Pharmacological profile of ALKS 7119, an investigational compound evaluated for the treatment of neuropsychiatric disorders, in healthy volunteers.

Autor: Dijkstra FM; Centre for Human Drug Research (CHDR), Leiden, The Netherlands.; Leiden University Medical Center, Leiden, The Netherlands., Zuiker RGJA; Centre for Human Drug Research (CHDR), Leiden, The Netherlands.; Leiden University Medical Center, Leiden, The Netherlands., Siebenga PS; Centre for Human Drug Research (CHDR), Leiden, The Netherlands., Leigh-Pemberton RA; Alkermes, Inc., Waltham, MA, USA., Sun L; Alkermes, Inc., Waltham, MA, USA., Manthis JD; Alkermes, Inc., Waltham, MA, USA., de Kam ML; Centre for Human Drug Research (CHDR), Leiden, The Netherlands., Lin R; Alkermes, Inc., Waltham, MA, USA., von Moltke LL; Alkermes, Inc., Waltham, MA, USA., Rezendes D; Alkermes, Inc., Waltham, MA, USA., van Gerven JMA; Centre for Human Drug Research (CHDR), Leiden, The Netherlands.; Leiden University Medical Center, Leiden, The Netherlands.
Jazyk: angličtina
Zdroj: British journal of clinical pharmacology [Br J Clin Pharmacol] 2022 Jun; Vol. 88 (6), pp. 2909-2925. Date of Electronic Publication: 2022 Jan 31.
DOI: 10.1111/bcp.15229
Abstrakt: Aims: ALKS 7119 is a novel compound with in vitro affinity highest for the SERT, and for μ receptor, α 1A -adrenoceptor, α 1B -adrenoceptor, NMDA receptor and sigma non-opioid intracellular receptor 1. This first-in-human study evaluated safety and PK/PD effects of single ascending doses (SAD) of ALKS 7119 in healthy males and compared effects with neurotransmitter modulators with partially overlapping targets.
Methods: In 10 cohorts (n = 10 subjects each), PK, safety and PD (NeuroCart tests, measuring neurophysiologic effects [pupillometry, pharmaco-EEG (pEEG)], visuomotor coordination, alertness, [sustained] attention [saccadic peak velocity, adaptive tracking], subjective drug effects [VAS Bowdle and VAS Bond and Lader] and postural stability [body sway]) were evaluated. Neuroendocrine effects (cortisol, prolactin, growth hormone) were measured. Data were analysed over the 12-hour post-dose period using mixed-effects model for repeated measure (MMRM) with baseline as covariate.
Results: ALKS 7119 demonstrated linear PK and was generally well tolerated. QTcF interval increases of 30-60 ms compared to baseline were observed with ALKS 7119 doses of ≥50 mg without related adverse events. Significant increases in left and right pupil/iris ratio were observed at dose levels ≥50 mg (estimate of difference [95% CI], P-value) (0.04 [0.01; 0.07], P < .01) and (0.06 [0.03; 0.09], P = .01), respectively. From dose levels ≥50 mg significant increases (% change) of serum cortisol (51.7 [8.4; 112.3], P = .02) and prolactin (77.9 [34.2; 135.8], P < .01) were observed.
Conclusion: In line with ALKS 7119's in vitro pharmacological profile, the clinical profile observed in this study is most comparable to SERT inhibition.
(© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
Databáze: MEDLINE
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