Morphine glucuronidation in preterm neonates, infants and children younger than 3 years.
ABSTRACT A considerable amount of drug use in children is still unlicensed or off-label. In order to derive rational dosing schemes, the influence of aging on glucuronidation capacity in newborns, including preterms, infants and children under the age of 3 years was studied using morphine and its major metabolites as a model drug.
A population pharmacokinetic model was developed with the nonlinear mixed-effects modelling software NONMEM V, on the basis of 2159 concentrations of morphine and its glucuronides from 248 infants receiving intravenous morphine ranging in bodyweight from 500 g to 18 kg (median 2.8 kg). The model was internally validated using normalized prediction distribution errors.
Formation clearances of morphine to its glucuronides and elimination clearances of the glucuronides were found to be primarily influenced by bodyweight, which was parameterized using an allometric equation with an estimated exponential scaling factor of 1.44. Additionally, a postnatal age of less than 10 days was identified as a covariate for formation clearance to the glucuronides, independent of birthweight or postmenstrual age. Distribution volumes scaled linearly with bodyweight.
Model-based simulations show that in newborns, including preterms, infants and children under the age of 3 years, a loading dose in microg/kg and a maintenance dose expressed in microg/kg1.5/h, with a 50% reduction of the maintenance dose in newborns younger than 10 days, results in a narrow range of morphine and metabolite serum concentrations throughout the studied age range. Future pharmacodynamic investigations are needed to reveal target concentrations in this population, after which final dosing recommendations can be made.
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ABSTRACT: Children differ from adults in their response to drugs. While this may be the result of changes in dose exposure (pharmacokinetics [PK]) and/or exposure response (pharmacodynamics [PD]) relationships, the magnitude of these changes may not be solely reflected by differences in body weight. As a consequence, dosing recommendations empirically derived from adults dosing regimens using linear extrapolations based on body weight, can result in therapeutic failure, occurrence of adverse effect or even fatalities. In order to define rational, patient-tailored dosing schemes, population PK-PD studies in children are needed. For the analysis of the data, population modelling using non-linear mixed effect modelling is the preferred tool since this approach allows for the analysis of sparse and unbalanced datasets. Additionally, it permits the exploration of the influence of different covariates such as body weight and age to explain the variability in drug response. Finally, using this approach, these PK-PD studies can be designed in the most efficient manner in order to obtain the maximum information on the PK-PD parameters with the highest precision. Once a population PK-PD model is developed, internal and external validations should be performed. If the model performs well in these validation procedures, model simulations can be used to define a dosing regimen, which in turn needs to be tested and challenged in a prospective clinical trial. This methodology will improve the efficacy/safety balance of dosing guidelines, which will be of benefit to the individual child.European Journal of Clinical Pharmacology 03/2010; 67 Suppl 1(Suppl 1):5-16. DOI:10.1007/s00228-009-0782-9 · 2.70 Impact Factor
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ABSTRACT: The primary focus of pain research in intellectually disabled individuals is still on pain assessment. Several observational pain assessment scales are available, each with its own characteristics, its own target group and its own validated use. Observational studies report differences in the treatment of intra- and postoperative pain of intellectually disabled children and almost all children with intellectual disability have comorbidities that need to be addressed. The scope of research has started to broaden. In this review we aim to answer the question: Can we integrate validated ways of pain assessment and postoperative pain treatment in intellectually disabled children to develop specific analgesic algorithms? Regrettably there is little knowledge on possible interaction effects and other relevant pharmacological issues. Possible genotype-phenotype associations related to pain in children with Down syndrome have several promises as six possible candidate genes are located on chromosome 21. In conclusion, the pain assessment tools for intellectually disabled children are there. We should now focus on tailoring the pain treatment. To this aim we need to perform pharmacokinetic and pharmacodynamic studies of analgesics and obtain information about the genotype-phenotype relationships for pain. This can lead to the development of specific analgesic algorithms.Developmental Disabilities Research Reviews 01/2010; 16(3):248-57. DOI:10.1002/ddrr.117 · 0.29 Impact Factor
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ABSTRACT: For propofol clearance, allometric scaling has been applied successfully for extrapolations between species (rats and humans) and within the human bodyweight range (children and adults). In this analysis, the human bodyweight range is explored to determine for which range an allometric model with a fixed or estimated exponent can be used to predict propofol clearance, without correction for maturation. The predictive value of the allometric equation, clearance (CL) is equal to 0.071 x bodyweight in kg0.78, which was developed from rats, children and adults, and the predictive value of a fixed exponent allometric model derived from the basal metabolic rate, CL is equal to CL standardized to a 70 kg adult x (bodyweight in kg standardized to a 70 kg adult)0.75, were evaluated across five independent patient groups including (i) 25 (pre)term neonates with a postmenstrual age of 27-43 weeks; (ii) 22 postoperative infants aged 4-18 months; (iii) 12 toddlers aged 1-3 years; (iv) 14 adolescents aged 10-20 years; and (v) 26 critically ill adults sedated long term. The median percentage error of the predictions was calculated using the equation %error = (CL(allometric) - CL(i))/CL(i) x 100, where CL(allometric) is the predicted propofol clearance from the allometric equations for each individual and CL(i) is the individual-predicted (post hoc) propofol clearance value derived from published population pharmacokinetic models. In neonates, the allometric model developed from rats, children and adults, and the fixed-exponent allometric model, systematically overpredicted individual propofol clearance, with median percentage errors of 288% and 216%, respectively, whereas in infants, both models systematically underpredicted individual propofol clearance, with median percentage errors of -43% and -55%, respectively. In toddlers, adolescents and adults, both models performed reasonably well, with median percentage errors of -12% and -32%, respectively, in toddlers, 16% and -14%, respectively, in adolescents, and 12% and -18%, respectively, in adults. Both allometric models based on bodyweight alone may be of use to predict propofol clearance in individuals older than 2 years. Approaches that also incorporate maturation are required to predict clearance under the age of 2 years.Clinical Pharmacokinetics 04/2010; 49(4):269-75. DOI:10.2165/11319350-000000000-00000 · 5.49 Impact Factor