{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T00:43:49Z","timestamp":1789951429038,"version":"4.0.1"},"reference-count":42,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2024,7,25]],"date-time":"2024-07-25T00:00:00Z","timestamp":1721865600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2024,11]]},"abstract":"<jats:p>\n                    (\n                    <jats:italic>R<\/jats:italic>\n                    ,\n                    <jats:italic>S<\/jats:italic>\n                    )\u2010Ketamine (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. (2\n                    <jats:italic>R<\/jats:italic>\n                    ,6\n                    <jats:italic>R<\/jats:italic>\n                    )\u2010Hydroxynorketamine (\n                    <jats:italic>RR\u2010<\/jats:italic>\n                    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\n                    <jats:italic>RR\u2010<\/jats:italic>\n                    HNK in a Phase 1 study in healthy volunteers (NCT04711005). A six\u2010level single\u2010ascending dose (SAD) (0.1\u20134\u2009mg\/kg) and a two\u2010level multiple ascending dose (MAD) (1 and 2\u2009mg\/kg) study was performed using a 40\u2010minute IV administration emulating the common practice for ketamine administration for depression. Safety assessments showed\n                    <jats:italic>RR\u2010<\/jats:italic>\n                    HNK possessed a minimal adverse event profile and no serious adverse events at all doses examined. Evaluations of dissociation and sedation demonstrated that\n                    <jats:italic>RR\u2010<\/jats:italic>\n                    HNK did not possess anesthetic or dissociative characteristics in the doses examined.\n                    <jats:italic>RR\u2010<\/jats:italic>\n                    HNK PK parameters were measured in both the SAD and MAD studies and exhibited dose\u2010proportional increases in exposure. Quantitative electroencephalography (EEG) measurements collected as a PD parameter based on preclinical findings and ketamine's established effect on gamma\u2010power oscillations demonstrated increases of gamma power in some participants at the lower\/mid\u2010range doses examined. Cerebrospinal fluid examination confirmed\n                    <jats:italic>RR\u2010<\/jats:italic>\n                    HNK exposure within the central nervous system (CNS). Collectively, these data demonstrate\n                    <jats:italic>RR\u2010<\/jats:italic>\n                    HNK is well tolerated with an acceptable PK profile and promising PD outcomes to support the progression into Phase 2.\n                  <\/jats:p>","DOI":"10.1002\/cpt.3391","type":"journal-article","created":{"date-parts":[[2024,7,26]],"date-time":"2024-07-26T02:15:26Z","timestamp":1721960126000},"page":"1314-1324","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["A Phase 1 Assessment of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of (2\n                    <i>R<\/i>\n                    ,6\n                    <i>R<\/i>\n                    )\u2010Hydroxynorketamine in Healthy Volunteers"],"prefix":"10.1002","volume":"116","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0216-1564","authenticated-orcid":false,"given":"Shruti M.","family":"Raja","sequence":"first","affiliation":[{"name":"Duke Early Phase Research Unit Duke University School of Medicine  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey T.","family":"Guptill","sequence":"additional","affiliation":[{"name":"Duke Early Phase Research Unit Duke University School of Medicine  Durham North Carolina USA"},{"name":"Argenx BV  Ghent Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Mack","sequence":"additional","affiliation":[{"name":"Duke Early Phase Research Unit Duke University School of Medicine  Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marni","family":"Peterson","sequence":"additional","affiliation":[{"name":"Fortrea Inc.  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