Introduction Over the last decade, low-dose ketamine has gained in popularity for treatment of chronic pain and therapy-resistant depression.1 Since its discovery in the early 1960s, ketamine has been administered mostly via the parenteral route for the induction of anesthesia and procedural sedation. With a broader range of indications and pre-hospital and out-of-hospital use of ketamine, the need for skilled venipunctures is a hurdle for chronic and repeated ketamine administrations. To overcome this problem, different routes of ketamine administration have been studied extensively, including inhaled, oral, sublingual, nasal, subcutaneous, intramuscular and rectal administrations. All of these routes have advantages, such as simplicity of administration, and drawbacks. For example, oral dosing results in slow absorption and is largely subject to intestinal and first-pass metabolism, with unpredictable bioavailability (7-25%). Others, such as the subcutaneous or intramuscular administration routes, are invasive and also result in a relatively slow absorption.2,3 Here we study the pharmacokinetics (and in part 2 of this study,4 the pharmacodynamics) of sublingual and buccal fast-dissolving oral-thin-films (OTFs) that contain 50 mg of S-ketamine, one of the stereoisomers of ketamine. In this report, we present the results of a pharmacokinetic analysis of the concentration-time curves following sublingual or buccal administration of 50 mg or 100 mg S-ketamine OTF in healthy volunteers. Apart from the simplicity of application, the use of an S-ketamine OTF may, depending on its bioavailability and first-pass effect, be advantageous in the treatment of pain and depression. An acceptable level of S-ketamine bioavailability will make it suitable for pain treatment in an acute setting,2,5 while a large first-pass effect with high concentrations of hydroxynorketamine will make the S-ketamine OTF an interesting alternative for the management of therapy-resistant depression as there is evidence that this metabolite is a potent antidepressant.6,7 We performed a population pharmacokinetic analysis of the S-ketamine OTF in healthy volunteers, and considered the parent compound and its metabolites, S-norketamine and S-hydroxynorketamine in the analysis. 14
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