Population clinical pharmacology of children: modelling covariate effects

Anderson, Brian J.; Allegaert, Karel; Holford, Nicholas H. G.

doi:10.1007/s00431-006-0189-x

Cited by 160 publications

(136 citation statements)

References 68 publications

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“…Following principles of pediatric clinical pharmacology and previous population PK models in infants (27), an allometric body weight-based model scaled to a 6-kg child (median body weight in this study) was first implemented to account for the influence of body size on morphine clearance and volume parameters. Considering the allometric weight model as the base model, we then investigated the effect of postnatal age, gestational age, gender, kidney function (evaluated by estimated glomerular filtration rate), hepatic function (evaluated by serum alanine transaminase (ALT) and aspartate transaminase (AST)), and congenital heart defects (tetralogy of Fallot (TOF), atrioventricular septal defects (AVSD), ventricular septal defect (VSD), or other) on morphine CL, CL D , VC, and VP.…”

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

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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.

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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

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“…Allometric scaling is a mechanistic approach that has a strong theoretical and empirical basis for this. West et al (18,19) explained that the 3/4 power law was derived from a general model that described how essential materials are transported through space-filled fractal networks of branching tubes. Fixing the power exponent of body weight allowed investigators to delineate secondary covariate effects from the effect of size.…”

Section: Discussionmentioning

confidence: 99%

Population Pharmacokinetic Analysis of Digoxin in Chinese Neonates and Infants

Gong

Chen

et al. 2014

J Pharmacol Sci

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Abstract. To obtain more information regarding the influence of various covariates on the disposition of digoxin in Chinese neonates and infants, routine clinical pharmacokinetic data were retrospectively collected from 131 hospitalized patients. A nonlinear mixed effects modeling (NONMEM) method was applied to the data. A one-compartment/first-order absorption model was employed to estimate the influence of total body weight (allometric power model), postnatal age, serum creatinine, gender, presence of heart congestive failure, and concomitant medications on apparent total clearance and apparent drug distribution of digoxin. Pharmacokinetic parameter estimates for CL/F and V/F were 0.147 L•h −1•kg −1 and 15.7 L/kg, respectively. Total body weight and postnatal age were identified as the important factors affecting total clearance of digoxin; total body weight was the covariate identified to influence the apparent distribution volume. Both internal (bootstrap method, visual predictive checks, and normalized prediction distributed error) and external validation supported the stable and predictive performance of the final model. We concluded that the model can be used to choose an appropriate dose regimen in Chinese neonates and infants.

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“…Therefore, comparative therapeutics will eliminate highly toxic and non-effective anticancer drugs [41]. Metabolic rate being related with BSA depends on body weight and exponent (1/4) [42] which further predicts pharmacokinetic mass exponents for clearance (3/4), elimination half-life (t1 ⁄ 2, 1/4), and volume of distribution. Clearance with BSA also scale with the 2/3 power.…”

Section: Discussionmentioning

confidence: 99%

Derivation of a Unique Body Surface Area (Bsa) Formula for Calculation of Relatively Safe Doses of Dog and Human Anticancer Drugs

Saganuwan¹

2017

J Cancer Sci Ther

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Population clinical pharmacology of children: modelling covariate effects

Abstract: Covariate investigation in children is improving the understanding of developmental aspects of drug disposition and effects in the paediatric population, ultimately leading to more effective use of medications.

Cited by 160 publications

References 68 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

Population Pharmacokinetic Analysis of Digoxin in Chinese Neonates and Infants

Derivation of a Unique Body Surface Area (Bsa) Formula for Calculation of Relatively Safe Doses of Dog and Human Anticancer Drugs

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