BACKGROUND: Esketamine nasal spray is approved for treatment-resistant depression. OBJECTIVE: The objective of this study was to characterize the pharmacokinetics of esketamine and noresketamine in healthy subjects and patients with treatment-resistant depression. METHODS: Esketamine and noresketamine were measured in > 9000 plasma samples collected from 820 individuals who received esketamine by the intranasal, intravenous, and oral routes. An open linear model for esketamine (three compartments) and noresketamine (two compartments) that included a hepato-portal compartment was developed using NONMEM® VII. The effects of covariates on esketamine pharmacokinetics and a model evaluation were performed using conventional methods. RESULTS: The fraction of a 28-mg intranasal dose absorbed through the nasal cavity (FRn) is 54% (100% of this fraction is completely absorbed); the remaining 46% is swallowed and undergoes intestinal and first-pass metabolism and 18.6% of the swallowed dose reaches the systemic circulation. The absolute bioavailability of 56 and 84 mg of intranasal esketamine is 54 and 51%, respectively. Esketamine volume at steady state and clearance were 752 L and 114 L/h, respectively. Noresketamine volume at steady state and apparent clearance were 185 L and 38 L/h, respectively. Relative to non-Asian subjects, Asian subjects showed a 64.0 and 19.4% decrease in the esketamine elimination rate constant and noresketamine apparent clearance, respectively. Japanese subjects exhibited a 34% increase in FRn vs other races. Hepatic blood flow decreased by 21.9 L/h for each decade in age in subjects aged > 60 years. These changes resulted in esketamine and noresketamine maximum concentration and area under the concentration-time curve after 24 h post-dose values that were up to 36% higher than those observed in other races or in younger adult subjects. CONCLUSIONS: Esketamine and noresketamine pharmacokinetics was successfully characterized in healthy subjects and patients with treatment-resistant depression. The model quantified esketamine absolute nasal and oral bioavailability, its hepatic flow-limited clearance and biotransformation to the major metabolite noresketamine, and the influence of intrinsic and extrinsic factors on esketamine pharmacokinetics. Clinical trials registration numbers of the studies included in the analysis: ESKETINTRD1001 (NCT01780259), ESKETINTRD1002 (NCT01980303), ESKETINTRD1003 (NCT02129088), ESKETINTRD1008 (NCT02846519), ESKETINTRD1009 (NCT02343289), ESKETINTRD1010 (NCT02568176), ESKETINTRD1012 (NCT02345148), 54135419TRD1015 (NCT02682225), ESKETINTRD2003 (NCT01998958), ESKETINSUI2001 (NCT02133001), ESKETINTRD3001 (NCT02417064), ESKETINTRD3002 (NCT02418585), and ESKETINTRD3005 (NCT02422186).
BACKGROUND: Esketamine nasal spray is approved for treatment-resistant depression. OBJECTIVE: The objective of this study was to characterize the pharmacokinetics of esketamine and noresketamine in healthy subjects and patients with treatment-resistant depression. METHODS: Esketamine and noresketamine were measured in > 9000 plasma samples collected from 820 individuals who received esketamine by the intranasal, intravenous, and oral routes. An open linear model for esketamine (three compartments) and noresketamine (two compartments) that included a hepato-portal compartment was developed using NONMEM® VII. The effects of covariates on esketamine pharmacokinetics and a model evaluation were performed using conventional methods. RESULTS: The fraction of a 28-mg intranasal dose absorbed through the nasal cavity (FRn) is 54% (100% of this fraction is completely absorbed); the remaining 46% is swallowed and undergoes intestinal and first-pass metabolism and 18.6% of the swallowed dose reaches the systemic circulation. The absolute bioavailability of 56 and 84 mg of intranasal esketamine is 54 and 51%, respectively. Esketamine volume at steady state and clearance were 752 L and 114 L/h, respectively. Noresketamine volume at steady state and apparent clearance were 185 L and 38 L/h, respectively. Relative to non-Asian subjects, Asian subjects showed a 64.0 and 19.4% decrease in the esketamine elimination rate constant and noresketamine apparent clearance, respectively. Japanese subjects exhibited a 34% increase in FRn vs other races. Hepatic blood flow decreased by 21.9 L/h for each decade in age in subjects aged > 60 years. These changes resulted in esketamine and noresketamine maximum concentration and area under the concentration-time curve after 24 h post-dose values that were up to 36% higher than those observed in other races or in younger adult subjects. CONCLUSIONS: Esketamine and noresketamine pharmacokinetics was successfully characterized in healthy subjects and patients with treatment-resistant depression. The model quantified esketamine absolute nasal and oral bioavailability, its hepatic flow-limited clearance and biotransformation to the major metabolite noresketamine, and the influence of intrinsic and extrinsic factors on esketamine pharmacokinetics. Clinical trials registration numbers of the studies included in the analysis: ESKETINTRD1001 (NCT01780259), ESKETINTRD1002 (NCT01980303), ESKETINTRD1003 (NCT02129088), ESKETINTRD1008 (NCT02846519), ESKETINTRD1009 (NCT02343289), ESKETINTRD1010 (NCT02568176), ESKETINTRD1012 (NCT02345148), 54135419TRD1015 (NCT02682225), ESKETINTRD2003 (NCT01998958), ESKETINSUI2001 (NCT02133001), ESKETINTRD3001 (NCT02417064), ESKETINTRD3002 (NCT02418585), and ESKETINTRD3005 (NCT02422186).
Authors: Ella J Daly; Jaskaran B Singh; Maggie Fedgchin; Kimberly Cooper; Pilar Lim; Richard C Shelton; Michael E Thase; Andrew Winokur; Luc Van Nueten; Husseini Manji; Wayne C Drevets Journal: JAMA Psychiatry Date: 2018-02-01 Impact factor: 21.596
Authors: Rodrigo Machado-Vieira; Giacomo Salvadore; David A Luckenbaugh; Husseini K Manji; Carlos A Zarate Journal: J Clin Psychiatry Date: 2008-06 Impact factor: 4.384
Authors: Maggie Fedgchin; Madhukar Trivedi; Ella J Daly; Rama Melkote; Rosanne Lane; Pilar Lim; Dawn Vitagliano; Pierre Blier; Maurizio Fava; Michael Liebowitz; Arun Ravindran; Raphael Gaillard; Hans Van Den Ameele; Sheldon Preskorn; Husseini Manji; David Hough; Wayne C Drevets; Jaskaran B Singh Journal: Int J Neuropsychopharmacol Date: 2019-10-01 Impact factor: 5.176
Authors: Sean Bentley; Hewa Artin; Eamonn Mehaffey; Fred Liu; Kevin Sojourner; Andrew Bismark; David Printz; Ellen E Lee; Brian Martis; Sharon De Peralta; Dewleen G Baker; Jyoti Mishra; Dhakshin Ramanathan Journal: Pharmacotherapy Date: 2022-02-24 Impact factor: 4.705
Authors: Hong Jin Jeon; Po-Chung Ju; Ahmad Hatim Sulaiman; Salina Abdul Aziz; Jong-Woo Paik; Wilson Tan; Daisy Bai; Cheng-Ta Li Journal: Clin Psychopharmacol Neurosci Date: 2022-02-28 Impact factor: 2.582
Authors: Pieter Simons; Erik Olofsen; Monique van Velzen; Maarten van Lemmen; René Mooren; Tom van Dasselaar; Patrick Mohr; Florian Hammes; Rutger van der Schrier; Marieke Niesters; Albert Dahan Journal: Front Pain Res (Lausanne) Date: 2022-07-11
Authors: Briana K Chen; Gwenaëlle Le Pen; Adam Eckmier; Gilles Rubinstenn; Therese M Jay; Christine A Denny Journal: Int J Neuropsychopharmacol Date: 2021-07-14 Impact factor: 5.176
Authors: Immaculate M Langmia; Katja S Just; Sabrina Yamoune; Jürgen Brockmöller; Collen Masimirembwa; Julia C Stingl Journal: Front Genet Date: 2021-07-12 Impact factor: 4.599