318 - Pharmacogenetic Influences On Escitalopram and Sertraline Pharmacokinetics in Pediatric Patients

Poster Number: 318
Publication Number: 318.444

Ethan A. Poweleit, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States; SAMUEL VAUGHN, Cincinnati Children's Hospital Medical Center, CINCINNATI, OH, United States; Zeruesenay Desta, Indiana University, Indianapolis, IN, United States; Jeffrey R. Strawn, University of Cincinnati, Cincinnati, OH, United States; Laura Ramsey, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States

Background: The selective serotonin reuptake inhibitors (SSRIs) sertraline and escitalopram are commonly prescribed for anxiety and depressive disorders in children and adolescents. Both SSRIs are primarily metabolized by cytochrome P450 2C19. The gene encoding this enzyme, CYP2C19, is highly polymorphic and these polymorphisms have been associated with altered pharmacokinetics in adults and small samples of children and adolescents. To date, few studies have evaluated the impact of polymorphisms in CYP2C19 on sertraline or escitalopram pharmacokinetics in youth. 

Objective: To evaluate the impact of CYP2C19 phenotype on sertraline and escitalopram pharmacokinetics in a large sample of pediatric patients.

Design/Methods: Using remnant samples from 364 children and adolescents, aged 5 to 20 years who received either of these medications during an inpatient hospitalization, we determined plasma concentrations of sertraline (n=192 samples, mean age: 14.2±2.2 years, 70% female) and escitalopram (n=216 samples, mean age: 14.7±1.8 years, 68% female). Some patients provided multiple samples. From buccal swabs or whole blood collected during routine clinical care, genomic DNA was isolated and patients were genotyped for 7 no function alleles (*2, *3, *4, *5, *6, *7, *8) and the increased function allele (*17); *1 genotype was inferred from the absence of the previous alleles. CYP2C19 phenotypes were determined based on the Clinical Pharmacogenetics Implementation Consortium standard. Dose-normalized pharmacokinetic models were used to determine exposure (area under the curve, AUC) and Cmax for each phenotype.

Results: Sertraline samples consisted of poor (n=2), intermediate (n=65), normal (n=71), rapid (n=49) and ultrarapid (n=5) metabolizers and escitalopram samples consisted of poor (n=7), intermediate (n=59), normal (n=88), rapid (n=56) and ultrarapid (n=6) metabolizers. Concentration-to-dose ratios were significantly decreased in patients with faster CYP2C19 metabolism relative to those with slower metabolism for both sertraline (ANOVA test for linear trend, p=0.002) and escitalopram (ANOVA test for linear trend, p< 0.001). Dose-normalized models revealed higher Cmax and AUC for slower CYP2C19 metabolizers compared to normal metabolizers for both sertraline and escitalopram (p < 0.001).Conclusion(s): In children and adolescents, CYP2C19 affects sertraline and escitalopram pharmacokinetics across the dosing range. These data may inform dosing strategies that leverage CYP2C19 phenotypes to standardize exposure, which may decrease concentration-dependent side effects in adolescents treated with sertraline or escitalopram.