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...
Autores principales: | , , , , , , , , , , |
---|---|
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 |