Morphine Glucuronidation in Preterm Neonates, Infants and Children Younger than 3 Years

Knibbe, Catherijne A. J.; Krekels, Elke H. J.; Anker, Johannes N. van den; DeJongh, Joost; Santen, Gijs; Dijk, Monique van; Simons, Sinno; Lingen, Richard A. van; Jacqz-Aigrain, Évelyne; Danhof, Meindert; Tibboel, Dick

doi:10.2165/00003088-200948060-00003

Cited by 132 publications

(176 citation statements)

References 41 publications

Supporting

Mentioning

164

Contrasting

Unclassified

Order By: Relevance

“…Consistent with previous pediatric studies (25,31), a twocompartment model corresponding to plasma and tissue distribution was adequate to describe morphine PK. The large between-subject variability in morphine PK parameters (Table II) supports a previous suggestion that morphine disposition is extremely variable, especially in children with complex pathophysiology (7).…”

Section: Discussionsupporting

confidence: 73%

“…The metabolite compartment is parameterized in terms of formation clearance, elimination clearance, and metabolite volume of distribution. For the metabolite parameters to be identifiable, the distribution volume is either fixed to literature adult values scaled by body weight (24) or expressed as fraction of morphine central volume of distribution (25). Choice of morphine and metabolite structural models was based on the Akaike information criterion (AIC) (26).…”

Section: Population Pharmacokinetic Analysismentioning

confidence: 99%

See 1 more Smart Citation

Pharmacokinetics of Morphine and Its Metabolites in Infants and Young Children After Congenital Heart Surgery

Elkomy

Drover

Glotzbach

et al. 2015

AAPS J

View full text Add to dashboard Cite

ABSTRACT. The objective of this study was to characterize morphine glucuronidation in infants and children following cardiac surgery for possible treatment individualization in this population. Twenty children aged 3 days to 6 years, admitted to the cardiovascular intensive care unit after congenital heart surgery, received an intravenous (IV) loading dose of morphine (0.15 mg/kg) followed by subsequent intermittent IV bolus doses based on a validated pain scale. Plasma samples were collected over 6 h after the loading dose and randomly after follow-up doses to measure morphine and its major metabolite concentrations. A population pharmacokinetic model was developed with the non-linear mixed effects software NONMEM. Parent disposition was adequately described by a linear two-compartment model. Effect of growth (size and maturation) on morphine parameters was accounted for by allometric body weight-based models. An intermediate compartment with Emax model best characterized glucuronide concentrations. Glomerular filtration rate was identified as a significant predictor of glucuronide formation time delay and maximum concentrations. Clearance of morphine in children with congenital heart disease is comparable to that reported in children without cardiac abnormalities of similar age. Children 1-6 months of age need higher morphine doses per kilogram to achieve an area under concentration-time curve comparable to that in older children. Pediatric patients with renal failure receiving morphine therapy are at increased risk of developing opioid toxicity due to accumulation of morphine metabolites.

show abstract

Section: Discussionsupporting

confidence: 73%

Section: Population Pharmacokinetic Analysismentioning

confidence: 99%

Pharmacokinetics of Morphine and Its Metabolites in Infants and Young Children After Congenital Heart Surgery

Elkomy

Drover

Glotzbach

et al. 2015

AAPS J

View full text Add to dashboard Cite

show abstract

“…Activity remains low in the first 10 days of post-natal life and then begins to increase in both term and preterm babies [50]. Again co-morbidities, surgery and gene polymorphisms can affect this pattern of development [45].…”

Section: Metabolismmentioning

confidence: 99%

“…The capacity of morphine metabolism by UGT2B7 is closely related to body weight as opposed to surface area and post-natal age after the first 10 days of life. During the first 2 weeks of life capacity increases quickly followed by 2 years of gradual increases to adult levels [50].…”

Section: Metabolismmentioning

confidence: 99%

Pharmacokinetics in neonatal prescribing: evidence base, paradigms and the future

O’Hara

Wright

Schneider

et al. 2015

Brit J Clinical Pharma

View full text Add to dashboard Cite

Paediatric patients, particularly preterm neonates, present many pharmacological challenges. Due to the difficulty in conducting clinical trials in these populations dosing information is often extrapolated from adult populations. As the processes of absorption, distribution, metabolism and excretion of drugs change throughout growth and development extrapolation presents risk of over or underestimating the doses required. Information about the development these processes, particularly drug metabolism pathways, is still limited with weight based dose adjustment presenting the best method of estimating pharmacokinetic changes due to growth and development. New innovations in pharmacokinetic research, such as population pharmacokinetic modelling, present unique opportunities to conduct clinical trials in these populations improving the safety and effectiveness of the drugs used. More research is required into this area to ensure the best outcomes for our most vulnerable patients.

show abstract

“…Fifth, 50th and 95th percentiles of observed concentrations; 5th, 50th and 95th percentiles of simulated concentrations paediatric modelling within a narrow age range, especially for young children [24]. It has recently been applied to the pharmacokinetics of morphine in children aged <3 years, including preterm and term neonates, in which an estimated exponent of 1.44 adequately described clearance [25]. After incorporating weight, the age and height were not significant.…”

Section: Figurementioning

confidence: 99%

Population pharmacokinetics and maximum a posteriori probability Bayesian estimator of abacavir: application of individualized therapy in HIV‐infected infants and toddlers

Zhao

Cella

Pasqua

et al. 2012

Brit J Clinical Pharma

View full text Add to dashboard Cite

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Abacavir is used to treat HIV infection in both adults and children. The recommended paediatric dose is 8 mg kg−1 twice daily up to a maximum of 300 mg twice daily. • Weight was identified as the central covariate influencing pharmacokinetics of abacavir in children. WHAT THIS STUDY ADDS • A population pharmacokinetic model was developed to describe both once and twice daily pharmacokinetic profiles of abacavir in infants and toddlers. • Standard dosage regimen is associated with large interindividual variability in abacavir concentrations. • A maximum a posteriori probability Bayesian estimator of AUC0–t based on three time points (0, 1 or 2, and 3 h) is proposed to support area under the concentration–time curve (AUC) targeted individualized therapy in infants and toddlers. AIMS To develop a population pharmacokinetic model for abacavir in HIV‐infected infants and toddlers, which will be used to describe both once and twice daily pharmacokinetic profiles, identify covariates that explain variability and propose optimal time points to optimize the area under the concentration–time curve (AUC) targeted dosage and individualize therapy. METHODS The pharmacokinetics of abacavir was described with plasma concentrations from 23 patients using nonlinear mixed‐effects modelling (NONMEM) software. A two‐compartment model with first‐order absorption and elimination was developed. The final model was validated using bootstrap, visual predictive check and normalized prediction distribution errors. The Bayesian estimator was validated using the cross‐validation and simulation–estimation method. RESULTS The typical population pharmacokinetic parameters and relative standard errors (RSE) were apparent systemic clearance (CL) 13.4 l h−1 (RSE 6.3%), apparent central volume of distribution 4.94 l (RSE 28.7%), apparent peripheral volume of distribution 8.12 l (RSE14.2%), apparent intercompartment clearance 1.25 l h−1 (RSE 16.9%) and absorption rate constant 0.758 h−1 (RSE 5.8%). The covariate analysis identified weight as the individual factor influencing the apparent oral clearance: CL = 13.4 × (weight/12)1.14. The maximum a posteriori probability Bayesian estimator, based on three concentrations measured at 0, 1 or 2, and 3 h after drug intake allowed predicting individual AUC0–t. CONCLUSIONS The population pharmacokinetic model developed for abacavir in HIV‐infected infants and toddlers accurately described both once and twice daily pharmacokinetic profiles. The maximum a posteriori probability Bayesian estimator of AUC0–t was developed from the final model and can be used routinely to optimize individual dosing.

show abstract

Morphine Glucuronidation in Preterm Neonates, Infants and Children Younger than 3 Years

Cited by 132 publications

References 41 publications

Pharmacokinetics of Morphine and Its Metabolites in Infants and Young Children After Congenital Heart Surgery

Pharmacokinetics of Morphine and Its Metabolites in Infants and Young Children After Congenital Heart Surgery

Pharmacokinetics in neonatal prescribing: evidence base, paradigms and the future

Population pharmacokinetics and maximum a posteriori probability Bayesian estimator of abacavir: application of individualized therapy in HIV‐infected infants and toddlers

Contact Info

Product

Resources

About