2 S-ketamine oral thin film pharmacokinetics only. In the liver, S-norketamine is metabolized via cyclohexanone ring hydroxylation to form 4-, 5- and 6-hydroxynorketamine by CYP2B6 and CYP2A6 enzymes.12 A small amount of S-norketamine is dehydrogenated into dehydronorketamine by CYP2B6, while some dehydronorketamine may additionally be produced fromS-hydroxynorketamine by dehydration.12 In the current analysis we just modeled the major metabolic pathways and assumed that 70% of S-norketamine was metabolized into S-hydroxynorketamine. This is based on earlier modeling studies that showed that a hydroxynorketamine to dehydronorketamine metabolic ratio of 70%:30% reflected best their measured plasma concentrations.10 Finally, all hydroxy products are glucuronidated in the liver and subsequently eliminated via bile and kidney.12 Bioavailability of the oral thin film was on average 26% with a somewhat higher bioavailability for the 50 mg film than for the 100 mg film (F1 50 mg = 29%, F1 100 mg = 23%). Similar dose-dependency of bioavailability was observed for intranasal S-ketamine formulation that showed a decrease in bioavailability from 63% for a 28 mg S-ketamine dose to 50% for a 112 mg S-ketamine dose.18 Possibly a saturation in absorption is observed here. Alternatively, a longer absorption time by expanding the “do not swallow” period following film application would have increased F1 at the expense of the first-pass effect. In other words, S-ketamine bioavailability following OTF application is reciprocally related to the S-norketamine and S-hydroxynorketamine concentrations (Figure 2.4). This is also reflected in the ratio S-norketamine over S-ketamine. Earlier studies indicated that this ratio equals 5 following oral ketamine administration and 2 after sublingual application of a ketamine lozenge.19 In our study the ratio equals 4.6 after the 50 mg OTF and 5.1 after the 100 mg film. This and our model analysis indicate a large first-pass effect related to the transition of the S-ketamine into the gut after the ingestion of the remainingS-ketamine from the film after the 10-min “do not swallow” period and subsequently into the portal vein, or to metabolism directly in the mucosa of either the oral cavity or the remaining intestinal tract. As indicated above, we are unable to discriminate among these first-pass metabolic pathways. It is important to realize that depending on the clinical need, a large first-pass effect may be advantageous as it results in relatively high plasma concentrations of the ketamine metabolites. Particularly, high concentrations of hydroxynorketamine may be of interest when treating patients suffering from therapy-resistant depression.6 Figure2.1 shows that OTF 50 and 100 mg Shydroxynorketamine concentrations (as observed from t = 0 to 6 h) exceed the increase in S-hydroxynorketamine concentration from t = 6 to 8 h following the 20 mg intravenous S-ketamine infusion. To obtain similar concentration of S-hydroxynorketamine following intravenous S-ketamine administration would require much higher intravenous doses that would coincide with a higher probability of unwanted side effects.5 Whether hydroxynorketamine is analgesic 33
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