2 S-ketamine oral thin film pharmacokinetics Methods Ethics and Subjects The protocol was approved by the Central Committee on Research Involving Human Subjects (Competent authority: Centrale Commissie Mensgebonden Onderzoek (CCMO), The Hague, the Netherlands; registration number NL75727.058.20) and the Medical Research Ethics Committee at Leiden University Medical Center (Medische Ethische Toetsingscommissie LeidenDen Haag-Delft, the Netherlands; identification number P20.111). The study was registered at the trial register of the Dutch Cochrane Center (www.onderzoekmetmensen.nl) under identifier NL9267 and at the European Union Drug Regulating Authorities Clinical Trials (EudraCT) database under number 2020-005185-33. All procedures were performed in compliance with the latest version of the Declaration of Helsinki and followed Good Clinical Practice guidelines. Healthy male and female volunteers, aged 18-45 years and with a body mass index ≥19 kg/m2 and ≤30 kg/m2, were recruited. After recruitment, all subjects gave written and oral informed consent, after which they were screened. Additional inclusion criteria were the ability to communicate with the research staff, non-smoking for at least 3 months prior to screening, and deemed suitable by the investigators. Exclusion criteria included: presence or history of any medical or psychiatric disorder (including a history of substance abuse, anxiety, or a chronic pain syndrome), use of medication in the three months prior to screening (including vitamins and herbs, excluding oral contraceptives), use of more than 21 units of alcohol per week, use of illicit substances (including cannabis) in the 4 weeks prior to the study, a positive urine drug test or an alcohol breath test at screening or on the morning of test drug dosing, pregnancy, lactating or a positive pregnancy test at screening or on the morning of dosing, participation in another (drug) trial in the 60 days prior to dosing. Eating, drinking, tooth brushing or gum chewing was not allowed on the morning of oral thin film application to avoid changes/variabilities in saliva pH, which could potentially affect the mucosal permeability and S-ketamine uptake. Study Design S-Ketamine Oral Thin Film Placement – Randomization – Intravenous S-ketamine Infusion This phase 1 study had an open-label randomized crossover design. The subjects were randomized to receive one oral thin film on one occasion (50 mg S-ketamine) and two on another visit (100 mg S-ketamine) with at least 7 days between visits. The thin film is a rectangular 4.5 cm2 orodispersible 15
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