Oxcarbazepine and its active metabolite 10-monohydroxycarbamazepine clearance maturation in paediatric patients with epilepsy
Daniela Milosheska (1), Tomaž Vovk (1), Robert Roškar (1), Zvonka Rener Primec (2), Barbara Gnidovec Stražišar (2), David Neubauer (2), Iztok Grabnar (1)
(1) University of Ljubljana, Faculty of Pharmacy, Ljubljana, Slovenia, (2) University Children's Hospital Ljubljana, Department of Child, Adolescent and Developmental Neurology, Ljubljana, Slovenia
Introduction: Oxcarbazepine (OXC) is a second generation antiepileptic drug approved for treatment of partial seizures in adults and children as monotherapy or adjunctive therapy. After oral administration OXC is rapidly absorbed and metabolized to its 10-monohydroxy derivative (MHD) which is mostly responsible for the pharmacological effects. MHD is further metabolised with glucuronidation, is eliminated renally and to minor extent by metabolism to dihidroxy derivative [1]. There is a high variability in reported therapeutic ranges of MHD suggesting high variability in pharmacokinetics and a potential benefit of therapeutic drug monitoring (reference range of MHD trough concentrations 3-35 mg/L). Oxcarbazepine use in paediatric patients is particularly challenging due to lack of pharmacokinetic studies to support dosing regimen [2-9].
Objectives: The objective of this study was to develop OXC-MHD parent-metabolite population pharmacokinetic model in paediatric patients (0.5-3 years) to assess the OXC and MHD clearance maturation and to evaluate the recommended dosing regimen in children. To our knowledge this is the only OXC-MHD model in this age group.
Methods: In this prospective study we included 18 patients with epilepsy on stable mono- or combination therapy with OXC for at least one month. Steady-state blood samples were collected immediately before dosing (0) and after 1, 2, 4, 6, and 8 h post dose for determination of OXC and MHD plasma concentration. Pharmacokinetic analysis was performed in NONMEM (ver. 7.3), Perl-speaks-NONMEM and Xpose were used for model development and evaluations. FOCE-I was used for parameter estimation. Initially, only OXC concentration measurements were analysed to develop the structural model of the parent drug. The structural models tested were one- and two-compartment models with first-order absorption and elimination (ADVAN2 and ADVAN4 subroutines). This preliminary analysis confirmed that pharmacokinetics of OXC are more adequately described by a two-compartment model. Subsequently, we built a parent-metabolite model with user-defined differential equations (ADVAN 9). Based on previous analyses [10] we assumed complete OXC absorption. Absorption was modelled as a first-order process. Additionally, we assumed that 10% of OXC is presystemically metabolized to MHD (first-pass metabolism) and that OXC is completely transformed to MHD [10]. Patient weight (WT) and age were introduced into the model using a theoretical allometric relationship and a sigmoidal maturation function (MF) of post menstrual age (PMA in weeks) [11].
Results: The structural model comprised of a two-compartment model for the disposition of OXC and a one-compartment model for the disposition of MHD. The estimated parameters were absorption rate constant (Ka), volume of the central and peripheral compartment of the parent drug (V1,OXC and V2,OXC, respectively), elimination and distribution clearance of the parent drug (CLOXC and QOXC, respectively), and clearance and distribution volume of the metabolite (CLMHD and V1,MHD, respectively). Available data allowed estimation of interindividual variability (IIV) of of Ka, V1,OXC, CLOXC, and CLMHD. Allometric scaling of all clearance and volume parameters with theoretic exponents of 0.75 and 1, respectively; improved the model fit and decreased OFV by 37.2 units. After adjustment for size the significance of clearance maturation was investigated. Inclusion of the maturation function on CLOXC decreased OFV by 10.6. Further inclusion of the maturation function on CLMHD provided additional decrease of OFV by 5.43. The final model was:
Ka = 0.863 h-1; IIV = 75.0%
CLOXC = 127×(WT/70)0.75×(PMA4.57/(58.24.57+PMA4.57)) L/h; IIV = 7.40%
V1,OXC = 141×(WT/70)1 L; IIV = 206%
V2,OXC = 2260×(WT/70)1 L
QOXC = 103×(WT/70)0.75 L/h
CLMHD = 0.489×(WT/70)0.75×(PMA6.15/(55.16.15+PMA6.15)) L/h; IIV = 12.7%
V1,MHD = 19.7×(WT/70)1 L
The standard diagnostic plots and VPC indicated no significant bias.
Conclusion: A population OXC-MHD parent-metabolite pharmacokinetic model was developed which confirms important changes in pharmacokinetics in infants. The model can be used to evaluate the recommended dosage regimen with Monte Carlo simulations.
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