A Phase 1 Assessment of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of (2R,6R)-Hydroxynorketamine in Healthy Volunteers

Ahmadkhaniha and colleagues conducted a Phase 1, three-part study (NCT04711005) to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and central nervous system (CNS) penetration of (2R,6R)-hydroxynorketamine (RR-HNK) administered as a 40-minute intravenous infusion in healthy adult volunteers. The primary objective was to establish a safe dosing range for future Phase II evaluations in indications such as major depressive disorder. The study was approved by the Duke University Health System Institutional Review Board and enrolled healthy men and women aged 18–65 who met the stated inclusion and exclusion criteria; informed consent was obtained from all participants. Operational details such as study responsibility, blinding methodology and informed-consent processes are reported in the Supplementary Information (S1) referenced by the authors. The clinical protocol comprised a six-level single-ascending dose (SAD) stage with doses of 0.1, 0.25, 0.5, 1, 2 and 4 mg/kg, and a two-level multiple-ascending dose (MAD) stage with 1 and 2 mg/kg administered four times over two weeks in a T/F/T/F schedule (three doses in the first week and one in the second week, as described). Safety assessments included routine adverse-event monitoring and specific evaluations of dissociation and sedation. PK sampling was performed to derive Cmax, Tmax, half-life (t1/2) and AUC metrics. Pharmacodynamic measures included quantitative electroencephalography (qEEG) with visual-evoked-potential (VEP) paradigms at baseline, ~1 hour and ~2–3 hours post-infusion, and cerebrospinal fluid (CSF) sampling in a CSF substudy to assess CNS penetration. The extracted text does not clearly report the statistical analysis plan or whether analyses used an intention-to-treat approach.

Seventy-four participants were enrolled across the SAD, MAD and CSF substudy components; 55 received active study drug and 19 received placebo. In the MAD cohort two, three participants were replaced after an out-of-specification report (visible particulate matter) for the drug product halted their treatment course; one participant was withdrawn for failure to return for week two of dosing. Baseline characteristics are described in tabular form in the full report but are not clearly reported in the extracted text. Safety and tolerability outcomes were favourable across dose levels. There were no serious adverse events (SAEs). The only reported adverse events were mild and resolved without medical intervention. Measures of sedation and dissociation did not indicate anaesthetic or dissociative effects at any dose examined. Mood fluctuations measured by the Profile of Mood States (POMS) were interpreted as within normal clinical-trial variability and were not classified as adverse events. Pharmacokinetic findings indicated dose-proportional exposure. In the SAD study RR-HNK Cmax increased with dose, ranging from 124 ng/mL (538 nM) at 0.1 mg/kg to 4,280 ng/mL (17.8 μM) at 4 mg/kg. Tmax was approximately 0.68–0.98 hour and t1/2 ranged from 6.67 to 8.18 hours across doses; AUC0–last values increased proportionally with dose. The authors compared these direct-administration PK results with RR/SS-HNK exposure following a standard ketamine infusion (0.5 mg/kg): after ketamine, RR/SS-HNK Cmax is approximately 30–40 ng/mL (125–167 nM), which corresponds to roughly 30% of the Cmax of the lowest directly administered RR-HNK dose and less than 1% of the highest dose. The half-life of RR/SS-HNK following ketamine (~14 hours) was longer than that observed after direct RR-HNK administration (6.67–8.18 hours). The AUC of RR/SS-HNK after ketamine administration (~1,400 ng·h/mL) lies between the AUCs measured for the 0.1 mg/kg (918 ng·h/mL) and 0.25 mg/kg (2,560 ng·h/mL) RR-HNK doses. CSF measurements demonstrated CNS penetration after direct administration. A single 0.25 mg/kg RR-HNK infusion produced CSF concentrations of 78.9 ± 27.7 ng/mL (~329 nM) at 1 hour post-infusion initiation and 111.9 ± 16.2 ng/mL (~467 nM) at 8 hours post-infusion. These CSF values exceed estimates of brain exposure following a standard 0.5 mg/kg ketamine infusion reported by the authors. qEEG (VEP) pharmacodynamic data showed increases in cortical gamma power in a subset of participants at the lower/mid SAD dose ranges (0.1, 0.25 and 0.5 mg/kg) when expressed as percent change from baseline; raw gamma values suggested a possible response in the 1 mg/kg cohort. Placebo participants showed less deviation from baseline. The authors note these PD data were not adequately powered, did not achieve statistical significance, displayed substantial within-cohort variability, and are difficult to compare directly with previous ketamine studies because of methodological differences.

Ahmadkhaniha and colleagues conclude that RR-HNK administered as a slow 40-minute intravenous infusion is safe and well tolerated in healthy volunteers at single doses up to 4 mg/kg and at repeated dosing of up to 2 mg/kg given four times over two weeks (T/F/T/F). No anaesthetic, sedative or dissociative effects were observed at the doses tested, consistent with RR-HNK’s limited activity at the NMDA receptor as described in preclinical work. The PK profile following direct administration was largely linear and predictable; direct dosing achieved higher blood and CSF concentrations than those typically produced by a standard 0.5 mg/kg ketamine infusion. CSF concentrations following direct RR-HNK administration exceeded estimated CNS exposure after ketamine and in some cases were comparable to exposures associated with efficacy in murine models. qEEG measures showed gamma-power increases in a subset of participants at lower doses, but these findings were exploratory, not statistically significant and constrained by small cohort sizes and methodological heterogeneity. The authors acknowledge that cohort size limits the ability to draw conclusions about the relationship between RR-HNK exposure, gamma-power changes and potential therapeutic efficacy. Overall, the authors infer that the safety, tolerability, PK and preliminary PD results support progression of RR-HNK into Phase II clinical evaluations, while noting the need for larger, adequately powered studies to clarify PD signals and dose–response relationships.