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Clinical Trial
. 2024 Nov;116(5):1314-1324.
doi: 10.1002/cpt.3391. Epub 2024 Jul 25.

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

Shruti M Raja  1 , Jeffrey T Guptill  1   2 , Michelle Mack  1 , Marni Peterson  3 , Stephen Byard  4 , Robert Twieg  5 , Lynn Jordan  1 , Natalie Rich  3 , Richard Castledine  4 , Samuel Bourne  4 , Martin Wilmshurst  4 , Sarah Oxendine  1 , Satya G C Avula  5 , Helen Zuleta  1 , Paul Quigley  4 , Sheila Lawson  4 , Stephen J McQuaker  4 , Reza Ahmadkhaniha  6 , Lawrence G Appelbaum  1 , Kevin Kowalski  5 , Chineta T Barksdale  5 , Brandon T Gufford  7 , Asaad Awan  8 , Alfredo R Sancho  8 , Max C Moore  9 , Karim Berrada  9 , Gregory B Cogan  1 , Jesse DeLaRosa  1 , Jeanne Radcliffe  10 , Maryland Pao  10 , Michelle Kennedy  11 , Quentin Lawrence  11 , Lisa Goldfeder  8 , Leslie Amanfo  8 , Panos Zanos  12 , Jessica R Gilbert  13 , Patrick J Morris  14 , Ruin Moaddel  6 , Todd D Gould  15   16 , Carlos A Zarate Jr  13 , Craig J Thomas  14   17
Affiliations
Clinical Trial

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

Shruti M Raja et al. Clin Pharmacol Ther. 2024 Nov.

Abstract

(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.

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Conflict of interest statement

Conflict of Interest

The authors declare competing financial interests: R.M. and C.A.Z. are listed as coinventors on a patent for the use of RR-HNK, (S)-dehydronorketamine, and other stereoisomeric dehydroxylated and hydroxylated metabolites of (R,S)-ketamine in the treatment of depression and neuropathic pain. P.Z., R.M., P.J.M., C.J.T., C.A.Z., and T.D.G. are listed as coinventors on a patent application for the use of RR-HNK and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. P.J.M, R.C., S.B. and C.J.T. are listed as coinventors on a patent application detailing the synthesis and purification of RR-HNK. R.M., P.J.M., C.A.Z., and C.J.T. have assigned their patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government. P.Z. and T.D.G. have assigned their patent rights to the University of Maryland, Baltimore, but will share a percentage of any royalties that may be received by the University of Maryland, Baltimore. All other authors have no conflict of interest to declare, financial or otherwise.

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