• Kelly Jonkman, Andreas Duma, Erik Olofsen, Thomas Henthorn, Monique van Velzen, René Mooren, Liesbeth Siebers, Jojanneke van den Beukel, Leon Aarts, Marieke Niesters, and Albert Dahan.
• From the Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands (K.J., A. Duma, E.O., T.H., M.v.V., R.M., L.S., J.v.d.B., L.A., M.N., A. Dahan); Department of Anesthesiology, Intensive Care Medicine and Pain Management, Medical University of Vienna, Vienna, Austria (A. Duma); and Department of Anesthesiology, University of Colorado School of Medicine, Aurora, Colorado (T.H.).
• Anesthesiology. 2017 Oct 1; 127 (4): 675-683.

BackgroundEsketamine is traditionally administered via intravenous or intramuscular routes. In this study we developed a pharmacokinetic model of inhalation of nebulized esketamine with special emphasis on pulmonary absorption and bioavailability.MethodsThree increasing doses of inhaled esketamine (dose escalation from 25 to 100 mg) were applied followed by a single intravenous dose (20 mg) in 19 healthy volunteers using a nebulizer system and arterial concentrations of esketamine and esnorketamine were obtained. A multicompartmental pharmacokinetic model was developed using population nonlinear mixed-effects analyses.ResultsThe pharmacokinetic model consisted of three esketamine, two esnorketamine disposition and three metabolism compartments. The inhalation data were best described by adding two absorption pathways, an immediate and a slower pathway, with rate constant 0.05 ± 0.01 min (median ± SE of the estimate). The amount of esketamine inhaled was reduced due to dose-independent and dose-dependent reduced bioavailability. The former was 70% ± 5%, and the latter was described by a sigmoid EMAX model characterized by the plasma concentration at which absorption was impaired by 50% (406 ± 46 ng/ml). Over the concentration range tested, up to 50% of inhaled esketamine is lost due to the reduced dose-independent and dose-dependent bioavailability.ConclusionsWe successfully modeled the inhalation of nebulized esketamine in healthy volunteers. Nebulized esketamine is inhaled with a substantial reduction in bioavailability. Although the reduction in dose-independent bioavailability is best explained by retention of drug and particle exhalation, the reduction in dose-dependent bioavailability is probably due to sedation-related loss of drug into the air.

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