Predictive Performance of a Recently Developed Population Pharmacokinetic Model for Morphine and its Metabolites in New Datasets of (Preterm) Neonates, Infants and Children
ABSTRACT Model validation procedures are crucial when models are to be used to develop new dosing algorithms. In this study, the predictive performance of a previously published paediatric population pharmacokinetic model for morphine and its metabolites in children younger than 3 years (original model) is studied in new datasets that were not used to develop the original model.
Six external datasets including neonates and infants up to 1 year were obtained from four different research centres. These datasets contained postoperative patients, ventilated patients and patients on extracorporeal membrane oxygenation (ECMO) treatment. Basic observed versus predicted plots, normalized prediction distribution error analysis, model refitting, bootstrap analysis, subpopulation analysis and a literature comparison of clearance predictions were performed with the new datasets to evaluate the predictive performance of the original morphine pharmacokinetic model.
The original model was found to be stable and the parameter estimates were found to be precise. The concentrations predicted by the original model were in good agreement with the observed concentrations in the four datasets from postoperative and ventilated patients, and the model-predicted clearances in these datasets were in agreement with literature values. In the datasets from patients on ECMO treatment with continuous venovenous haemofiltration (CVVH) the predictive performance of the model was good as well, whereas underprediction occurred, particularly for the metabolites, in patients on ECMO treatment without CVVH.
The predictive value of the original morphine pharmacokinetic model is demonstrated in new datasets by the use of six different validation and evaluation tools. It is herewith justified to undertake a proof-of-principle approach in the development of rational dosing recommendations - namely, performing a prospective clinical trial in which the model-based dosing algorithm is clinically evaluated.
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ABSTRACT: Background and Objective Given the alarming increase in obesity among children undergoing surgery, the main aim of this study was to characterize propofol clearance in a cohort of morbidly obese children and adolescents in relation to their age and body weight characteristics. Methods A prospective pharmacokinetic study in morbidly obese children and adolescents undergoing elective surgery was conducted. Serial blood samples were collected and nonlinear mixed-effects modelling using NONMEM® was performed to characterize propofol pharmacokinetics with subsequent evaluation of age and body size descriptors. Results Twenty obese and morbidly obese children and adolescents with a mean age of 16 years (range 9–18 years), a mean total body weight (TBW) of 125 kg (range 70–184 kg) and a mean body mass index of 46kg/m2 (range 31–63 kg/m2) were available for pharmacokinetic modelling using a two-compartment pharmacokinetic model (n = 294 propofol concentration measurements). Compared with lean body weight and ideal body weight, TBW proved to be the most predictive covariate for clearance [CL (L/min)= 1.70 × (TBW/70)0.8]. Central volume of distribution, peripheral volume and intercompartmental clearance were 45.2 L, 128 L and 1.75 L/min, respectively, with no predictive covariates identifiable. Conclusion In the population pharmacokinetic model for propofol in morbidly obese children and adolescents, TBW proved to be the most significant determinant for clearance. As a result, it is anticipated that dosage of propofol for maintenance of anaesthesia in morbidly obese children and adolescents should be based on TBW using an allometric function. Trial registration number (clinicaltrials.gov) NCT00948597Clinical Pharmacokinetics 08/2012; 51(8). DOI:10.1007/BF03261930 · 5.49 Impact Factor
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ABSTRACT: Despite profound differences in response between children and adults, and between children of different ages, drugs are still empirically dosed in mg/kg in children. Since maturation of expression and function is typically a non-linear dynamic process which differs between biotransformation routes and pharmacological targets, paediatric dosing regimens should be based on the changing pharmacokinetic-pharmacodynamic (PKPD) relationship in children. In this respect, the population approach is essential, allowing for sparse sampling in each individual child. An example is presented on morphine glucuronidation, for which two covariates were identified and subsequently used to derive a model-based dosing algorithm for a prospective clinical trial in children. Using this novel dosing algorithm, similar morphine concentrations are expected while, depending on age, lower and higher morphine dosages are administered compared to mg/kg/h dosing. As the covariate functions may reflect system-specific information on the maturation of a specific drug-disposition pathway, its use for other drugs that share the same pathway is explored. For this purpose, prospective clinical trials and cross-validation studies are urgently needed. In conclusion, PKPD modelling and simulation studies are important to develop evidence-based and individualized dosing schemes for children, with the ultimate goal to improve drug safety and efficacy in this population.International Journal of Pharmaceutics 03/2011; 415(1-2):9-14. DOI:10.1016/j.ijpharm.2011.02.056 · 3.65 Impact Factor
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ABSTRACT: INTRODUCTION: There is a lack of high-quality data regarding optimal chemotherapy dosage regimens among infants. Dosing regimens for chemotherapy during the first year of life are commonly based on empiric recommendations extrapolated from older children; however, balancing efficacy and toxicity is critical as severe adverse drug reactions may lead to treatment failure or reduced adherence to needed medications. AREAS COVERED: This review describes pharmacokinetic and pharmacogenetic considerations when administering chemotherapeutic agents to infants. Examples of commonly used agents are provided with practical recommendations for dosing adjustments. EXPERT OPINION: Optimal chemotherapy for children and infants in particular has lagged behind the remarkable progress in cancer treatment and it is clear that far more basic and clinical research are needed with respect to the mechanistic basis of age-dependent differences in pharmacokinetic parameters. More recent studies which have combined pharmacokinetic data with clinical toxicity and outcome data have resulted in a number of more evidence-based guidelines at least for the initial chemotherapy dosing; however, at present, the dosing of chemotherapy drugs in neonates and infants remains largely empiric.Expert Opinion on Drug Metabolism & Toxicology 04/2012; 8(6):709-22. DOI:10.1517/17425255.2012.680884 · 2.93 Impact Factor