caa a22 4500 445313390 CHVBK 20180317142638.0 cr unu---uuuuu 170323e20110401xx s 000 0 eng 10.1007/s11095-010-0333-1 doi (NATIONALLICENCE)springer-10.1007/s11095-010-0333-1 Systematic Evaluation of the Descriptive and Predictive Performance of Paediatric Morphine Population Models [Elektronische Daten] [Elke Krekels, Johan van Hasselt, Dick Tibboel, Meindert Danhof, Catherijne Knibbe] ABSTRACT: Purpose: A framework for the evaluation of paediatric population models is proposed and applied to two different paediatric population pharmacokinetic models for morphine. One covariate model was based on a systematic covariate analysis, the other on fixed allometric scaling principles. Methods: The six evaluation criteria in the framework were 1) number of parameters and condition number, 2) numerical diagnostics, 3) prediction-based diagnostics, 4) η-shrinkage, 5) simulation-based diagnostics, 6) diagnostics of individual and population parameter estimates versus covariates, including measurements of bias and precision of the population values compared to the observed individual values. The framework entails both an internal and external model evaluation procedure. Results: The application of the framework to the two models resulted in the detection of overparameterization and misleading diagnostics based on individual predictions caused by high shrinkage. The diagnostic of individual and population parameter estimates versus covariates proved to be highly informative in assessing obtained covariate relationships. Based on the framework, the systematic covariate model proved to be superior over the fixed allometric model in terms of predictive performance. Conclusions: The proposed framework is suitable for the evaluation of paediatric (covariate) models and should be applied to corroborate the descriptive and predictive properties of these models. The Author(s), 2010 model evaluation nationallicence morphine nationallicence paediatric pharmacokinetic population modeling nationallicence IQR : inter quartile range nationallicence M3G : morphine-3-glucuronide nationallicence M6G : morphine-6-glucuronide nationallicence MPE : mean prediction error nationallicence NPDE : normalized prediction distribution error nationallicence PD : pharmacodynamics nationallicence PK : pharmacokinetics nationallicence PMA : postmenstrual age nationallicence PNA : postnatal age nationallicence RMSE : root mean square error nationallicence RSE : relative standard error nationallicence Krekels Elke Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands aut van Hasselt Johan Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands aut Tibboel Dick Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands aut Danhof Meindert Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands aut Knibbe Catherijne Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands aut Pharmaceutical Research Springer US; http://www.springer-ny.com 28/4(2011-04-01), 797-811 0724-8741 28:4<797 2011 28 11095 https://doi.org/10.1007/s11095-010-0333-1 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s11095-010-0333-1 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Krekels Elke Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands aut NATIONALLICENCE 700 1- van Hasselt Johan Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands aut NATIONALLICENCE 700 1- Tibboel Dick Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands aut NATIONALLICENCE 700 1- Danhof Meindert Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands aut NATIONALLICENCE 700 1- Knibbe Catherijne Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden, The Netherlands aut NATIONALLICENCE 773 0- Pharmaceutical Research Springer US; http://www.springer-ny.com 28/4(2011-04-01), 797-811 0724-8741 28:4<797 2011 28 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer