Population pharmacodynamic analysis Population parameters estimates are given in Table 3.1 on page 51, the best median and worst fits (based on R2) for all 4 endpoints are given in Supplementary Figure 1 online. The Goodness-of-Fit plots are given in Figure 3.3 and Figure 3.4 on page 52 and 53, panels C-E. Visual Predictive Checks (VPCs), comparing observations with model predictions, are given in Figure 3.5 on page 54. Inspection of the fits, Goodness-of-Fit plots and VPCs indicate that the PKPD models adequately describe the data with no differences between the 50 and 100 mg OTF-related data. No contribution of either Snorketamine or S-hydroxynorketamine could be detected, i.e. EFF(NK) and EFF(HNK) approached zero. Consequently, the antinociceptive and drug high effects are attributed solely to S-ketamine. S-ketamine potency was about 3to 5-fold lower for antinociception than for drug high: C50 1.2-1.7 nmol/mL vs. 0.3 nmol/mL for the nociceptive tests and for drug high, respectively. The onset/offset of the S-ketamine effect was similarly fast for all tests, nociceptive and drug high, and ranged from a value not different from zero (Table 3.1), indicative of an instantaneous effect to 5 min. In Figure 3.6 on page 55, the steady-state or effect-site concentration-effect relationships are given for the four pharmacodynamic endpoints. The dots in the figure depict the C50 values. No effect of the location of the OTF on parameter estimates was observed (p > 0.05). 50
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