P. Välitalo(1), K. Olkkola(2), M. Kokki(3), H. Kokki(3), V-P. Ranta(1), A. Hooker(4)
(1) Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland; (2) Department of Anesthesiology and Intensive Care, Turku University Hospital, Turku, Finland; (3) Department of Anesthesiology and Intensive Care, Kuopio University Hospital, Kuopio, Finland; (4) Department of Pharmaceutical Sciences, Uppsala Universitet, Uppsala, Sweden
Objectives: While the pharmacokinetics of oxycodone in children older than 6 months of age has been characterized, only one study is available for children aged 0-6 months[1]. Therefore we designed a new study about pharmacokinetics of oxycodone in children aged 0-24 months, which would include a larger number of patients than the previous study.
Methods: Data from two previous studies[1,2] was gathered and pooled (527 samples from 63 patients). The data were fitted into a two-compartment model, scaling clearance by weight with an exponent of 0.75, and estimating a sigmoidal age-dependent maturation function for clearance. The sampling times and number of children in different age groups were optimized using PopED[3]. Prior Fisher Information Matrix was incorporated into the optimization, because data from the new study will be combined with existing data from previous studies to fully characterize the developmental pharmacokinetics of oxycodone. The optimization results were verified by stochastic simulation and estimation (SSE).
Results: The clearance was well predicted by the maturation function (ωcl=43 %). The model predicted a weight-scaled clearance commensurate to 50% of adult value at time of birth, followed by a fast maturation. The other pharmacokinetic parameters were similar to those observed for older children. The optimized study design mostly contained children younger than 3 months of age. The data on optimal number of children of different ages, and optimal sampling times are presented as figures in the poster. The SSE procedure predicted relative standard errors below 20 % for all parameters.
Conclusions: Based on predicted standard errors, the upcoming study should be able to characterize the developmental pharmacokinetics of oxycodone with fairly good precision. Since the empirical maturation model predictions of oxycodone clearance are different from the maturation curves of the relevant CYP enzyme maturation curves[4], additional emphasis on the metabolic routes of oxycodone in children was considered important for the study. For that reason, collection of urinary samples was added to the study protocol.
References:
[1] Pokela M-L, Anttila E, Seppälä T, Olkkola KT. Marked variation in oxycodone pharmacokinetics in infants. Paediatr Anaesth. 2005;15(7):560–565.
[2] El-Tahtawy A, Kokki H, Reidenberg BE. Population pharmacokinetics of oxycodone in children 6 months to 7 years old. J Clin Pharmacol. 2006;46(4):433–442.
[3] Foracchia M, Hooker A, Vicini P, Ruggeri A. POPED, a software for optimal experiment design in population kinetics. Comput Methods Programs Biomed. 2004;74(1):29–46.
[4] Johnson TN, Rostami-Hodjegan A, Tucker GT. Prediction of the clearance of eleven drugs and associated variability in neonates, infants and children. Clin Pharmacokinet. 2006;45(9):931–956.
Reference: PAGE 21 () Abstr 2313 [www.page-meeting.org/?abstract=2313]
Poster: Study Design