Implications of pharmacogenetics for the therapeutic use of antiepileptic drugs.
BACKGROUND
Epilepsy is a chronic neurological disease manifesting as recurrent seizures. Despite the availability of numerous antiepileptic drugs (AEDs), one-third of the patients are not responsive to treatment. Such inter-individual variability in the response to AEDs may be partly explained by genetic differences. This review summarizes the pharmacogenetics (PGx) of AEDs. In addition, a model-based approach is presented that enables the integration of PGx data with other relevant sources of variability, such as demographic characteristics and co-medications.


METHODS
A comprehensive overview is provided of the data available in the literature on the evidence for correlations between genetic mutations and pharmacokinetic (PK) and/or pharmacodynamics (PD) of AEDs. This information is then used in an integrated manner in the second part, where PGx differences are parameterized as covariates in PK and PKPD models.


CONCLUSIONS
Polymorphisms are profuse in the PK and PD of AEDs. However, understanding of their clinical implication remains limited due to the lack of methodologies that discriminate the contribution of other sources of variability in CNS exposure to drugs. A model-based approach, in which other intrinsic (e.g., demographic covariates) and extrinsic (e.g., drug-drug interactions) factors are evaluated concurrently is needed to ensure optimization and individualization of treatment in epileptic patients.
Leiden University, LACDR, Division of Pharmacology , Leiden , The Netherlands.
Chiara
C
Piana
Natalicia de Jesus
Nde J
Antunes
Oscar
O
Della Pasqua
D000927:Anticonvulsants / Q000008:administration & dosage* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D008962:Models, Theoretical; D009154:Mutation; D010597:Pharmacogenetics / Q000379:methods*; D011110:Polymorphism, Genetic
D000927:Anticonvulsants