Population Pharmacokinetics of Morphine and Morphine-6-Glucuronide following Rectal Administration -A Dose Escalation Study

Anne Brokjær; Mads Kreilgaard; Anne Estrup Olesen; Ulrika S H Simonsson; Lona Louring Christrup; Albert Dahan; Asbjørn Mohr Drewes

Population Pharmacokinetics of Morphine and Morphine-6-Glucuronide following Rectal Administration -A Dose Escalation Study

Anne Brokjær, Mads Kreilgaard, Anne Estrup Olesen, Ulrika S H Simonsson, Lona Louring Christrup, Albert Dahan, Asbjørn Mohr Drewes

7 Citationer (Scopus)

Abstract

Introduction To safely and effectively administer morphine as liquid formulation via the rectal route, a thorough understanding of the pharmacokinetics is warranted. The aims were: (1) to develop a population pharmacokinetic model of liquid rectal morphine and morphine-6-glucoronide (M6G), (2) to simulate clinically relevant rectal doses of morphine and (3) to assess the tolerability and safety. Material and methods This open label, dose escalation, four-sequence study was conducted in 10 healthy males. Three escalating doses of morphine hydrochloride (10 mg, 15 mg and 20 mg) were administered 20 cm from the anal verge. A 2 mg morphine hydrochloride dose was administered intravenously as reference. Blood samples were drawn at baseline and at nine time points post dosing. Serum was obtained by centrifugation and assayed for contents of morphine and M6G with a validated high performance liquid chromatographic method. Modelling was performed using NONMEM 7.2 and the first order conditional estimation method with interaction. Results A two compartment distribution model with one absorption transit compartment for rectal administration and systemic clearance from the central compartment best described data. Systemic PK parameters were allometric scaled with body weight. The mean morphine absorption transit time was 0.6 h, clearance 78 L/h [relative standard error (RSE) 12%] and absolute bioavailability 24% (RSE 11%). To obtain clinically relevant serum concentrations, simulations revealed that a single morphine hydrochloride dose of 35 mg will provide sufficient peak serum concentration levels and a 46 mg dose four times daily is suggested to maintain clinically relevant steady-state concentrations. Body weight was suggested to be an important covariate for morphine exposure. No severe side effects were observed. Conclusion A population pharmacokinetic model of liquid rectal morphine and M6G was developed. The model can be used to simulate rectal doses to maintain analgesic activity in the clinic. The studied doses were safe and well tolerated.

Originalsprog	Engelsk
Tidsskrift	European Journal of Pharmaceutical Sciences
Vol/bind	68
Sider (fra-til)	78-86
Antal sider	9
ISSN	0928-0987
Status	Udgivet - 20 feb. 2015

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http://www.sciencedirect.com/science/article/pii/S0928098714004436

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title = "Population Pharmacokinetics of Morphine and Morphine-6-Glucuronide following Rectal Administration -A Dose Escalation Study",

abstract = "Introduction To safely and effectively administer morphine as liquid formulation via the rectal route, a thorough understanding of the pharmacokinetics is warranted. The aims were: (1) to develop a population pharmacokinetic model of liquid rectal morphine and morphine-6-glucoronide (M6G), (2) to simulate clinically relevant rectal doses of morphine and (3) to assess the tolerability and safety. Material and methods This open label, dose escalation, four-sequence study was conducted in 10 healthy males. Three escalating doses of morphine hydrochloride (10 mg, 15 mg and 20 mg) were administered 20 cm from the anal verge. A 2 mg morphine hydrochloride dose was administered intravenously as reference. Blood samples were drawn at baseline and at nine time points post dosing. Serum was obtained by centrifugation and assayed for contents of morphine and M6G with a validated high performance liquid chromatographic method. Modelling was performed using NONMEM 7.2 and the first order conditional estimation method with interaction. Results A two compartment distribution model with one absorption transit compartment for rectal administration and systemic clearance from the central compartment best described data. Systemic PK parameters were allometric scaled with body weight. The mean morphine absorption transit time was 0.6 h, clearance 78 L/h [relative standard error (RSE) 12%] and absolute bioavailability 24% (RSE 11%). To obtain clinically relevant serum concentrations, simulations revealed that a single morphine hydrochloride dose of 35 mg will provide sufficient peak serum concentration levels and a 46 mg dose four times daily is suggested to maintain clinically relevant steady-state concentrations. Body weight was suggested to be an important covariate for morphine exposure. No severe side effects were observed. Conclusion A population pharmacokinetic model of liquid rectal morphine and M6G was developed. The model can be used to simulate rectal doses to maintain analgesic activity in the clinic. The studied doses were safe and well tolerated.",

author = "Anne Brokj{\ae}r and Mads Kreilgaard and Olesen, {Anne Estrup} and Simonsson, {Ulrika S H} and Christrup, {Lona Louring} and Albert Dahan and Drewes, {Asbj{\o}rn Mohr}",

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T1 - Population Pharmacokinetics of Morphine and Morphine-6-Glucuronide following Rectal Administration -A Dose Escalation Study

AU - Brokjær, Anne

AU - Kreilgaard, Mads

AU - Olesen, Anne Estrup

AU - Simonsson, Ulrika S H

AU - Christrup, Lona Louring

AU - Dahan, Albert

AU - Drewes, Asbjørn Mohr

PY - 2015/2/20

Y1 - 2015/2/20

N2 - Introduction To safely and effectively administer morphine as liquid formulation via the rectal route, a thorough understanding of the pharmacokinetics is warranted. The aims were: (1) to develop a population pharmacokinetic model of liquid rectal morphine and morphine-6-glucoronide (M6G), (2) to simulate clinically relevant rectal doses of morphine and (3) to assess the tolerability and safety. Material and methods This open label, dose escalation, four-sequence study was conducted in 10 healthy males. Three escalating doses of morphine hydrochloride (10 mg, 15 mg and 20 mg) were administered 20 cm from the anal verge. A 2 mg morphine hydrochloride dose was administered intravenously as reference. Blood samples were drawn at baseline and at nine time points post dosing. Serum was obtained by centrifugation and assayed for contents of morphine and M6G with a validated high performance liquid chromatographic method. Modelling was performed using NONMEM 7.2 and the first order conditional estimation method with interaction. Results A two compartment distribution model with one absorption transit compartment for rectal administration and systemic clearance from the central compartment best described data. Systemic PK parameters were allometric scaled with body weight. The mean morphine absorption transit time was 0.6 h, clearance 78 L/h [relative standard error (RSE) 12%] and absolute bioavailability 24% (RSE 11%). To obtain clinically relevant serum concentrations, simulations revealed that a single morphine hydrochloride dose of 35 mg will provide sufficient peak serum concentration levels and a 46 mg dose four times daily is suggested to maintain clinically relevant steady-state concentrations. Body weight was suggested to be an important covariate for morphine exposure. No severe side effects were observed. Conclusion A population pharmacokinetic model of liquid rectal morphine and M6G was developed. The model can be used to simulate rectal doses to maintain analgesic activity in the clinic. The studied doses were safe and well tolerated.

AB - Introduction To safely and effectively administer morphine as liquid formulation via the rectal route, a thorough understanding of the pharmacokinetics is warranted. The aims were: (1) to develop a population pharmacokinetic model of liquid rectal morphine and morphine-6-glucoronide (M6G), (2) to simulate clinically relevant rectal doses of morphine and (3) to assess the tolerability and safety. Material and methods This open label, dose escalation, four-sequence study was conducted in 10 healthy males. Three escalating doses of morphine hydrochloride (10 mg, 15 mg and 20 mg) were administered 20 cm from the anal verge. A 2 mg morphine hydrochloride dose was administered intravenously as reference. Blood samples were drawn at baseline and at nine time points post dosing. Serum was obtained by centrifugation and assayed for contents of morphine and M6G with a validated high performance liquid chromatographic method. Modelling was performed using NONMEM 7.2 and the first order conditional estimation method with interaction. Results A two compartment distribution model with one absorption transit compartment for rectal administration and systemic clearance from the central compartment best described data. Systemic PK parameters were allometric scaled with body weight. The mean morphine absorption transit time was 0.6 h, clearance 78 L/h [relative standard error (RSE) 12%] and absolute bioavailability 24% (RSE 11%). To obtain clinically relevant serum concentrations, simulations revealed that a single morphine hydrochloride dose of 35 mg will provide sufficient peak serum concentration levels and a 46 mg dose four times daily is suggested to maintain clinically relevant steady-state concentrations. Body weight was suggested to be an important covariate for morphine exposure. No severe side effects were observed. Conclusion A population pharmacokinetic model of liquid rectal morphine and M6G was developed. The model can be used to simulate rectal doses to maintain analgesic activity in the clinic. The studied doses were safe and well tolerated.

M3 - Journal article

C2 - 25486331

SN - 0928-0987

VL - 68

SP - 78

EP - 86

JO - European Journal of Pharmaceutical Sciences

JF - European Journal of Pharmaceutical Sciences

ER -

Population Pharmacokinetics of Morphine and Morphine-6-Glucuronide following Rectal Administration -A Dose Escalation Study

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