Newly Published
Pain Medicine  |   August 2017
Pharmacokinetics and Bioavailability of Inhaled Esketamine in Healthy Volunteers
Author Notes
  • 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.).
  • K.J. and A. Duma contributed equally to this article.
    K.J. and A. Duma contributed equally to this article.×
  • Submitted for publication March 8, 2017. Accepted for publication June 27, 2017.
    Submitted for publication March 8, 2017. Accepted for publication June 27, 2017.×
  • Research Support: Supported in part by Eurocept BV (Ankeveen, The Netherlands) and institutional and/or departmental sources.
    Research Support: Supported in part by Eurocept BV (Ankeveen, The Netherlands) and institutional and/or departmental sources.×
  • Competing Interests: Dr. Dahan received consultancy and speaker fees from Eurocept BV (Ankeveen, The Netherlands) in the past. The other authors declare no competing interests.
    Competing Interests: Dr. Dahan received consultancy and speaker fees from Eurocept BV (Ankeveen, The Netherlands) in the past. The other authors declare no competing interests.×
  • Correspondence: Address correspondence to Dr. Dahan: Department of Anesthesiology, Leiden University Medical Center, H5, P.O. Box 9600, 2300 RC Leiden, The Netherlands. a.dahan@lumc.nl. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Pain Medicine / Pain Medicine / Pharmacology
Pain Medicine   |   August 2017
Pharmacokinetics and Bioavailability of Inhaled Esketamine in Healthy Volunteers
Anesthesiology Newly Published on August 3, 2017. doi:10.1097/ALN.0000000000001798
Anesthesiology Newly Published on August 3, 2017. doi:10.1097/ALN.0000000000001798
Abstract

Background: Esketamine 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.

Methods: Three 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.

Results: The 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–1 (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.

Conclusions: We 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.