.18‐ and 1.79‐fold on day 2, and by 2.13‐ and 4.54‐fold on day 11, respectively. A similar outcome was also shown in the additionally evaluated urinary 6β‐hydroxycortisol/cortisol ratio (6β‐CR), as the geometric mean ratio of the 6β‐CR showed a decrease to 0.78 on day 2 and to 0.61 on day 11. The most commonly reported adverse events (AEs) included somnolence and headache. All AEs were transient and of mild intensity. No treatment‐related effects on vital signs, clinical laboratory, and electrocardiogram were observed. In summary, the observed corresponding decrease of both the validated, exogenous (midazolam/1‐hydroxymidazolam ratio) and a frequently used endogenous (6β‐CR) marker of CYP3A activity is indicative of CYP3A inhibition occurring after ACT‐539313 treatment.