**2005 Report Submitted by Benchmark Steward:**

Tracy Glauser, M.D. (Cincinnati Children's Hospital)

**Background of the benchmark goal:**

Response to anticonvulsant therapy demonstrates marked inter-individual
variation both in drug efficacy and adverse effects. A significant
portion of this inter-individual variation is under genetic control.
Recent advances in genetic technology and analysis have permitted
investigations into the relationship between the response to
anticonvulsant therapy and polymorphisms in drug metabolizing enzymes,
drug transporters, and drug receptors.

**Current status of the field:**

Significant fundamental research is still needed to elucidate the
clinically significant associations that will form the basis for
developing a genetic fingerprint diagnostic test for anticonvulsant
efficacy, treatment resistance or adverse events. Currently, the two
main methodologies used in this research are 1) association studies
between response to therapy (efficacy, adverse effects) and single
nucleotide polymorphisms (SNPs) of drug metabolizing enzymes, drug
transporters, and drug receptors and 2) gene expression studies using
microarrays. Previously, association studies focused on known common
SNPs but since SNP databases are being found to be often incomplete, SNP
discovery is becoming more popular. In general, SNPs in drug
metabolizing enzymes alter anticonvulsant pharmacokinetics potentially
leading to unexpectedly high levels with subsequent adverse effects.
Similarly, SNPs in genes coding for drug efflux transporters alter the
anticonvulsant drug's ability to remain inside target cells resulting in
reduced efficacy and subsequent treatment resistance. Lastly, SNPs in
genes coding for the receptor drug binding site are potential causes for
reduced receptor binding and subsequent decreased drug action. A newer
approach has been to examine the relationship between response to
therapy and changes in gene expression following exposure to medication.

**Activities update:**

Published reports: During the past year, there have been four human
pharmacogenetic association studies and one human gene expression study.
Two studies (both published in Neurology September 2004) examined the
proposed relationship between a polymorphism in the drug efflux
transporter gene ABCB1 and treatment resistant epilepsy. The studies
reached contradictory conclusions about the potential association. In an
editorial in the same issue, these conflicting studies were used to
illustrate some of the methodological problems evident in current
epilepsy pharmacogenetic research. Another pharmacogenetic epilepsy
study utilized population pharmacokinetic modeling approaches to provide
phenytoin dosing recommendation based on the patient's CYP2C9/CYP2C19
genotype. In a separate study, a Japanese team did not find a
relationship between gingival overgrowth in phenytoin patients and CYP2C
polymorphisms. Lastly, a pilot trial reported distinct blood expression
profiles for patients on carbamazepine monotherapy compared to patients
on valproic acid monotherapy. This study also described a characteristic
blood expression profile for seizure free patients taking valproic acid
compared to patients with uncontrolled seizures.

Ongoing studies: NINDS has funded a 20 center 436 patient clinical trial
that is focused, in part, on elucidating the genetic contribution to the
interindividual variation in anticonvulsant efficacy and adverse events
in children with childhood absence epilepsy. For example the
relationship between anticonvulsant efficacy and polymorphisms in three
different T-type calcium channel genes is being investigated. The
Epilepsy Foundation is funding a study examining the relationship
between polymorphisms in carbamazepine and valproic acid drug
metabolizing enzymes and altered drug pharmacokinetics and adverse
events (as judged by a validated side effects questionnaire).

A NINDS funded project is utilizing microarray technology to investigate
different patterns of gene expression preliminarily associated with
valproic acid and carbamazepine efficacy in children with epilepsy. No
final results are yet available from this study but the pilot gene
expression publication described above resulted from this NINDS funded
research.

During the past year, there have been no workshops or symposiums focused
solely on the pharmacogenetics of anticonvulsant efficacy or toxicity.

**Top priorities for next 5-10 years:**

-   Develop a consortium of experienced epileptologists with an interest
    in pharmacogenetics to conduct coordinated studies combining
    extensive drug response phenotyping and with analysis of known SNP,
    SNP discovery studies, and microarray gene expression studies.

-   Through these large scale coordinated studies, identify which
    polymorphisms (or haplotypes) have clinical relevance for
    anticonvulsant efficacy or adverse events, and develop methodologies
    (e.g. specialized gene chips) for the rapid (\< 4-5 hour) outpatient
    assessment of these polymorphisms or haplotypes in patients with
    epilepsy.

-   Develop physician and nurse education programs (for all levels of
    experience) focused on incorporating pharmacogenetic testing into
    the routine clinical care of patients with epilepsy.

**Roadblocks to progress:**

-   Lack of a coordinated national effort to prioritize specific
    clinical questions to be answered by the proposed consortium.
    Efficiency is critical due to the time consuming nature and expense
    for each association or gene expression study.

-   Developing the bioinformatics computational approach and software to
    easily examine more complex relationships than 1 or 2 SNPs at a
    time, for example identification of complex haplotypes.

-   Reluctance by patient and families to enroll in genetic based
    research because of concern over future insurability depending on
    the test results.