Peter D van der Ark1, Georg Golor2, Luc van Nueten1, Partha Nandy3, Peter de Boer1. 1. 1 Department of Experimental Medicine Neuroscience, Janssen Research and Development, Beerse, Belgium. 2. 2 PAREXEL GmbH, Berlin, Germany. 3. 3 Department of Global Clinical Pharmacology, Janssen Research and Development US, Raritan, NJ, USA.
Abstract
BACKGROUND:Pharmacokinetics, pharmacodynamics and general safety and tolerability of JNJ-42847922, a selective orexin-2 receptor antagonist, were assessed in healthy subjects. METHODS:Five consecutive cohorts of healthy subjects were enrolled and received doses of 5-60 mg orally once daily over 10 days of JNJ-42847922 ( n=6) or placebo ( n=2). Concentrations of drug in plasma and urine were measured over 24 h after dosing on Days 1, 5 and 10. Observed- and self-reported somnolence was used to evaluate the principal pharmacodynamic effect of JNJ-42847922. A test battery to assess vigilance state, sedation and alertness was assessed at 4, 6 and 8 h after dosing. Safety assessments included recording of adverse events, vital signs, electrocardiograms, clinical laboratory assessments and suicidality per Columbia Suicide Severity Rating Scale. RESULTS: JNJ-42847922 was rapidly absorbed after the morning dose administration. The median tmax ranged from 0.5-1.5 h and mean t1/2 values from 2-3 h. At JNJ-42847922 dose levels ⩾20 mg, mean Cmax and mean area under the curve, values increased less than dose proportionally. At doses ⩾20 mg, JNJ-42847922 consistently induced somnolence on all study days. At four hours post-dose administration, dose levels >5 mg JNJ-42847922 were identified as sedating by the Addiction Research Center Inventory-49. Except for a mild decrease in attention (Bond and Lader Visual Analogue Scale Factor 1) at dose levels >10 mg at four hours post-dose, no clinically relevant changes in other central measures have been observed. JNJ-42847922 was well tolerated.
RCT Entities:
BACKGROUND: Pharmacokinetics, pharmacodynamics and general safety and tolerability of JNJ-42847922, a selective orexin-2 receptor antagonist, were assessed in healthy subjects. METHODS: Five consecutive cohorts of healthy subjects were enrolled and received doses of 5-60 mg orally once daily over 10 days of JNJ-42847922 ( n=6) or placebo ( n=2). Concentrations of drug in plasma and urine were measured over 24 h after dosing on Days 1, 5 and 10. Observed- and self-reported somnolence was used to evaluate the principal pharmacodynamic effect of JNJ-42847922. A test battery to assess vigilance state, sedation and alertness was assessed at 4, 6 and 8 h after dosing. Safety assessments included recording of adverse events, vital signs, electrocardiograms, clinical laboratory assessments and suicidality per Columbia Suicide Severity Rating Scale. RESULTS: JNJ-42847922 was rapidly absorbed after the morning dose administration. The median tmax ranged from 0.5-1.5 h and mean t1/2 values from 2-3 h. At JNJ-42847922 dose levels ⩾20 mg, mean Cmax and mean area under the curve, values increased less than dose proportionally. At doses ⩾20 mg, JNJ-42847922 consistently induced somnolence on all study days. At four hours post-dose administration, dose levels >5 mg JNJ-42847922 were identified as sedating by the Addiction Research Center Inventory-49. Except for a mild decrease in attention (Bond and Lader Visual Analogue Scale Factor 1) at dose levels >10 mg at four hours post-dose, no clinically relevant changes in other central measures have been observed. JNJ-42847922 was well tolerated.