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Absorption of Bupivacaine after Administration of a Lozenge as Topical Treatment for Pain from Oral Mucositis

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Mogensen, Stine ; Sverrisdóttir, Eva ; Sveinsdóttir, Kolbrún ; Treldal, Charlotte ; Jensen, Kenneth ; Jensen, Anders Bonde ; Kristensen, Claus Andrup ; Jacobsen, Jette ; Kreilgaard, Mads ; Petersen, Janne ; Andersen, Ove. / Absorption of Bupivacaine after Administration of a Lozenge as Topical Treatment for Pain from Oral Mucositis. I: Basic & clinical pharmacology & toxicology. 2017 ; Bind 120, Nr. 1. s. 71-78.

Bibtex

@article{50c5904cb03143af9e154f1e896d1a4d,
title = "Absorption of Bupivacaine after Administration of a Lozenge as Topical Treatment for Pain from Oral Mucositis",
abstract = "The aim was to investigate systemic exposure after administration of a novel bupivacaine lozenge in healthy individuals with normal mucosa and in head and neck cancer (HNC) patients with oral mucositis. A lozenge containing 5 mg, 10 mg, 25 mg and 50mg bupivacaine, respectively, was administered as single dose to 10 healthy invididuals and lozenge containing 25 mg bupivacaine was administered as single dose to 10 HNC patients with oral mucositis and as multiple doses to 5 HNC patients. Blood samples were collected for 6 hr from the healthy individuals and 3 hr from the HNC patients, respectively, after administration. The plasma concentration-time profiles of bupivacaine were fitted to pharmacokinetic models using non-linear mixed effects modelling, evaluating demographics and health status as covariates. The population pharmacokinetics (PK) of bupivacaine lozenge was best described by a two-compartment distribution model with absorption transit compartments. All observed plasma concentrations were well below bupivacaine concentrations (2000-2250 ng/ml) which have caused toxic symptoms. The PK model suggested that relative bioavailability was 2-fold higher in HNC patients with oral mucositis grade 1-2, and 3-fold higher in HNC patients with oral mucositis grade 3-4 than in the healthy individuals. Simulations showed that the plasma concentrations would be below the toxic limit after repeated dosing every second hour with 25 mg bupivacaine for 5 days. The 25 mg bupivacaine lozenges were safe without systemic toxic levels of bupivacaine or risk of side effects. Based on PK simulations of repeated doses of 25 mg every 2 hr for 16 hr a day, the lozengscan be administered with minimum risk of exceeding the toxic limit. This article is protected by copyright. All rights reserved.",
author = "Stine Mogensen and Eva Sverrisd{\'o}ttir and Kolbr{\'u}n Sveinsd{\'o}ttir and Charlotte Treldal and Kenneth Jensen and Jensen, {Anders Bonde} and Kristensen, {Claus Andrup} and Jette Jacobsen and Mads Kreilgaard and Janne Petersen and Ove Andersen",
note = "This article is protected by copyright. All rights reserved.",
year = "2017",
month = jan,
doi = "10.1111/bcpt.12644",
language = "English",
volume = "120",
pages = "71--78",
journal = "Basic and Clinical Pharmacology and Toxicology",
issn = "1742-7835",
publisher = "Wiley-Blackwell Publishing Ltd",
number = "1",

}

RIS

TY - JOUR

T1 - Absorption of Bupivacaine after Administration of a Lozenge as Topical Treatment for Pain from Oral Mucositis

AU - Mogensen, Stine

AU - Sverrisdóttir, Eva

AU - Sveinsdóttir, Kolbrún

AU - Treldal, Charlotte

AU - Jensen, Kenneth

AU - Jensen, Anders Bonde

AU - Kristensen, Claus Andrup

AU - Jacobsen, Jette

AU - Kreilgaard, Mads

AU - Petersen, Janne

AU - Andersen, Ove

N1 - This article is protected by copyright. All rights reserved.

PY - 2017/1

Y1 - 2017/1

N2 - The aim was to investigate systemic exposure after administration of a novel bupivacaine lozenge in healthy individuals with normal mucosa and in head and neck cancer (HNC) patients with oral mucositis. A lozenge containing 5 mg, 10 mg, 25 mg and 50mg bupivacaine, respectively, was administered as single dose to 10 healthy invididuals and lozenge containing 25 mg bupivacaine was administered as single dose to 10 HNC patients with oral mucositis and as multiple doses to 5 HNC patients. Blood samples were collected for 6 hr from the healthy individuals and 3 hr from the HNC patients, respectively, after administration. The plasma concentration-time profiles of bupivacaine were fitted to pharmacokinetic models using non-linear mixed effects modelling, evaluating demographics and health status as covariates. The population pharmacokinetics (PK) of bupivacaine lozenge was best described by a two-compartment distribution model with absorption transit compartments. All observed plasma concentrations were well below bupivacaine concentrations (2000-2250 ng/ml) which have caused toxic symptoms. The PK model suggested that relative bioavailability was 2-fold higher in HNC patients with oral mucositis grade 1-2, and 3-fold higher in HNC patients with oral mucositis grade 3-4 than in the healthy individuals. Simulations showed that the plasma concentrations would be below the toxic limit after repeated dosing every second hour with 25 mg bupivacaine for 5 days. The 25 mg bupivacaine lozenges were safe without systemic toxic levels of bupivacaine or risk of side effects. Based on PK simulations of repeated doses of 25 mg every 2 hr for 16 hr a day, the lozengscan be administered with minimum risk of exceeding the toxic limit. This article is protected by copyright. All rights reserved.

AB - The aim was to investigate systemic exposure after administration of a novel bupivacaine lozenge in healthy individuals with normal mucosa and in head and neck cancer (HNC) patients with oral mucositis. A lozenge containing 5 mg, 10 mg, 25 mg and 50mg bupivacaine, respectively, was administered as single dose to 10 healthy invididuals and lozenge containing 25 mg bupivacaine was administered as single dose to 10 HNC patients with oral mucositis and as multiple doses to 5 HNC patients. Blood samples were collected for 6 hr from the healthy individuals and 3 hr from the HNC patients, respectively, after administration. The plasma concentration-time profiles of bupivacaine were fitted to pharmacokinetic models using non-linear mixed effects modelling, evaluating demographics and health status as covariates. The population pharmacokinetics (PK) of bupivacaine lozenge was best described by a two-compartment distribution model with absorption transit compartments. All observed plasma concentrations were well below bupivacaine concentrations (2000-2250 ng/ml) which have caused toxic symptoms. The PK model suggested that relative bioavailability was 2-fold higher in HNC patients with oral mucositis grade 1-2, and 3-fold higher in HNC patients with oral mucositis grade 3-4 than in the healthy individuals. Simulations showed that the plasma concentrations would be below the toxic limit after repeated dosing every second hour with 25 mg bupivacaine for 5 days. The 25 mg bupivacaine lozenges were safe without systemic toxic levels of bupivacaine or risk of side effects. Based on PK simulations of repeated doses of 25 mg every 2 hr for 16 hr a day, the lozengscan be administered with minimum risk of exceeding the toxic limit. This article is protected by copyright. All rights reserved.

U2 - 10.1111/bcpt.12644

DO - 10.1111/bcpt.12644

M3 - Journal article

C2 - 27430990

VL - 120

SP - 71

EP - 78

JO - Basic and Clinical Pharmacology and Toxicology

JF - Basic and Clinical Pharmacology and Toxicology

SN - 1742-7835

IS - 1

ER -

ID: 48263469