The allometric exponent for propofol clearance varies with age
C. Wang(1),(3), K. Allegaert(2), M.Y.M. Peeters(4), Tibboel(3), M. Danhof(1), C.A.J. Knibbe(1),(4)
1) Department of Pharmacology, LACDR, Leiden University, the Netherlands (2) Neonatal Intensive Care Unit, University Hospitals Leuven, Belgium (3) Departments of Paediatric Surgery and Paediatrics, Erasmus MC Sophia Children’s Hospital, Rotterdam, the Netherlands (4) Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, the Netherlands
Objectives: For scaling clearance to pediatrics, the allometric scaling function is used in occasions either having both adult data and pediatric data together or having only pediatric data. In order to investigate the influence of the different combinations of datasets on the allometric scaling exponent of propofol clearance, we studied the allometric exponents of propofol clearance in different populations which are grouped both by the study population and by the age range of the FDA guidance.
Methods: Seven previously published propofol studies [1,2,3,4,5,6,7] were included in the analysis. The data were grouped by the study population into six datasets and grouped by the age range from the FDA guidance for pediatric study [8] into five datasets.
For the analysis grouped by the study population, we systematically selected two out of six datasets in two ways:one pediatric dataset and one adult dataset; two pediatric datasets. For the analysis grouped by the FDA guidance [8], we selected two out of five datasets which comprised one pediatric dataset and one adult dataset.
We performed the population pharmacokinetic analysis using NONMEM 7 on each of the combined datasets with a three-compartment model together with an bodyweight allometric scaling model for the clearance, in order to estimate the exponents (EXPCL) for different data composition.
Results: In the analysis grouped by the study population, the estimated allometric scaling exponent varied from 0.57 to 1.15 when the data was composed of one pediatric dataset and one adult dataset. It varied from 0.2 to 2.01 when the data was composed of one pediatric dataset and another pediatric dataset.
In the analysis grouped by the FDA guidance, the estimated allometric scaling exponent varied from 0.61 to 1.15, which was very similar to the results in the analysis grouped by the study population.
In all models of the analysis, the diagnostic plots of the observed concentrations versus population predicted concentrations shown adequate model fitting for each of the two combined datasets, although some of the bias existed in the combinations which had the infant dataset in the analysis grouped by the study population.
Conclusions: When scaling propofol clearance from adults to neonates, the allometric scaling exponent is above 1.When scaling propofol clearance from adults to any pediatric dataset other than neonates, the scaling exponent varies between 0.57 and 0.81.When scaling propofol clearance between pediatric datasets, the scaling exponent varies between 0.2 to 2.
References:
[1] Allegaert, K., et al. Br J Anaesth, 2007
[2] Peeters, M.Y., et al., Anesthesiology, 2006
[3] Murat, I., et al., Anesthesiology, 1996
[4] Kataria, B.K., et al., Anesthesiology, 1994
[5] Blussé van Oud-Alblas, H.J., et al., in submission
[6] Knibbe, C.A., et al., Br J Clin Pharmacol, 1999
[7] Schnider, T.W., et al., Anesthesiology, 1998
[8] FDA Guidance for industry: General Considerations for Pediatric Pharmacokinetic Studies for Drugs and Biological Products, 1998
