Cargando…

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

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 populatio...

Descripción completa

Detalles Bibliográficos
Autores principales: Simons, Pieter, Olofsen, Erik, van Velzen, Monique, van Lemmen, Maarten, Mooren, René, van Dasselaar, Tom, Mohr, Patrick, Hammes, Florian, van der Schrier, Rutger, Niesters, Marieke, Dahan, Albert
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9309697/
https://www.ncbi.nlm.nih.gov/pubmed/35899184
http://dx.doi.org/10.3389/fpain.2022.946486
_version_ 1784753224581906432
author Simons, Pieter
Olofsen, Erik
van Velzen, Monique
van Lemmen, Maarten
Mooren, René
van Dasselaar, Tom
Mohr, Patrick
Hammes, Florian
van der Schrier, Rutger
Niesters, Marieke
Dahan, Albert
author_facet Simons, Pieter
Olofsen, Erik
van Velzen, Monique
van Lemmen, Maarten
Mooren, René
van Dasselaar, Tom
Mohr, Patrick
Hammes, Florian
van der Schrier, Rutger
Niesters, Marieke
Dahan, Albert
author_sort Simons, Pieter
collection PubMed
description 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.
format Online
Article
Text
id pubmed-9309697
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-93096972022-07-26 S-Ketamine Oral Thin Film—Part 1: Population Pharmacokinetics of S-Ketamine, S-Norketamine and S-Hydroxynorketamine Simons, Pieter Olofsen, Erik van Velzen, Monique van Lemmen, Maarten Mooren, René van Dasselaar, Tom Mohr, Patrick Hammes, Florian van der Schrier, Rutger Niesters, Marieke Dahan, Albert Front Pain Res (Lausanne) Pain Research 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. Frontiers Media S.A. 2022-07-11 /pmc/articles/PMC9309697/ /pubmed/35899184 http://dx.doi.org/10.3389/fpain.2022.946486 Text en Copyright © 2022 Simons, Olofsen, van Velzen, van Lemmen, Mooren, van Dasselaar, Mohr, Hammes, van der Schrier, Niesters and Dahan. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pain Research
Simons, Pieter
Olofsen, Erik
van Velzen, Monique
van Lemmen, Maarten
Mooren, René
van Dasselaar, Tom
Mohr, Patrick
Hammes, Florian
van der Schrier, Rutger
Niesters, Marieke
Dahan, Albert
S-Ketamine Oral Thin Film—Part 1: Population Pharmacokinetics of S-Ketamine, S-Norketamine and S-Hydroxynorketamine
title S-Ketamine Oral Thin Film—Part 1: Population Pharmacokinetics of S-Ketamine, S-Norketamine and S-Hydroxynorketamine
title_full S-Ketamine Oral Thin Film—Part 1: Population Pharmacokinetics of S-Ketamine, S-Norketamine and S-Hydroxynorketamine
title_fullStr S-Ketamine Oral Thin Film—Part 1: Population Pharmacokinetics of S-Ketamine, S-Norketamine and S-Hydroxynorketamine
title_full_unstemmed S-Ketamine Oral Thin Film—Part 1: Population Pharmacokinetics of S-Ketamine, S-Norketamine and S-Hydroxynorketamine
title_short S-Ketamine Oral Thin Film—Part 1: Population Pharmacokinetics of S-Ketamine, S-Norketamine and S-Hydroxynorketamine
title_sort s-ketamine oral thin film—part 1: population pharmacokinetics of s-ketamine, s-norketamine and s-hydroxynorketamine
topic Pain Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9309697/
https://www.ncbi.nlm.nih.gov/pubmed/35899184
http://dx.doi.org/10.3389/fpain.2022.946486
work_keys_str_mv AT simonspieter sketamineoralthinfilmpart1populationpharmacokineticsofsketaminesnorketamineandshydroxynorketamine
AT olofsenerik sketamineoralthinfilmpart1populationpharmacokineticsofsketaminesnorketamineandshydroxynorketamine
AT vanvelzenmonique sketamineoralthinfilmpart1populationpharmacokineticsofsketaminesnorketamineandshydroxynorketamine
AT vanlemmenmaarten sketamineoralthinfilmpart1populationpharmacokineticsofsketaminesnorketamineandshydroxynorketamine
AT moorenrene sketamineoralthinfilmpart1populationpharmacokineticsofsketaminesnorketamineandshydroxynorketamine
AT vandasselaartom sketamineoralthinfilmpart1populationpharmacokineticsofsketaminesnorketamineandshydroxynorketamine
AT mohrpatrick sketamineoralthinfilmpart1populationpharmacokineticsofsketaminesnorketamineandshydroxynorketamine
AT hammesflorian sketamineoralthinfilmpart1populationpharmacokineticsofsketaminesnorketamineandshydroxynorketamine
AT vanderschrierrutger sketamineoralthinfilmpart1populationpharmacokineticsofsketaminesnorketamineandshydroxynorketamine
AT niestersmarieke sketamineoralthinfilmpart1populationpharmacokineticsofsketaminesnorketamineandshydroxynorketamine
AT dahanalbert sketamineoralthinfilmpart1populationpharmacokineticsofsketaminesnorketamineandshydroxynorketamine