Scoping review of paediatric population pharmacokinetic models of morphine

Abstract

OBJECTIVE AND PURPOSE: This scoping review aimed to summarise all available population pharmacokinetic models of morphine and its metabolites (morphine-3-glucoronide [M3G], morphine-6-glucoronide [M6G]) in children and describe how morphine exposure varies across paediatric age groups and settings. Identifying the factors that contribute to pharmacokinetic variability may improve our understanding of a patient's pharmacodynamic response to morphine. METHODS: We searched Embase and MEDLINE databases from inception to 8 March 2024 for paediatric population pharmacokinetic models of morphine and its metabolites. Two reviewers independently screened abstracts and full texts and extracted the data. The review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. RESULTS: In total, 21 paediatric population pharmacokinetic models of morphine were identified; 12 studies also included morphine metabolites (M3G and/or M6G). Neonates and young children (< 6 years) were the most studied age groups (18/21; 86%), whereas older children (> 6 years) and adolescents (> 10 years) were included in only 6 of the 21 (29%) models. Morphine pharmacokinetics were most commonly described with two-compartment (52%) and one-compartment (38%) structure with first-order elimination. Several model covariates were identified: bodyweight, post-natal age for neonates, body temperature, therapeutic cooling, duration of mechanical ventilation, and genetic variation in drug transporters that mediate the uptake of morphine (e.g. OCT1). CONCLUSIONS: Several population pharmacokinetic models of morphine and its metabolites in paediatrics have been published across diverse patient groups. Bodyweight and age-related covariates emerged as the most common factors affecting clearance and distribution; other covariates, including mechanical ventilation, therapeutic cooling, and genetic variation, also impacted morphine pharmacokinetics. Further research should focus on validating the predictive accuracy of paediatric morphine models in different patient populations and the combined effect of covariates, such as those related to critical illness and genetic variation, on morphine pharmacokinetics.