3 S-ketamine oral thin film pharmacodynamics three were measured on a visual analogueue score from 0 (no effect) to 10 cm (maximum effect). In the pharmacokinetic-pharmacodynamic data analysis, we included the effect of the OTF on drug high derived from the Bowdle questionnaire. The description of the effect of the S-ketamine OTF on the other endpoints, internal and external perception, is given in the in Supplementary Figure 1 online. Population pharmacodynamic analysis Data were analyzed in a stepwise fashion. First, the pharmacokinetic data were analyzed using a population-based approach (see chapter 2). Next, the pharmacodynamic data were analyzed with individual concentration profiles of S-ketamine and its metabolites (based on the empirical Bayesian estimates of the pharmacokinetic parameters) as input of the sigmoid EMAX pharmacodynamic models. The metabolites were assumed to be agonists or antagonists, with the total effect, EFF, modeled as: EFF =EEF(K)+EFF(NK)+EFF(HNK) With EFF(K)=CE,K/C50,K EFF(NK)=CE,NK/C50,NK EFF(HNK)=CE,HNK/C50,HNK or EFF =EFF(K)= CE,K/C50 with C50 =C50,K × [1+EFF(NK)+EFF(HNK)] and EFF(NK)= CE,NK/C100,NK EFF(HNK)= CE,HNK/C100,HNK under the agonistic and antagonistic assumptions, respectively. CE,K, CE,NK andCE,HNKare the effect-site concentrations of S-ketamine, S-norketamine and 45
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