S-Ketamine Oral Thin Film—Part 1: Population Pharmacokinetics of S-Ketamine, S-Norketamine and S-Hydroxynorketamine

Abstract

Ketamine is administered predominantly via the intravenous route for the various indications, including anesthesia, pain relief and treatment of depression. Here we report on the pharmacokinetics of sublingual and buccal fast-dissolving oral-thin-films that contain 50 mg of S-ketamine in a population of healthy male and female volunteers. Twenty volunteers received one or two oral thin films on separate occasions in a randomized crossover design. The oral thin films were placed sublingually (n = 15) or buccally (n = 5) and left to dissolve for 10 min in the mouth during which the subjects were not allowed to swallow. For 6 subsequent hours, pharmacokinetic blood samples were obtained after which 20 mg S-ketamine was infused intravenously and blood sampling continued for another 2-hours. A population pharmacokinetic analysis was performed in NONMEM pharmacokinetic model of S-ketamine and its metabolites S-norketamine and S-hydroxynorketamine; p < 0.01 were considered significant. S-ketamine bioavailability was 26 ± 1% (estimate ± standard error of the estimate) with a 20% lower bioavailability of the 100 mg oral thin film relative to the 50 mg film, although this difference did not reach the level of significance. Due to the large first pass-effect, 80% of S-ketamine was metabolized into S-norketamine leading to high plasma levels of S-norketamine following the oral thin film application with 56% of S-ketamine finally metabolized into S-hydroxynorketamine. No differences in pharmacokinetics were observed for the sublingual and buccal administration routes. The S-ketamine oral thin film is a safe and practical alternative to intravenous S-ketamine administration that results in relatively high plasma levels of S-ketamine and its two metabolites.

S-Ketamine oral thin film—Part 2: Population pharmacodynamics of S-ketamine, S-norketamine and S-hydroxynorketamine

“…This report is accompanied by a report on the population pharmacokinetics of the S-ketamine OTF (2). Here, we describe the pharmacodynamic endpoints that were collected simultaneously with the pharmacokinetic data.…”

“…All recruited subjects gave written and oral informed consent, after which they were screened. Inclusion and exclusion criteria are given in (2). Eating, drinking, brushing teeth, or gum chewing was not allowed in the morning of the OTF application to avoid changes/variabilities in saliva pH, which could potentially affect the mucosal permeability and S-ketamine plasma concentration variability.…”

“…The OTFs were obtained from LTS Lohmann Therapie-Systeme AG (Andernach, Germany) and were dispensed by the pharmacy on the morning of dosing. Measurement of pharmacodynamic endpoints lasted for 6 h. For blood sampling and measurement of Sketamine, S-norketamine, and S-hydroxynorketamine, see the accompanying report (2).…”

“…Data were analyzed in a stepwise fashion. First, the pharmacokinetic data were analyzed using a population-based approach [see (2)]. Next, the pharmacodynamic data were analyzed with individual concentration profiles of S-ketamine and its metabolites (based on the empirical Bayesian estimates of the pharmacokinetic parameters) as input of the sigmoid E MAX pharmacodynamic models.…”

“…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 S-ketamine, 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 Snorketamine and S-hydroxynorketamine (2). 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.…”