A randomized, double-blind, placebo-controlled, Phase 1 study to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of an immediate-release oral ketamine capsule in healthy volunteers.

A single dose of immediate-release oral ketamine (40–240 mg) was safe and generally well-tolerated in healthy adults, with no unexpected safety signals or discontinuations due to side effects. Eighty mild or moderate treatment-emergent adverse events occurred after ketamine doses, most commonly dissociation, dizziness, and headache, while only five occurred after placebo. Dissociation events increased with higher doses. Ketamine and its metabolites showed dose-proportional pharmacokinetics. Transient mood and dissociation changes appeared one hour after dosing and resolved within about four hours. These results support further investigation of oral ketamine capsules for treatment-resistant depression.

Study at a glance

Abstract

Ketamine, a rapid-acting N-methyl-D-aspartate receptor antagonist used as a therapeutic for treatment-resistant depression (TRD), is usually administered intravenously or intranasally. This randomized, double-blind, placebo-controlled, Phase 1 study investigated safety and tolerability (primary endpoint), pharmacokinetics (PK) and pharmacodynamics (PD) of an immediate-release oral ketamine. Healthy volunteers (18-55 years) were randomized to each receive two single doses of oral ketamine (40-240 mg) and one oral placebo dose. Treatment-emergent adverse events (TEAEs) and PK and PD assessments (e.g., Bond and Lader visual analogue scale, Modified Observer's Assessment of Alertness/Sedation Scale) were assessed up to 24 h after dosing. Descriptive statistics were used. Nineteen participants were randomized (mean age: 31 years; male, 68%); 18 completed the study. Eighty mild or moderate TEAEs were reported following oral ketamine (40-240 mg) and five following placebo. There were no TEAE-related discontinuations. Most TEAEs (86%) were considered probably related to study drug. The most common TEAEs with oral ketamine were dissociation (26 events), dizziness (nine events) and headache (nine events). A positive relationship between increasing ketamine doses and dissociation events was observed. PK parameters (Cmax, AUCinf) of oral ketamine and its primary metabolites (2S,6S;2R,6R-hydroxynorketamine, R/S-norketamine) were dose proportional. Transient changes in mood and dissociation were detected 1 h postdose with a return to predose values after ~4 h. There were no unexpected safety signals with oral ketamine. PK properties were consistent with those reported for other rapid-acting formulations. These findings warrant further investigation of oral ketamine capsules in TRD (EudraCT No. 2019-001019-22).