Introduction The N-methyl-D-aspartate receptor antagonist ketamine experiences a clinical renaissance due to the introduction of various new indications.1 While initially developed as an anesthetic and a substitute for phencyclidine, it later gained popularity as an analgesic and currently is available as a rapid-acting antidepressant.1 Ketamine has multiple administration routes that may be divided into those that require a sometimes painful injection or venipuncture (intravenous and subcutaneous delivery) and those that circumvent the disadvantages of delivery by injection and allow an easy and painless treatment. The latter route includes delivery by oral, intranasal, transcutaneous, or rectal routes. Here, we study the pharmacodynamics [and in part 1 of this study, the pharmacokinetics, see chapter 2]2 of sublingual and buccal fast-dissolving oral-thin-films (OTFs) that contain 50 mg of S-ketamine, one of the isomers of ketamine. The OTF is a rectangular 4.5 cm2 thin film that is loaded with an active substance that immediately dissolves in the mouth and is rapidly absorbed through the mucosa. Ketamine is a complex drug for various reasons; it is a racemic mixture of S- and R-isomers and is metabolized into active compounds such as norketamine and hydroxynorketamine.3,4 All these differ in pharmacokinetics and dynamics, and consequently may influence the ultimate effect of the drug and consequently the S-ketamine OTF.3,4 In the current study, we present the results of a pharmacodynamic analysis of the effect of one and two OTFs, containing, respectively, 50 and 100 mg Sketamine, administered sublingually or buccally. In the accompanying report, we showed that the S-ketamine OTF undergoes a large first-pass effect causing relatively high concentrations of S-norketamine and S-hydroxynorketamine.3 We studied the OTF on two end-points, nociception, by testing three distinct pain assays (pressure pain, electrical pain, and thermal pain), and drug high, one of the psychotomimetic effects of S-ketamine. Our main interest is the description of the pharmacodynamic effects of S-ketamine in the S-ketamine OTF. Additionally, we quantified the contribution of the S-ketamine metabolites in the production of antinociception and drug high. Earlier studies demonstrated that S-norketamine has a little analgesic effect in humans and is possibly even pro-algesic,5 while animal data indicate that S-hydroxynorketamine has potent analgesic and antidepressant properties.6,7 We performed a population pharmacodynamic analysis of the S-ketamine OTF in a group of healthy volunteers and built a pharmacodynamic model that incorporates the contribution of S-norketamine andS-hydroxynorketamine. Pharmacokinetic–pharmacodynamic modeling is an important tool in the development of new therapies (including new administration modes of existing therapies) to quantify the therapeutic index or utility in terms of wanted and unwanted effects and determine the contribution of metabolites. 42
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