PI-035 - A POPULATION PHARMACOKINETIC ANALYSIS OF ESCITALOPRAM AND THE EFFECT OF CYP2C19 ON CLEARANCE IN CHILDREN AND ADOLESCENTS.

E. Poweleit¹, T. Mizuno², Z. Taylor², S. Vaughn², Z. Desta³, J. Strawn¹, L. Ramsey²; ¹University of Cincinnati, Cincinnati, OH, USA, ²Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA, ³Indiana University, Indianapolis, IN, USA.

Background: The selective serotonin reuptake inhibitor escitalopram is commonly prescribed to treat anxiety and depressive disorders in youth. Variability in escitalopram pharmacokinetics (PK) can be explained by numerous factors, including CYP2C19 enzyme activity, which is primarily responsible for escitalopram metabolism, but previous models have focused on adult populations. Our objective was to develop a population PK model of escitalopram and assess how clinical, demographic, and pharmacogenetic covariates influence escitalopram PK in youth.

Methods: Clinical and demographic data from escitalopram-treated, psychiatrically-hospitalized children and adolescents (N=288, mean age: 14.7 years, age range: 10-18 years, 72% female) were extracted from the electronic health record. CYP2C19 and CYP2D6 genotyping was performed as part of routine care. Population PK analysis using 315 plasma concentrations and relevant covariates was performed using NONMEM.

Results: A one-compartment model with proportional error best described the data. CYP2C19 phenotype explained a significant amount of inter-individual variability in clearance. CYP2C19 poor metabolizers had over a 3-fold decrease (4.5 L/h), and ultrarapid metabolizers had a 1.4-fold increase (20.9 L/h) in escitalopram clearance compared to normal metabolizers (14.8 L/h). Body surface area was a significant covariate for clearance and volume of distribution, and concomitant CYP2C19 and CYP2D6 inhibitor use was retained as a covariate for clearance.

Conclusion: This is the first escitalopram population PK model developed in children and adolescents. The effect of CYP2C19 phenotype on escitalopram clearance followed the expected trend observed in adult populations. Further studies to evaluate an exposure-toxicity threshold for pediatric patients are needed.