2 S-ketamine oral thin film pharmacokinetics One subject declined further participation after completing the first session, receiving 100 mg S-ketamine OTF sublingually, due to psychotomimetic side effects that occurred during the intravenous S-ketamine infusion. The mean and individual S-ketamine, S-norketamine and S-hydroxynorketamine data for both the sublingual and buccal OTF and intravenous infusion are given in Figure 2.1 on page 22. Since no differences were observed in plasma concentrations for the sublingual (n = 15) or buccal (n =5) locations of the OTF (individual data in Figure 2.1 panels D-I with in red buccal administration and in black sublingual administration) and in the subject characteristics (Table 2.1), we merged the two subgroups in the pharmacokinetic model analyses. Peak concentration (CMAX), time of peak concentration (TMAX) and area-under-the-concentrationtime curves (AUC) of S-ketamine and its metabolites are given in Table 2.2 on page 23. These data indicate that increasing the S-ketamine OTF dose produces dose a dependent increase in CMAXfor S-ketamine and its metabolites, with a delay in CMAX for the downstream metabolites. Comparing these data to the values observed after the intravenous S-ketamine in Figure 1, panels A-C, administration indicate the greater metabolism of the S-ketamine from the OTF compared to the 20 mg intravenous S-ketamine. Peak S-ketamine concentrations after the intravenous infusion were 273 (259-287) ng/mL (mean (95% confidence interval)) after treatment with the 50 mg S-ketamine OTF and 260 (251-269) ng/mL after treatment with the 100 mg S-ketamine OTF (Figure 2.1). 21
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