Population Pharmacokinetics of Lamotrigine with Data from Therapeutic Drug Monitoring in German and Spanish Patients with Epilepsy

Abstract

This study develops a population pharmacokinetic model for lamotrigine (LTG) in Spanish and German patients diagnosed with epilepsy. LTG steady-state plasma concentration data from therapeutic drug monitoring were collected retrospectively from 600 patients, with a total of 1699 plasma drug concentrations. The data were analyzed according to a one-compartment model using the nonlinear mixed effect modelling program. The influences of origin (Germany or Spain), sex, age, total body weight, and comedication with valproic acid (VPA), levetiracetam, and enzyme-inducing antiepileptic drugs (phenobarbital [PB], phenytoin [PHT], primidone [PRM], and carbamazepine [CBZ]) were investigated using step-wise generalized additive modelling. The final regression model for LTG clearance (CL) was as follows: CL(L/h) = 0.028*total body weight*e(-0.713*VPA)*e0.663*PHT*e0.588*(PB or PRM)*e0.467*CBZ*e0.864*IND, where IND refers to two or more inducers added to LTG treatment; this factor as well as VPA, PHT, PB, PRM, and CBZ take a value of zero or one according to their absence or presence, respectively. The administration of inducers led to a significant increase in mean LTG CL (values of 0.045-0.070 L/h/kg vs. 0.028 L/h/kg being reached in monotherapy), whereas VPA led to a significant decrease in CL (0.014 L/h/kg). Thus, comedication with these analyzed drugs can partly explain the interindividual variability in population LTG CL, which decreased from the basic model by more than 40%. The proposed model may be very useful for clinicians in establishing initial LTG dosage guidelines. However, the interindividual variability remaining in the final model (clearance coefficient of variation close to 30%) make these a priori dosage predictions imprecise and justifies the need for LTG plasma level monitoring to optimize dosage regimens. Thus, this final model allows easy implementation in clinical pharmacokinetic software and its application in dosage individualization using the Bayesian approach.

Population pharmacokinetics of lamotrigine in Chinese children with epilepsy

“…This unexplained variability was of similar magnitude to those reported in earlier studies [7,[13][14][15][16][32][33][34] .…”

Influence of Concomitant Antiepileptic Drugs on Plasma Lamotrigine Concentration in Adult Japanese Epilepsy Patients

“…Our findings allowed us to estimate the LTG concentration in Japanese patients with epilepsy by applying coefficients for age, gender, LTG dose, and the AED regimens to a multiple regression model. In addition, the r 2 value for the relation between the measured and estimated LTG concentrations was 0.72 (p<0.001) in our model, which was equal that reported for a multiple regression model 10) (r 2 =0.72) and better than that for a population pharmacokinetic model 14) (r 2 =0.62) in Caucasian patients (Fig. 5).…”

Population pharmacokinetic of antiepileptic drugs in different populations

“…On the other hand, the effects of phenobarbital on CL LTG was not shown (this covariate was not well represented in our population). Earlier studies have reported about significant influence of phenobarbital on mean population value of lamotrigine clearance [43,45].…”

“…Equation for the final model which described value of population LTG clearance was as following [10]: Previous studies have shown that total body weight described part of the interindividual variability of LTG clearance in other studies, too [41][42][43][44][45][46]. Increase of CL LTG with increase in TBW was noted in a heterogenous Spanish population and also in pediatric and elderly population of epileptic patients [41,42,44,46].…”

“…A large part of lamotrigine variability could be explained by the influence of concomitant AEL therapy, especially with enzyme inductors or inhibitors [43][44][45][46]. Although LTG is neither an enzyme inducer nor inhibitor CYP P450 isoenzyme, the proces of its metabolism is the main location for numerous drug interactions when they are added in therapy.…”