The clinical impact of pharmacogenetics on the treatment of epilepsy.
Drug treatment of epilepsy is characterized by unpredictability of efficacy, adverse drug reactions, and optimal doses in individual patients, which, at least in part, is a consequence of genetic variation. Since genetic variability in drug metabolism was reported to affect the treatment with phenytoin more than 25 years ago, the ultimate goal of pharmacogenetics is to use the genetic makeup of an individual to predict drug response and efficacy, as well as potential adverse drug events. However, determining the practical relevance of pharmacogenetic variants remains difficult, in part because of problems with study design and replication. This article reviews the published work with particular emphasis on pharmacogenetic alterations that may affect efficacy, tolerability, and safety of antiepileptic drugs (AEDs), including variation in genes encoding drug target (SCN1A), drug transport (ABCB1), drug metabolizing (CYP2C9, CYP2C19), and human leucocyte antigen (HLA) proteins. Although the current studies associating particular genes and their variants with seizure control or adverse events have inherent weaknesses and have not provided unifying conclusions, several results, for example that Asian patients with a particular HLA allele, HLA-B*1502, are at a higher risk for Stevens-Johnson syndrome when using carbamazepine, are helpful to increase our knowledge how genetic variation affects the treatment of epilepsy. Although genetic testing raises ethical and social issues, a better understanding of the genetic influences on epilepsy outcome is key to developing the much needed new therapeutic strategies for individuals with epilepsy.
Löscher
Wolfgang
W
Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine, Hannover, Germany. wolfgang.loescher@tiho-hannover.de
Klotz
Ulrich
U
Zimprich
Fritz
F
Schmidt
Dieter
D
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000483:Alleles; D000927:Anticonvulsants / Q000627:therapeutic use*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065731:Cytochrome P-450 CYP2C19; D065729:Cytochrome P-450 CYP2C9; D004351:Drug Resistance; D004827:Epilepsy / Q000188:drug therapy* / Q000235:genetics*; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics; D006801:Humans; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015222:Sodium Channels / Q000235:genetics*
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000927:Anticonvulsants; D006680:HLA Antigens; D062550:NAV1.1 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; C568242:SCN1A protein, human; D015222:Sodium Channels; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19