Abstracts

Rationale: Pharmacogenetics, the study of genetic variation on drug response, has been studied as a possible contributor to the high treatment failure rate in patients with epilepsy. While it is apparent that pharmacogenetic variants in genes encoding cytochrome P450 (CYP) and other drug-metabolizing enzymes could affect dosing and response, particularly 2C9 for phenytoin and 2C19 for phenobarbital, the prevalence of these variants is unknown. Since patients can range from being ultra-rapid to poor metabolizers of these enzymes, dose adjustments may be warranted to ensure optimal response. This is of particular importance as these medications are used in status epilepticus. The purpose of this study is to describe the prevalence of selected pharmacogenetic variants in pediatric neurology patients who underwent whole exome sequencing (WES) at Texas Children’s Hospital. Secondary objectives are to describe the prevalence of these variants in patients with epilepsy, and to compare serum drug levels of select AEDs (phenytoin, and phenobarbital) in patients with CYP polymorphisms versus wild type.Methods: This retrospective study included patients who received WES by the neurology service at Texas Children’s Hospital between May 2012 and September 2014. Baseline demographics (gender, age, race/ethnicity, weight, height, and diagnoses) were collected and analyzed. Type and number of the following pharmacogenetic variants were collected for each patient: CYP2C9*1, CYP2C9*2, CYP2C9*3, CYP2C9*5, CYP2C9*6, CYP2C19*1, CYP2C19*2, CYP2C19*3, CYP2C19*4, CYP2C19*5, CYP2C19*8, CYP2C19*10, and CYP2C19*17. Data regarding medication orders and levels for phenytoin, fosphenytoin, and phenobarbital, were also collected. Descriptive and inferential statistics were utilized where appropriate. All research was approved by the Institutional Review Board of Baylor College of Medicine.Results: A total of 244 met inclusion criteria and received WES through the neurology department. The majority of patients were male (55%), with a median age of 7.8 years (0.01-17.92). Of those, two-thirds had some type of variant in 2C9, 2C19 or both that may affect drug dosing. A quarter had a variant in 2C9, while 47% had a variant in 2C19. Half of these patients (n=123) were patients with epilepsy. Two thirds had some type of variant in 2C9, 2C19, or both that may affect drug dosing, with similar results of variants as the total population. Delineation of ultra-rapid vs extensive vs intermediate vs poor metabolizer status will be reported. Analysis undergoing for serum drug levels.Conclusions: The majority of included patients with WES had a variant in 2C9, 2C19, or both. The same results were seen when including only those patients diagnosed with epilepsy. This high prevalence of 2C9 and 2C19 polymorphisms in pediatric patients with WES demonstrates the possible need for medication dosing alterations, particularly for phenobarbital and phenytoin/fosphenytoin, as well as increased need for monitoring in this patient population.