2 S-ketamine oral thin film pharmacokinetics Population Pharmacokinetic Analysis The schematic diagram of the final pharmacokinetic model of the absorption of S-ketamine from the OTF and disposition of S-ketamine, with three compartments, and its metabolites S-norketamine and S-hydroxynorketamine, with each 2 compartments, is given in Figure 2.2 on page 26. Model parameter estimates are given in Table 2.4 on page 27; S-ketamine and S-norketamine distribution- and clearance-related parameters are in close correspondence with earlier data derived from a pooled-analysis of data from the literature.11 Gastrointestinal absorption of S-ketamine and the metabolism of S-ketamine andS-norketamine were best described by two delay or metabolism compartments. The model parameters given in Table 2.4 are explained in Figure 2.2. All pharmacokinetic data fits are presented in Supplementary Figure 1 online; the goodness-of-fit plots (individual predicted concentration vs. measured concentration; individual weighted residuals over time; normalized prediction discrepancy errors) are given in Figure 2.3 on page 30. Inspection of these plots together with the individual data fits indicate that the final model adequately described the plasma concentration-time data of S-ketamine and its two measured metabolites. The bioavailability of S-ketamine from the OTF was 26.3 ± 1.0%, with a duration of absorption (D1) of 13 min and an absorption rate constant of 0.04 min-1 (KA1), with one outlier (subject #4) who had a KA1 value of 0.012 min-1. The bioavailability for the 50 mg and 100 mg OTF differed by about 20% (F1 50 mg = 29%, F1 100 mg = 23%), but this did not reach the level of significance (p ≈0.01). The S-ketamine that was not absorbed in the mouth was ingested and was absorbed in the remainder of the gastrointestinal system into the portal vein. This process was modeled by two delay compartments defined by an absorption rate constant KA2 and a mean transit time (MTTG, Figure 2.4. The gastrointestinal absorption (F2) took 30 min. Around 75% of the initial amount of S-ketamine was directly metabolized into S-norketamine without participating in the distribution of S-ketamine in the systemic circulation. Metabolism into S-norketamine was modeled by two delay compartments with the delay defined by two mean transit times (MTT K →NK, Table 2.2 and Figure 2.2), which has a population value of around 20 min (again with outlier subject #4 who had a value of 9 min). Twenty percent of S-ketamine was not metabolized into S-norketamine but was either metabolized into other metabolites (e.g. hydroxyketamine) or was lost in the gut. S-norketamine was metabolized into S-hydroxynorketamine via two metabolism compartments with the delay defined by two mean transit times (NK→HNK, Table 2.2 and Figure 2.2), which had a population value of around 1 min. Thirty percent of S-norketamine was not metabolized into S-hydroxynorketamine but was metabolized to other metabolites such as S-dehydronorketamine. 25
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