Absorption of Bupivacaine after Administration of a Lozenge as Topical Treatment for Pain from Oral Mucositis
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Absorption of Bupivacaine after Administration of a Lozenge as Topical Treatment for Pain from Oral Mucositis. / Mogensen, Stine; Sverrisdóttir, Eva; Sveinsdóttir, Kolbrún; Treldal, Charlotte; Jensen, Kenneth; Jensen, Anders Bonde; Kristensen, Claus Andrup; Jacobsen, Jette; Kreilgaard, Mads; Petersen, Janne; Andersen, Ove.
In: Basic & Clinical Pharmacology & Toxicology, Vol. 120, No. 1, 2017, p. 71-78.Research output: Contribution to journal › Journal article › Research › peer-review
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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
Y1 - 2017
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: 164156276