Abstracts

Rationale: It is increasingly recognised that genetic variability in proteins involved in the pharmacokinetics and pharmacodynamics of therapeutic agents can influence their dosing requirements. Lamotrigine (LTG) is a modern antiepileptic drug which acts on voltage-gated sodium channels and which may be transported across biological membranes by P-glycoprotein. We have investigated sodium channel and P-glycoprotein gene variants in an effort to identify predictors of LTG maintenance dose.Methods: A total of 94 epilepsy patients (51% male; median age 38 years, range 17-85 years) who had been seizure-free for at least one year on LTG monotherapy were included in the analysis. Clinical information was extracted from case records. Common genetic variants in SCN2A (c.56G>A) and ABCB1 (c.1236C>T & c.3435C>T) were identified by polymerase chain reaction - restriction fragment length polymorphism. Associations were characterised by linear regression analyses.Results: Univariate analysis suggested that gender (r²=0.09, p=0.001) and the ABCB1 c.1236C>T variant (r²=0.06, p=0.01) were associated with LTG maintenance dose. There was no association with age, the SCN2A c.56G>A variant or the ABCB1 c.3435C>T variant. A multivariate model incorporating gender and a multiplicative interaction between c.1236C>T and c.3435C>T variants was sufficiently strong to predict LTG maintenance dose (r²=0.17; p<0.001).Conclusions: This analysis suggests that a combination of gender and genetic variants of the ABCB1 gene can predict effective maintenance doses of LTG. These findings also lend weight to the potential involvement of P-glycoprotein in LTG pharmacokinetics. Further studies incorporating additional clinical factors and genetic variants are required to strengthen the prognostic value of this observation.