Abstract
Aims To characterize the population pharmacokinetics of lamotrigine in
Jordanian epileptic patients and to identify factors affecting therapeutic
parameters.
Patients and Methods A population pharmacokinetics model for lamotrigine
was established based on a prospectively collected data of 52 steady-state
concentrations from 38 adult and pediatric patients with epilepsy. Lamotrigine
concentrations were determined by a dried blood spot liquid chromatography
method. Data were analyzed according to a one-compartment model with first-order
absorption and elimination using the nonlinear mixed effect modeling program.
The covariates effect of total body weight, gender, age, and co-medication with
topiramate, carbamazepine, phenytoin, phenobarbital, and valproic acid on
lamotrigine clearance were investigated using a stepwise forward addition
followed by a stepwise backward elimination.
Results The final population pharmacokinetics model for lamotrigine
clearance was as follows:
CL/Fpop=θ1*exp
(θ3*age)*exp
(θ5*carbamazepine)*exp
(θ6*valproic acid) , where θ1
is the relative clearance (L/hr) estimated, and θ3,
θ5, and θ6 are the fixed parameters
relating to age and co-medication with carbamazepine and valproic acid,
respectively.The population mean value of lamotrigine total clearance generated
in the final model (with covariates) was 2.12 L/hr.
Inter-individual variability and residual unexplained variability expressed as
the coefficient of variation was 37.1 and 26.1%, respectively.
Conclusion Lamotrigine total clearance in the Jordanian patients is
comparable to that reported by others for Caucasian patients. Age and
concomitant therapy with carbamazepine and valproic acid significantly affected
lamotrigine clearance, and accounted for 48% of its inter-individual
variability.
A systematic review of population pharmacokinetics of valproic acid