Pharmacological profile of ALKS 7119, an investigational compound evaluated for the treatment of neuropsychiatric disorders, in healthy volunteers. Issue 6 (31st January 2022)

• Record Type: Journal Article
• Authors: Dijkstra, Francis M.; Zuiker, Rob G. J. A.; Siebenga, Pieter S.; Leigh‐Pemberton, Richard A.; Sun, Lei; Manthis, Joan D.; de Kam, Marieke L.; Lin, Richard; von Moltke, Lisa L.; Rezendes, David; van Gerven, Joop M. A.
• Other Names: Mifsud Janet guestEditor.; Cranswick Noel guestEditor.
• Is Part Of: British journal of clinical pharmacology. Volume 88:Issue 6(2022)
• Page Start: 2909
• Page End: 2925
• Publication Date: 2022-01-31
• Subjects: drug development -- neuropsychiatric disorders -- pharmacological effects -- SERT; Pharmacology -- Periodicals; Drugs -- Periodicals; 615.1
• DOI: 10.1111/bcp.15229
• Languages: English
• ISSNs: 0306-5251

Abstract

Abstract : Aims: ALKS 7119 is a novel compound with in vitro affinity highest for the SERT, and for μ receptor, α1A ‐adrenoceptor, α1B ‐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.