Christelle Rodrigues, Catherine Chiron, Elisabeth Rey, Emmanuelle Comets, Gérard Pons, Vincent Jullien
INSERM, U1129; INSERM, U738
Objectives: Oxcarbazepine is a recent antiepileptic drug (AED) used in focal seizures in both children and adults. Its activity is mostly due to its major metabolite, MHD. The aim of this study was to develop the first parent-metabolite population pharmacokinetic model in order to evaluate the consistency between the recommended pediatric doses and the target trough concentration of MHD (Cmin) for therapeutic drug monitoring.
Methods: The data used were provided by a published non compartmental study of oxcarbazepine and its 10-monohydroxy derivative [1]. They included 31 epileptic children (2-12y) who were randomized to receive a single oral dose of 5 or 15 mg/kg. Blood samples were collected at times 0, 1, 2, 4, 6, 8, 12, 24, 36 and 48h. A parent-metabolite pharmacokinetic model was developed with Monolix 4.3.2. For each patient, the first value below the limit of quantificationwas kept in the data. The probability to obtain Cmin between 3-35 mg/L [2] were determined by Monte Carlo simulations with doses of 10, 20, 25, 30, 40, 50, 60 and 90 mg/kg/day.
Results: A parent-metabolite model with two compartments for oxcarbazepine and one compartment for MHD was the best to describe the pharmacokinetics of the two compounds. The parameter estimates were, for oxcarbazepine, Ka = 2.19 (86.6%) h-1, CL = 37.2 (62.2%) L/h, Vc = 43.6 (45.8%) L, Q = 44.7 (87.9%) L/h and Vp = 183 (70.6%) L, and for MHD, CL = 2.19 (48.1%) L/h and Vc = 10 (49.4%) L. Clearance of MHD was related to body weight via an allometric model. For smaller children, a dose of 60 mg/kg/day allowed more than 90% of Cmin to be within the target range and, for bigger children, a dose of 25 mg/kg/day was necessary to obtain the same results. Inducing AEDs (EIAEDs) increased MHD clearance by 21%. Children taking EIAEDs needed higher doses to have a high probabilty to be within the target range.
Conclusions: The first parent-metabolite population PK model of oxcarbazepine was successfully developed and evidenced that the doses currently used are appropriate to obtain trough concentrations of MHD within the recommended target range, except for 10kg children taking EIAEDs.
References:
[1] E. Rey, C. Bulteau, J. Motte, A. Tran, Y. Sturm, J. D’Souza, S. Markabi, G. Pons, and O. Dulac. Oxcarbazepine Pharmacokinetics and Tolerability in Children With Inadequately Controlled Epilepsy. J. Clin. Pharmacol.(2004) 44: 1290–1300
[2] P. N. Patsalos, D. J. Berry, B. F. D. Bourgeois, J. C. Cloyd, T. A. Glauser, S. I. Johannessen, I. E. Leppik, T. Tomson, and E. Perucca. Antiepileptic drugs — best practice guidelines for therapeutic drug monitoring?: A position paper by the subcommission on therapeutic drug monitoring , ILAE Commission on Therapeutic Strategies. Epi (2008) 49(7): 1239–1276
Reference: PAGE 25 () Abstr 5949 [www.page-meeting.org/?abstract=5949]
Poster: Drug/Disease modeling - Paediatrics