Catherijne Knibbe
Department of Clinical Pharmacy, St. Antonius Hospital Nieuwegein and Division of Pharmacology, Leiden-Amsterdam Centre for Drug Research, Leiden University, Leiden, The Netherlands.
In order to develop dosing recommendations for pediatric clinical practice, detailed understanding of the influence of developmental growth in conjunction with other covariates such as severity of illness, co-medication, and genetics, across the pediatric population is required. In population PK or PD models in children, developmental growth is often quantified on the basis of bodyweight and/or age. In the pediatric population, bodyweight and age are highly correlated in a non linear way, and this correlation shows high variability. As a result, in case one of these two covariates proves to be of significant influence, the other covariate is of influence as well. This complicates covariate analysis in the pediatric population.
In this presentation, modeling of developmental growth is illustrated using morphine PK in children, ranging in age between preterm born neonates and three years, as an example. In the first model [1], a common way to analyze pediatric datasets is applied. In this approach the influence of bodyweight is fixed using a 0.75 allometric function. Due to the correlation between bodyweight and age, by dosing so, part of the influence of age is incorporated as well. Since particularly in children under the age of 2 years, large deviations from this 0.75 fixed bodyweight based function are expected, a second function based on age, is applied. In the presentation it is shown that this second so-called maturation function does not only describe the influence of age, because part of the influence of age is already incorporated by the introduction of the covariate bodyweight into the model. As a result the meaning of the maturation function is different from the common and intuitive definition. Additionally, introduction of the 0.75 fixed allometric approach complicates the data fitting process, because only one covariate (age) is left to fit the data as the influence of the other covariate (bodyweight) is fixed in an unidirectional way.
A second way to analyze the data is optimization of the influence of the most predictive covariate for developmental growth in the model before introducing a second covariate for this process [2]. In the example it is shown that by using bodyweight in an exponential function with estimated exponent of 1.44, there is hardly any influence of the covariate age left, so that the dosing recommendations can easily be derived.
It is highlighted that before models can be used for deriving dosing regimen and simulation purposes, validations of the models are essential. Beside extensive internal (goodness of fit and particularly observed versus population-predicted plots, NPDE, bootstrap etc), and external validations, prospective validation of the developed dosing regimens is of importance. This is the ultimate proof of the validity of the developed models and proposed dosing regimens and will facilitate acceptance of nonlinear dosing regimen in pediatric clinical practice.
In conclusion, PK and PK-PD models are the basis for dosing recommendations in children. These models should identify dosing algorithms for individualization of therapy that can be used in clinical practice. The influence of covariates characterizing developmental growth should be estimated based on the data, while underlying correlations between covariates and their physiological relevance should not be ignored. Proper internal, external and where possible prospective validations of the PK and PD models and evaluation of the proposed dosing algorithms in prospective clinical trials are a prerequisite for the predictive value and acceptance in clinical practice.
References
[1]. Bouwmeester NJ, Anderson BJ, Tibboel D, Holford NH. Developmental pharmacokinetics of morphine and its metabolites in neonates, infants and young children. Br J Anaesth. 2004 Feb;92(2):208-17.
[2]. Knibbe CAJ, EHJ Krekels, JN van den Anker, J DeJongh, GWE Santen, M van Dijk, SHP Simons, RA van Lingen, EM Jacqz-Aigrain, M Danhof, D Tibboel. Morphine glucuronidation in (preterm) neonates and young infants. Clin Pharmacokinet 2009, in press
Reference: PAGE 18 () Abstr 1678 [www.page-meeting.org/?abstract=1678]
Poster: Oral Presentation: Pediatrics