Impact of the Selective Orexin‐1 Receptor Antagonist ACT‐539313 on the Pharmacokinetics of the CYP3A Probe Drug Midazolam in Healthy Male Subjects

Berger, Benjamin; Kaufmann, Priska; Koch, Annelize; Dingemanse, Jasper

doi:10.1002/jcph.1588

Cited by 11 publications

(34 citation statements)

References 25 publications

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“…The midazolam PK parameters when administered alone were comparable to those reported elsewhere under fed and fasted conditions 24,37–39 . After concomitant administration with 100 mg ACT‐1014‐6470, midazolam AUC 0–12 h increased 1.5‐fold.…”

Section: Discussionsupporting

confidence: 78%

Evaluation of the cytochrome P450 2C19 and 3A4 inhibition potential of the complement factor 5a receptor 1 antagonist ACT‐1014‐6470 in vitro and in vivo

Ort

Dingemanse

Delahaye

et al. 2023

Clinical Translational Sci

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ACT-1014-6470 is an orally available complement factor 5a receptor 1 antagonist and a novel treatment option in auto-inflammatory diseases. The in vitro inhibition potential of ACT-1014-6470 on cytochrome P450 isozymes (CYPs) and its effect on the pharmacokinetics (PK) of the CYP2C19 and CYP3A4 substrates omeprazole and midazolam, respectively, in humans were assessed. In vitro assays were conducted with isoform-specific substrates in human liver microsomes. In an open-label, two-period, fixed-sequence cocktail study, single doses of 20 mg omeprazole and 2 mg midazolam were administered concomitantly to 20 healthy male subjects alone (treatment A) and after a single dose of 100 mg ACT-1014-6470 (treatment B) under fed conditions. Safety and PK assessments were performed. Geometric mean ratios (GMRs) and 90% confidence intervals (CIs) of noncompartmental PK parameters of treatment B versus treatment A were calculated. In vitro, no time-dependent inhibition was observed and the lowest inhibition constant of 4.3 μM ACT-1014-6470 was recorded for CYP2C19. In humans, GMRs (90% CI) of omeprazole PK were 1.9 (1.5-2.5) for maximum plasma concentration (C max ) and 1.9 (1.5-2.3) for area under the plasma concentrationtime curve from 0 to 12 h (AUC 0-12 h ). Midazolam PK showed GMRs (90% CI) of 1.1 (1.1-1.2) for C max and 1.5 (1.4-1.6) for AUC 0-24 h . All treatments were welltolerated. In line with in vitro results and regulatory risk factor calculation, the increased exposure to omeprazole and midazolam in humans after concomitant administration with a single dose of 100 mg ACT-1014-6470 reflected a weak inhibition of CYP2C19 and CYP3A4.

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Section: Discussionsupporting

confidence: 78%

Evaluation of the cytochrome P450 2C19 and 3A4 inhibition potential of the complement factor 5a receptor 1 antagonist ACT‐1014‐6470 in vitro and in vivo

Ort

Dingemanse

Delahaye

et al. 2023

Clinical Translational Sci

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“…To date, a number of Hcrt‐R1 selective antagonists have been described in the scientific and patent literature (reviewed in [6, 29]; see also [90]). Clinical data of Hcrt‐R1 drug candidates have been published for ACT‐539313 [Idorsia Pharmaceuticals Ltd., 91, 92]–the first report of a Hcrt‐R1 antagonist in humans and JNJ‐61393215 [Janssen Research & Development LLC; 93]. ACT‐539313 was tested for PK/PD, single and multiple ascending dose safety and tolerability and drug‐drug interaction potential [91, 92, 237].…”

Section: Drug Discovery and Developmentmentioning

confidence: 99%

“…Clinical data of Hcrt‐R1 drug candidates have been published for ACT‐539313 [Idorsia Pharmaceuticals Ltd., 91, 92]–the first report of a Hcrt‐R1 antagonist in humans and JNJ‐61393215 [Janssen Research & Development LLC; 93]. ACT‐539313 was tested for PK/PD, single and multiple ascending dose safety and tolerability and drug‐drug interaction potential [91, 92, 237]. A Phase I study with JNJ‐61393215 provided positive proof of concept in CO 2 ‐induced panic in male healthy volunteers [93].…”

Section: Drug Discovery and Developmentmentioning

confidence: 99%

“…These data are promising for the advancement of Hcrt-R1 antagonists into clinical investigations for binge eating and possibly bulimia nervosa. Idorsia is developing ACT-539313, an Hcrt-R1 antagonist for various indications including binge eating and first in humans data have been published [91,92,237]. On the other hand, very extensive Phase III studies with the DORAs suvorexant, lemborexant and daridorexant, which lasted up to 12-14 months, have not resulted in weight reduction in these insomnia patients whether lean or obese (or for that matter in healthy controls) [see 55,59,60,129,238].…”

Section: Eating Disordersmentioning

confidence: 99%

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Hypocretins (orexins): The ultimate translational neuropeptides

2022

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The hypocretins (Hcrts), also known as orexins, are two neuropeptides produced exclusively in the lateral hypothalamus. They act on two specific receptors that are widely distributed across the brain and involved in a myriad of neurophysiological functions that include sleep, arousal, feeding, reward, fear, anxiety and cognition. Hcrt cell loss in humans leads to narcolepsy with cataplexy (narcolepsy type 1), a disorder characterized by intrusions of sleep into wakefulness, demonstrating that the Hcrt system is nonredundant and essential for sleep/wake stability. The causal link between Hcrts and arousal/wakefulness stabilisation has led to the development of a new class of drugs, Hcrt receptor antagonists to treat insomnia, based on the assumption that blocking orexin‐induced arousal will facilitate sleep. This has been clinically validated: currently, two Hcrt receptor antagonists are approved to treat insomnia (suvorexant and lemborexant), with a New Drug Application recently submitted to the US Food and Drug Administration for a third drug (daridorexant). Other therapeutic applications under investigation include reduction of cravings in substance‐use disorders and prevention of neurodegenerative disorders such as Alzheimer's disease, given the apparent bidirectional relationship between poor sleep and worsening of the disease. Circuit neuroscience findings suggest that the Hcrt system is a hub that integrates diverse inputs modulating arousal (e.g., circadian rhythms, metabolic status, positive and negative emotions) and conveys this information to multiple output regions. This neuronal architecture explains the wealth of physiological functions associated with Hcrts and highlights the potential of the Hcrt system as a therapeutic target for a number of disorders. We discuss present and future possible applications of drugs targeting the Hcrt system for the treatment of circuit‐related neuropsychiatric and neurodegenerative conditions.

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“…Two Phase I studies of nivasorexant in healthy participants (evaluating pharmacokinetics, pharmacodynamics, safety, and drug-drug interaction potential) have been performed (Berger et al, 2020;Kaufmann et al, 2020Kaufmann et al, , 2021. The objectives of this Phase II proofof-concept study were to evaluate the efficacy, safety, and tolerability of nivasorexant in the treatment of individuals with BED.…”

Section: Introductionmentioning

confidence: 99%

Efficacy, safety, and tolerability of nivasorexant in adults with binge‐eating disorder: A randomized, Phase II proof of concept trial

McElroy

Coloma

Berger

et al. 2023

Intl J Eating Disorders

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ObjectiveThis Phase II, placebo‐controlled, double‐blind study investigated the efficacy, safety, and tolerability of nivasorexant in the treatment of adults with moderate to severe binge‐eating disorder (BED).MethodsAdults meeting the DSM‐5 BED criteria were randomized 1:1 to placebo or nivasorexant (100 mg b.i.d.). The primary endpoint was the change from baseline to Week 12 in the number of binge eating (BE) days per week. Exploratory efficacy endpoints included cessation of BE in the last 4 weeks of treatment; and change from baseline to Week 12 in the number of BE episodes/week, the clinician global impression (CGI) of change, the Yale‐Brown Obsessive‐Compulsive Scale modified for BE, and the Hamilton rating scale for depression (HAMD‐17). Key safety outcomes included treatment‐emergent adverse events (TEAEs) and adverse events of special interest (i.e., somnolence and fatigue).ResultsSixty‐eight participants were randomized to each treatment arm. The change from baseline to Week 12 in the number of BE days/week was the same for placebo (least squares mean [LSM]: −2.93) and nivasorexant (LSM: −2.93), with no difference between the treatment groups (LSM difference = .000 [95% confidence interval (CI): −.69, .69], p = .9992). Furthermore, no differences between treatment groups were observed in the exploratory efficacy endpoints. Nivasorexant was well tolerated; the overall incidence of TEAEs was balanced between treatment groups, and the frequency of somnolence and fatigue in the nivasorexant group were similar to placebo.DiscussionIn this proof‐of‐concept study, 100 mg b.i.d. nivasorexant did not improve BE in adults with moderate to severe BED.Public SignificanceThe results of this Phase II study indicate that nivasorexant was well tolerated in adults with BED, but did not improve binge eating behavior over placebo. Further research is needed to improve our understanding of the role of the orexin‐1 receptor in BED.

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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

Cited by 11 publications

References 25 publications

Evaluation of the cytochrome P450 2C19 and 3A4 inhibition potential of the complement factor 5a receptor 1 antagonist ACT‐1014‐6470 in vitro and in vivo

Evaluation of the cytochrome P450 2C19 and 3A4 inhibition potential of the complement factor 5a receptor 1 antagonist ACT‐1014‐6470 in vitro and in vivo

Hypocretins (orexins): The ultimate translational neuropeptides

Efficacy, safety, and tolerability of nivasorexant in adults with binge‐eating disorder: A randomized, Phase II proof of concept trial

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