In a Phase 1 single- and multiple-ascending IV dosing study in healthy volunteers, (2R,6R)-hydroxynorketamine was well tolerated with minimal adverse events, showed no anesthetic or dissociative effects and demonstrated dose-proportional pharmacokinetics with confirmed CNS exposure in CSF. Quantitative EEG showed increases in gamma power in some participants, supporting progression of RR‑HNK into Phase 2 development.
(R,S)‐Ketamine (ketamine) is a dissociative anesthetic that also possesses analgesic and antidepressant activity. Undesirable dissociative side effects and misuse potential limit expanded use of ketamine in several mental health disorders despite promising clinical activity and intensifying medical need. (2R,6R)‐Hydroxynorketamine (RR‐HNK) is a metabolite of ketamine that lacks anesthetic and dissociative activity but maintains antidepressant and analgesic activity in multiple preclinical models. To enable future assessments in selected human indications, we report the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of RR‐HNK in a Phase 1 study in healthy volunteers (NCT04711005). A six‐level single‐ascending dose (SAD) (0.1–4 mg/kg) and a two‐level multiple ascending dose (MAD) (1 and 2 mg/kg) study was performed using a 40‐minute IV administration emulating the common practice for ketamine administration for depression. Safety assessments showed RR‐HNK possessed a minimal adverse event profile and no serious adverse events at all doses examined. Evaluations of dissociation and sedation demonstrated that RR‐HNK did not possess anesthetic or dissociative characteristics in the doses examined. RR‐HNK PK parameters were measured in both the SAD and MAD studies and exhibited dose‐proportional increases in exposure. Quantitative electroencephalography (EEG) measurements collected as a PD parameter based on preclinical findings and ketamine's established effect on gamma‐power oscillations demonstrated increases of gamma power in some participants at the lower/mid‐range doses examined. Cerebrospinal fluid examination confirmed RR‐HNK exposure within the central nervous system (CNS). Collectively, these data demonstrate RR‐HNK is well tolerated with an acceptable PK profile and promising PD outcomes to support the progression into Phase 2.
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.
Objectives, participants, and oversight NCT04711005 is a three-part, Phase 1 assessment of the safety, tolerability, PK, pharmacodynamic (PD), and CNS penetration of RR-HNK administered via a 40-minute IV infusion in healthy volunteers. This study was approved by the Duke University Health System Institutional Review Board for Clinical Investigations, and all participants provided written informed consent. The primary objective was to determine a safe dosing range for Phase 2 evaluations in several indications including major depressive disorder (MDD). Participants were healthy male and female adult volunteers (aged 18-65) who met all established inclusion/ exclusion criteria. Key operational conduct and oversite methods including study responsibility, blinding methodology, and informed consent details are summarized in Supplementary Information S1.
A total of 74 participants were enrolled in the SAD, MAD, and CSF studies. A total of 55 received study drug and 19 received placebo. In MAD cohort two, three participants were replaced after their treatment course was halted due to an out-of-specification (OOS) report for the drug product (visible particulate matter in one of the drug vials). One participant was withdrawn due to failure to return for week two of dosing in the MAD study. Baseline characteristics for the SAD and MAD participants are summarized in Tablesand.
Depression is one of the most common mental health disorders that presents with a variety of symptoms, severity levels, longitudinal trajectories, and treatment concepts.Encouragingly, new therapies are emerging for the hardest to treat forms of depression including ketamine and psychedelic therapies that can elicit rapid-acting and durable antidepressant effects.Ketamine is among the most exciting new therapies for a variety of mental health disorders including MDD and TRD.Several ketamine metabolites persist in the human body at appreciable concentrations for days following a single ketamine infusion.One of these is the RR-HNK metabolite which also demonstrates antidepressant activity in a variety of pre-clinical models.Mechanistically, RR-HNK does not possess appreciable activity at the NMDA receptor which would predict a lack of anesthetic, sedation, and dissociative qualities.Studies have implicated the potentiation of glutamatergic transmission, BDNF/ mTOR signaling, and increase in AMPA receptor density and signaling as components of RR-HNK's activity in preclinical models.Importantly, while a consensus mechanism of action has yet to be described, neuronal/synaptic plasticity is commonly implicated in preclinical RR-HNK studies.Collectively, the primary and confirmatory activity of RR-HNK in multiple preclinical models of depression and pain coupled with its predicted lack of misuse-related side effects provided ample justification for further human clinical evaluation. Prior to RR-HNK drug product evaluations in human populations with MDD/TRD, we sought to establish safety, tolerability, route of administration, dose ranges, and schedule administration of the drug (Figure). For the management of TRD, ketamine is commonly administered as a solution-based product given at subanesthetic concentrations (typically 0.5 mg/kg) over 40 minutes. Schedules of ketamine administration vary but are rarely compressed to more than three doses over 7 days.In hopes of establishing a reasonably comparable study to standard ketamine therapy, we established a solution-based drug product of RR-HNK and a preclinical toxicity assessment that enabled safety evaluations at doses up to 4 mg/kg with a frequency of four doses given over 2 weeks. We conducted a human evaluation of RR-HNK in healthy volunteers using a six-level (0.1, 0.25, 0.5, 1, 2 and 4 mg/kg) single ascending dose (SAD) study and a two-level (1 and 2 mg/kg), fourdose (T/F/T/F) multiple ascending dose (MAD) study. There were no SAEs, and the only AEs were mild and resolved without medical intervention. Importantly, neither sedation nor dissociation was experienced at any dose evaluated indicating a lack of NMDA receptor interactions at the doses explored. Fluctuations in mood state as judged by the POMS rating were consistent with normal clinical trial temperament fluctuations and not considered as AEs in this study. The safety outcomes from both the SAD and MAD studies are consistent with the other reported preclinical evaluations RR-HNK and the GLP toxicology studies done in support of this study. Collectively, these studies suggest that RR-HNK is safe and tolerable at the doses and schedule explored without abuse or misuse potential. We collected PK data for both the SAD and MAD studies (Figure, Tablesand). In the SAD study, the exposure of RR-HNK was linear and predictable based on the dose. RR-HNK demonstrated exposures ranging from a C max of 124 ng/ mL (538 nM) (0.1 mg/kg dose) to 4,280 ng/mL (17.8 μM) (4 mg/ kg). Similarly, the AUC 0-last values proportionally increased from The T max (approximately 0.68-0.98 hour) and t 1/2 values (6.67-8.18 hour) were consistent across dose ranges. We compared the PK outcomes for RR-HNK administered directly to the exposure profile of RR-HNK following ketamine administration. After a standard administration of ketamine (0.5 mg/kg), the C max of 2R,6R/2S,6Shydroxynorketamine (RR/SS-HNK) is approximately 30-40 ng/ mL (125-167 nM).This corresponds to roughly 30% of the C max of the lowest RR-HNK dose and less than 1% of the C max of the highest RR-HNK dose explored in this study.The halflife of RR/SS-HNK in the human body was longer following ketamine administration (~ 14 hours) relative to direct administration of RR-HNK (6.67-8.18 hour). Accordingly, the AUC values of HNK following ketamine administration and direct administration of RR-HNK have a degree of overlap. Following administration of ketamine (0.5 mg/kg), the AUC of RR/SS-HNK approximately 1,400 ng•h/mL. This ranges between the 0.1 mg/kg and 0.25 mg/kg dose of RR-HNK (918 ng•h/mL and 2,560 ng•h/mL, respectively). The PK profile of RR-HNK has also been reported following direct administration in rats, dogs, and, importantly, mice where most preclinical evaluations are conducted.In mice, a common efficacious dose of 10 mg/kg administered IP yields a C max of between 1,200 and 3,000 ng/mL (5.0-12.5 μM) and an AUC value of between 750 and 950 ng•h/mL. Thus, the C max of the mouse exposure aligns with the higher dose levels in humans (i.e., 1 and 2 mg/kg) while the AUC aligns with the lower doses (i.e., 0.1 and 0.25 mg/kg). From an allometric standpoint, a 10 mg/kg mouse dose is equivalent to a ~ 0.8 mg/kg human dose. These data may reveal the role of rapid or sustained RR-HNK exposure as a governing factor for possible efficacy. RR-HNK is known to readily cross the blood-brain barrier of rodents with significant CNS exposure following ketamine administration or direct administration. A 10 mg/kg IP ketamine dose in mice achieves a peak RR/SS-HNK brain concentration of 1.54-2.46 μmol/kg whereas direct administration of RR-HNK (10 mg/kg I.P.) yields CNS exposure ranging from 10.66 to 17.80 μmol/kg.Recently, it was determined that RR-HNK is found in the CSF of humans following ketamine administration at concentrations similar to plasma levels.Importantly, studies estimate the brain exposure of RR-HNK in humans following a standard antidepressant ketamine administration (0.5 mg/kg I.V.) to be ≤ 38 nM.In this study, we find that a single administration of RR-HNK (0.25 mg/kg) yields an exposure in the CSF of 78.9 ± 27.7 ng/mL (~ 329 nM) at 1 hour postinfusion initiation and 111.9 ± 16.2 ng/mL (~ 467 nM) at 8 hours post-infusion initiation. Collectively, these data suggest that relevant dose ranges explored in this study will likely exceed CNS exposure levels of RR-HNK that follow a common ketamine administration for the treatment of depression and be comparable to RR-HNK exposure in responding murine models. Biomarkers of clinical efficacy for pharmacotherapy in mental health disorders are sorely needed. Among the few that yield evidence of synaptic potentiation by a drug are measurements of gamma oscillations and power using electrophysiology.Increases in cortical gamma power have been identified during ketamine infusion in both humans and rodents, and in RR-HNK administration in mice.In this study, we collected qEEG measurements throughout the SAD study including VEP measurements at a baseline timepoint prior to RR-HNK infusion and at two timepoints post-infusion initiation (1 hour and between 2 and 3 hours). The outcomes, shown in Figure-e, show evidence of gamma power increases during the VEP measurements based on the % change from baseline for a subset of participants in the lower dose ranges (0.1, 0.25, and 0.5 mg/kg). The raw gamma power values (Figure) provide important context to this data and may indicate a response in cohort four (1 mg/kg). Importantly, participants in the placebo group showed lower deviation from baseline. These treatment groups were not adequately powered, and the data do not achieve statistical significance. Furthermore, within each responding cohort the standard deviation of response is substantial. It is also unclear how gamma power and oscillations are modified by therapy in a healthy population. Finally, differences in data collection methods, VEP techniques, and analysis approaches make broad comparisons of the gamma power alterations captured in this study to those previously reported for ketamine difficult. Thus, these data are presented without conclusion but rather to offer information and guidance for future assessments. Limitations of this study include the relative size of each cohort which restricts our ability to draw key conclusions including the relationship of drug administration, gamma power changes, and the potential for efficacy in patient populations. Primarily, this study offers insight into the safety, tolerability, and exposure of RR-HNK given as a stand-alone therapy in a diverse population of healthy volunteers. In conclusion, RR-HNK given as a stand-alone therapy via a slow IV administration is safe and tolerable at doses up to 4 mg/ kg individually and up to 2 mg/kg given four times over 2 weeks (T/F/T/F). RR-HNK does not possess anesthetic, sedative, or dissociative properties at any of the doses examined. The PK profile is largely linear and predictable across all doses. Direct administration of RR-HNK at all dose levels achieves a higher concentration of drug exposure in both blood and CSF relative to the achieved
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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.