Validation of a population pharmacokinetic model for adjunctive lamotrigine therapy in children.
OBJECTIVE
This analysis was performed to validate a previously developed population pharmacokinetic model for lamotrigine in order to establish a basis for dosage recommendations for children.


METHODS
(a) The importance of the covariates in the final model was confirmed using the model validation dataset. Population and individual (Bayesian estimate) pharmacokinetic parameters were estimated using both the initial model, which included none of the covariates, and the final model. Accuracy and precision of parameter estimation and of concentration prediction were compared between the two models. (b) The performance in predicting the validation concentrations by the final model parameters obtained previously from the model development dataset was assessed. (c) The parameters of the final model were refined using a dataset combining both the development and validation data.


RESULTS
Prediction performance of the final pharmacostatistical model was superior to that of the initial model. The results of the validation confirmed that concomitant antiepileptic drugs that increased or reduced lamotrigine clearance in adults had similar effects in children. The validation also verified the linear relationship between weight and clearance. The previously seen small sex effect on clearance was found statistically insignificant.


CONCLUSIONS
The current analysis confirmed the previous findings. To achieve the same concentrations, children receiving enzyme-inducing antiepileptic drugs without valproate require higher doses than those receiving valproate; and heavier children require higher doses.
Division of Clinical Pharmacology, Glaxo Wellcome Research & Development, Greenford, Middlesex, UK. cc43264@glaxowellcome.co.uk
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D000293:Adolescent; D000927:Anticonvulsants / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001835:Body Weight / Q000502:physiology*; D002648:Child; D002675:Child, Preschool; D004347:Drug Interactions; D005260:Female; D006801:Humans; D000077213:Lamotrigine; D008297:Male; D008954:Models, Biological; D017711:Nonlinear Dynamics; D014227:Triazines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D000927:Anticonvulsants; D014227:Triazines; D000077213:Lamotrigine