Population pharmacokinetics of lamotrigine in epileptic patients with data proceeding of therapeutic drug monitoring

N. Rivas, D Santos Buelga, J. Santos Borbujo, MJ Otero, A. Domínguez-Gil1, MJ García

Department of Pharmacy and Pharmaceutical Tecnology, University of Salamanca, Salamanca, Spain

Population pharmacokinetics of lamotrigine in epileptic patients with data proceeding of therapeutic drug monitoring

N. Rivas, D Santos Buelga, J. Santos Borbujo, MJ Otero, A. Domínguez-Gil1, MJ García

Department of Pharmacy and Pharmaceutical Technology, University of Salamanca, Salamanca, Spain

Objetive: This study aims to develop a population pharmacokinetic (PK) model of lamotrigina (LTG) in epileptic patients in order to implement it in Bayesian algorithms, to optimize LTG therapy.

Methods: The study was carried on 85 epileptic patients (1-86 years old) treated with LTG (200±150 mg/day). From routine clinical setting, 155 through plasma LTG concentrations were retrospectively collected at steady-state. Samples were analysed by HPLC-UV. The limit of sensitivity was .025 mg/mL. Inter- an intraday CV’s were 8.4% and 5.2%, respectively. PK analysis was performed with a nonlinear mixed-effect modelling program (NONMEM V). Exponential error-models were assumed to describe interindividual and residual variabilities. The first-order conditional estimation was used throughout. A one-compartment model with first-order absorption and elimination was considered. Influence of age, gender, total body weigth (TBW), body surface area and concurrent antiepileptic therapy with valproic acid (VPA) and inducers (IND) were analysed in the model. To elucidate preliminary relationship between clearance (CL) Bayesian estimated (POSTHOC) and covariates, a graphical approach exploratory data analysis and the stepwise generalized additive modelling implemented in Xpose were used.

Results. From the scatterplot of CL vs age a higher clearance in children than in adults was apparent, so we used two age groups, which got a better fit of data. TBW explained part of the interindividual variability of CL in both groups. In addition, the association with VPA produces a LTG delayed elimination. Only in adult population, IND showed significant influence on CL, because in children this covariate was not well represented (2%) Final regression models for CL were as follows:

Children £ 14 y old

CL (L/h)=(.038*TBW)*e^-.763*VPA CV=38.3% CV_residual=35.6%

Adults:

CL (L/h)=(.029*TBW)*e^-.724*VPA*e^.444*IND CV=33.2%

CV_residual=25.9%

Where VPA and IND denotes presence (1) or absence (0) of associated medication

In the final model, the initial variability in CL was reduced by 39% and 42% for children and adults, respectively.

Conclusions: The population model proposed could be used to estimate LTG appropriate dosage regimens. Moreover their simple structure will allow an easy implementation in clinical PK software and their application in dosage individualization by Bayesian approach. A prospective study is necessary in order to confirm the suitability of this population model in clinical practice.

Reference: PAGE 14 () Abstr 732 [www.page-meeting.org/?abstract=732]

Poster: poster