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A Compartmental Analysis for Morphine and Its Metabolites in Young Children After a Single Oral Dose.

Abstract：

BACKGROUND AND OBJECTIVES:Currently, the majority of the surgical procedures performed in paediatric hospitals are done on a day care basis, with post-operative pain being managed by caregivers at home. Pain after discharge of these post-operative children has historically been managed with oral codeine in combination with paracetamol (acetaminophen). Codeine is an opioid, which elicits its analgesic effects via metabolism to morphine and codeine-6-glucuronide. Oral morphine is a feasible alternative for outpatient analgesia; however, the pharmacokinetics of morphine after oral administration have been previously described only sparsely, and there is little information in healthy children. METHODS:The clinical trial included 40 children from 2 to 6 years of age, with an American Society of Anaesthesiologists physical status classification of 1 or 2, who were undergoing surgical procedures requiring opioid analgesia. Morphine was orally administered prior to surgery in one of three doses: 0.1 mg/kg, 0.2 mg/kg and 0.3 mg/kg. Blood samples were collected for plasma morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) concentrations at 30, 60, 90, 120, 180 and 240 min after administration. All analyses were performed with the non-linear mixed-effect modelling software NONMEM version 7.2, using the first-order conditional estimation (FOCE) method. RESULTS:A pharmacokinetic model was developed to simultaneously describe the plasma profiles of morphine and its metabolites M3G and M6G after a single dose of oral morphine in young children (2-6 years of age). The disposition of morphine, M3G and M6G in plasma was best described by a one-compartment model. M3G and M6G metabolite formation was best described by a delay transit compartment, indicating a delay in the appearance of these two major metabolites. CONCLUSION:This model provides a foundation on which to further evaluate the use of oral morphine and its safety in young children. Longer follow-up time for morphine oral doses and incorporation of other important covariates, such as phenotype, will add value and will help overcome the limitations of the presented population pharmacokinetic analysis.

journal_name

Clin Pharmacokinet

journal_title

Clinical pharmacokinetics

authors

Velez de Mendizabal N,Jimenez-Mendez R,Cooke E,Montgomery CJ,Dawes J,Rieder MJ,Aleksa K,Koren G,Jacobo-Cabral CO,Gonzalez-Ramirez R,Castañeda-Hernandez G,Carleton BC

doi

10.1007/s40262-015-0256-4

subject

Has Abstract

pub_date

2015-10-01 00:00:00

pages

1083-90

issue

eissn

0312-5963

issn

1179-1926

pii

10.1007/s40262-015-0256-4

journal_volume

pub_type

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A Compartmental Analysis for Morphine and Its Metabolites in Young Children After a Single Oral Dose.