in humans has not yet been tested as no hydroxynorketamine is available for human use. One animal study did find analgesic efficacy from (2R,6R)- hydroxynorketamine in several acute and chronic pain animal models.20 In part 2 of our analysis, we performed a pharmacokinetic-pharmacodynamic analysis and took, apart from S-ketamine, both metabolites into account in the pharmacodynamic model. This (indirect) approach could not substantiate any effect of S-norketamine or S-hydroxynorketamine in the antinociceptive behavior of the S-ketamine OTF.4 The level of the sublingual/buccal S-ketamine bioavailability we observed fits well with earlier findings on sublingual ketamine formulations that ranged from 24 to 29%.2,21 Bioavailability after oral administration is more variable and ranges from 8 to 24%.2,3,22,23 A recent report on the population pharmacokinetics of S-ketamine nasal spray indicate a bioavailability of 54% from passage through the nasal cavity with about 19% of the swallowed dose reaching the systemic circulation.18 Finally, inhalation of S-ketamine has a bioavailability of 70% but is depending on the ketamine plasma concentration.7 At higher concentrations, due to sedation, ketamine is lost to the environment, and bioavailability decreases (at 275 and 375 ng/ml bioavailability is 50% and 38%, respectively). So, in comparison, bioavailability for the different administration routes are oral <sublingual <intranasal <inhalation (albeit dose-dependent) <intravenous administration. As indicated extending the sublingual or buccal absorption time of the OTF would likely have increased the S-ketamine concentration in plasma in our study (Figure 2.4). This may be an important consideration when treating acute pain with the OTF. Additionally, the S-ketamine oral thin film metabolic profile differs from other administration forms that exhibit a lesser first-pass effect (including intravenous administration, Figure 2.5;the greater the first pass effect, the more norketamine and hydroxynorketamine is formed). This together with the differences in bioavailability will evidently affect the efficacy profile of the formulation for treatment of pain and depression. Finally, since S-ketamine is an important treatment option for therapy-resistant depression,1 we simulated the S-ketamine and S-hydroxynorketamine profiles following 0.5 mg/kg intravenous ketamine given over 40 min to a 70 kg individual, which is the usual treatment dose for depression, and compared these profiles to those observed after the 100 mg S-ketamine oral thin film. The results indicate greater S-ketamine concentrations after the intravenous infusion but lower S-hydroxynorketamine concentrations compared to the oral thin film (Figure 2.5on page 35). Since the role of the various ketamine metabolites such as hydroxynorketamine remain unknown in producing the antidepressant effects of ketamine,1,12 a study on the effect of the S-ketamine oral thin film in patients with depression may shed light on this matter. 34
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