Population Pharmacokinetics of Phenobarbital in Children, Adolescents and Young Adults Patients.
Teixeira P (1), Pérez-Blanco JS (1), García García MP (2), García Sánchez MJ (1), Otero MJ (2), Santos Buelga D (1).
(1) Department of Pharmacy and Pharmaceutical Technology, University of Salamanca, Spain, (2) Service of Pharmacy, University Hospital of Salamanca, Spain.
Objectives: The main goal of this work was to develop an updated population pharmacokinetic model to identify and quantify the influence of demographics, clinical and treatment factors on the clearance (CL) of phenobarbital (PBT) in Children, Adolescents and Young Adults Patients.
Methods: Serum concentrations of PBT were taken from patients aged 0.08-25 years old, who had been treated with this drug. These patients were included in the TDM program, conducted in the University Hospital of Salamanca over the last 20 years. After applying the inclusion/exclusion criteria previously established, the final database included 304 serum concentrations from 118 patients. Pharmacokinetic analysis was performed with NONMEM V7.3 (FOCEI) considering a one-compartment model, fixing the absorption constant and volume of distribution at 1.33 h-1 and 0.9 L/kg, respectively [1-3]. Proportional error models were assumed to describe interindividual and residual variabilities. The analysed covariates were: weight (WGT), age, gender (SEX), and concomitant treatment with carbamazepine (CBZ), clonazepam (CLO), phenytoin (PHT), lamotrigine (LTG), topiramate (TOP) and valproic (VLP) and another comedication with potential interaction (ACC). The predictive capacity was evaluated using a Bootstrap technique (n=1000).
Results: The covariates with significant influence on CL/FPBT were: WGT (according to an allometric function [4]) and concomitant treatment with CBZ, PHT, VLP and ACC. ACC was excluded in the backward elimination process (p<0.01). The covariate CBZ was also eliminated in the final model because of the low clinical significance (PBT was as follows:
CL/FPBT (L/h) = 0.26×((WGT/70)0.58)×(0.84×PHT)×(0.67×VLP)
w2CL/F = 0.026 (shrinkage=9 %)
s2= 0.012 (shrinkage=17 %)
The standard estimation errors were lower than 15 % for all parameters.
The results obtained in the bootstrap show acceptable performance of the proposed model.
Conclusions:
The developed population pharmacokinetic model for PBT in children, adolescents and young adults patients includes WGT and the concomitant administration of PHT and VLP on CL/FPBT. The inclusion of these covariates reduced interindividual and residual variabilities for 84 % y 43 %, respectively. This model appears to be adequate for clinical application in TDM. However, we consider necessary to carry out an external validation to confirm the results shown in this study.
References:
[1] Patsalos PN. Antiepileptic drug interactions. A clinical guide. 2nd ed. Springer; London. 2013.
[2] Walt JS, Wilmhurst JM, Karlsson MO. Population pharmacokinetics of phenobarbitone administered as oral rescue therapy in children with refractory status epilepticus. 2008; Available at: http://www.paganz.org/abstracts/population-pharmacokinetics-of-phenobarbitone-administered-as-oral-rescue-therapy-in-children-with-refractory-status-epilepticus/. Accessed January/15, 2015.
[3] Kern Pharma. Ficha técnica del fenobarbital. 2004; Available at: http://www.kernpharma.es/wp-content/uploads/2010/02/luminal.pdf. Accessed January/15, 2015.
[4] Holford N, Anderson B. Mechanism-Based Concepts of Size and Maturity. 2008; Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Presentation/2009/11/WC500009792.pdf. Accessed January/15, 2015.
