Details

Autor(en) / Beteiligte

• Muehlan, C
• Brooks, S
• Zuiker, R
• van Gerven, J
• Dingemanse, J

Titel

0007 Multiple-Ascending-Dose Study Of ACT-541468, A Novel Dual Orexin Receptor Antagonist: Characterization Of Its Multiple-Dose Pharmacokinetics, Pharmacodynamics, Safety, And Tolerability

Ist Teil von

• Sleep (New York, N.Y.), 2018-04, Vol.41 (suppl_1), p.A3-A3

Ort / Verlag

US: Oxford University Press

Erscheinungsjahr

2018

Quelle

Oxford Journals 2020 Medicine

Beschreibungen/Notizen

• Abstract Introduction The orexin system regulates sleep and arousal. Following entry-into-humans with ACT-541468, a dual orexin receptor antagonist, multiple-ascending oral dose pharmacokinetics (PK) including dose-proportionality and accumulation, pharmacodynamics (PD), safety, and tolerability were investigated. Methods Double-blind, placebo-controlled, randomized, multiple-ascending dose study in 30 healthy male and female subjects (10, 25, and 75 mg once daily (o.d.) in the morning for 5 consecutive days, 8/2 active/placebo per group). PK, PD (saccadic peak velocity (SPV), adaptive tracking, body sway, Bond and Lader visual analog scales (VAS), Karolinska Sleepiness Scale (KSS), VAS Bowdle for assessment of psychedelic effects), safety, and tolerability were assessed. Results Following administration of 10, 25, or 75 mg of ACT-541468 o.d. the drug was rapidly absorbed, with a median tmax of 1.0–2.0 h. The geometric mean elimination half-life on Day 5 was between 5.6 and 8.5 h, and the exposure (area under the curve (AUC)) showed dose proportionality, while the maximum plasma concentration increased slightly less than proportionally to the dose administered. No relevant accumulation (based on AUC) was observed. No influence of sex on the multiple-dose PK parameters of ACT-541468 was observed. PD were assessed for 10 h on Days 1 and 5. There were no effects at 10 mg. At 25 and 75 mg, distinct effects on psychomotor functions (SPV, adaptive tracking, body sway) were observed. Onset of effects was within 1 h, maximum effects at 2 h, and return to baseline at approximately 4–10 h post-dose. Subjective alertness decreased dose-dependently. An increase in the KSS score was observed with 25 and 75 mg, and VAS Bowdle showed small increases at 75 mg. Conclusion Multiple-dose PK/PD of ACT-541468 are compatible with a drug for the treatment of insomnia and support further development in patients with insomnia disorders. Support (If Any) Clemens Muehlan and Jasper Dingemanse are employees at Idorsia, the sponsor of the clinical study. The investigators Joop van Gerven, Rob Zuiker, and Sander Brooks are employees of CHDR. The authors disclosed no other relevant affiliations or financial interest.