A phase 1 study to assess potential interaction between ASP8062 and alcohol in healthy adult subjects

Abstract

Background: ASP8062 is a novel orally active GABAB receptor positive allosteric modulator in clinical development for the treatment of alcohol use disorder (AUD) and opioid use disorder (OUD). Aims: This study assessed the potential pharmacokinetic/pharmacodynamic interaction between ASP8062 and alcohol under single-dose conditions in healthy adults. Methods: A double-blind, placebo-controlled, crossover phase 1 study was conducted in which 20 subjects were randomly assigned to four treatment sequences (ASP8062 + alcohol; ASP8062 + placebo alcohol; placebo + alcohol; placebo + placebo alcohol) each consisting of four treatment periods, separated by washout periods of at least 14 days. An analysis of variance was used to assess pharmacokinetic interaction and a mixed-effects analysis of covariance was used to assess pharmacodynamic interaction. Results/outcomes: After administration of alcohol, a mild to minimal increase in plasma exposure (AUCinf and Cmax) of ASP8062 was observed, but tmax and t½ for ASP8062 remained unchanged after administration of alcohol. In contrast, ASP8062 did not affect the AUClast and Cmax of ethanol. No clinically relevant differences in cognition measurements were observed with ASP8062 compared with placebo, but there were expected impairments in psychomotor and executive function with alcohol alone. ASP8062 in combination with alcohol resulted in worse scores in cognition measurements than alcohol alone, but this potentiation was not consistent. ASP8062 administered alone was safe and well-tolerated and safety findings in subjects administered alcohol alone were not augmented when ASP8062 was administered in combination with alcohol. Conclusion/interpretation: The data support further clinical studies investigating ASP8062 in patients with AUD.

A phase 1b study to investigate the potential interactions between ASP8062 and buprenorphine/naloxone in patients with opioid use disorder

“…Consistent with previous studies (Ito et al, 2022; Walzer et al, 2020), mean (SD) plasma concentrations of ASP8062 peaked at 128 (33.1) ng/mL 3 h after administration (Figure 5(A)) and were cleared with a mean t ½ of 47 h. Variability of exposures between patients was moderate; one patient had a limited sample on Day 11 and was excluded from the parameter calculations.…”

“…With this sample size typical for a phase 1 study, the combination of multiple B/N doses with a single dose administration of ASP8062 was safe and well tolerated, and a single dose of ASP8062 had no significant effect on clinical laboratory parameters, potential for misuse, or suicidal ideation. Safety and tolerability of ASP8062 in combination with B/N was similar to ASP8062 alone as described in previous studies of healthy volunteers (Ito et al, 2022;Walzer et al, 2020Walzer et al, , 2021. There was a single report of dizziness in one (8.3%) patient receiving ASP8062 and B/N in this study, in contrast with results from a previous phase 2 study investigating use of ASP8062 in patients with fibromyalgia, in which approximately 30% of patients experienced one or more events of dizziness after treatment with 30 mg of ASP8062 (NCT03092726, 2022).…”

“…Safety and tolerability of ASP8062 in combination with B/N was similar to ASP8062 alone as described in previous studies of healthy volunteers (Ito et al, 2022; Walzer et al, 2020, 2021). There was a single report of dizziness in one (8.3%) patient receiving ASP8062 and B/N in this study, in contrast with results from a previous phase 2 study investigating use of ASP8062 in patients with fibromyalgia, in which approximately 30% of patients experienced one or more events of dizziness after treatment with 30 mg of ASP8062 (NCT03092726, 2022).…”

“…This difference may be due to the different patient population, including comorbidities and demographics, or the single versus multiple dosing regimen. Previous studies had rates of dizziness ranging from 5% to 22% with ASP8062 treatment (Ito et al, 2022;Walzer et al, 2020Walzer et al, , 2021.…”

“…ASP8062 entered the central nervous system (CNS) rapidly with 41%-49% of the unbound drug reaching the cerebrospinal fluid; thus, ASP8062 may be effective in enhancing GABA B receptor activity in the CNS (Walzer et al, 2020). Additional studies on the effect of a single dose of ASP8062 on sleep (Walzer et al, 2021) and a drug-drug interaction study with alcohol (Ito et al, 2022) support the finding that ASP8062 was safe and well tolerated when administered in single and multiple ascending doses or with alcohol, with impacts on sleep that suggest a CNS effect of ASP8062.…”