3 S-ketamine oral thin film pharmacodynamics Data analysis was performed using NONMEM version 7.5.0 (ICON Development Solutions, Hanover, MD, USA). Inter-occasion variability (ν2)was determined for baseline values only, as we assumed that other parameter values would not differ between the two occasions and were drug-dose independent. Determining whether the metabolites contributed to the measured effect and the level of significance of model parameters were based on the log-likelihood criterion (-2LL; a decrease of more than 6.6 is significant at the p <0.01 level for one additional parameter). The Goodness-of-Fit was based on the visual inspection of the model fits and Goodness-of-Fit plots (individual predicted versus measured, individual weighted residuals vs. time and normalized prediction discrepancy error vs. time). Additionally, visual predictive checks (PVCs) were generated to ensure that the models were able to reproduce the data used for model building. Although no pharmacokinetic differences were observed in the sublingual and mucosal applications, we compared the location of the application on the pharmacodynamic parameter estimates. 47
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