098: CYP2B6 & CYP2C19 Phenotypes Influence Sertraline Exposure in Children & Adolescents

Statement of Purpose, Innovation or Hypothesis: CYP2C19 affects sertraline pharmacokinetics, although recent studies in adults also suggest that CYP2B6 influences sertraline metabolism. We sought to determine how CYP2B6 influences pharmacokinetics of sertraline in pediatric patients.

Description of Methods & Materials: Remnant plasma samples were collected from 508 pediatric patients aged 5-18 years who received sertraline within the prior 24 hours. Sertraline concentrations were measured by liquid chromatography-mass spectrometry either at the University of California, San Diego or Indiana University. Pharmacogenetic testing was performed as part of routine care upon psychiatric admission. Using the Agena MassARRAY system, eight CYP2C19 alleles were tested, including seven no function alleles (*2, *3, *4, *5, *6, *7, and *8) and the increased function allele (*17). Two CYP2B6 alleles were tested in a subset of patients (*6, decreased function; and *18, no function). Using linear regression in R, the log-transformed dose-normalized concentration was tested for associations with age, sex, weight, race, ethnicity, CYP2C19 phenotype, CYP2B6 phenotype, assay site, and time since the last dose.

Data & Results: In univariate analyses, the dose-normalized sertraline concentration was associated with sex, weight, ethnicity, the time since the last dose, CYP2C19 phenotype, and CYP2B6 phenotype. The best model (lowest Akaike information criterion) included weight, time since the last dose, CYP2C19 phenotype and CYP2B6 phenotype. CYP2C19 phenotype explained 13% of the variability in the dose-normalized sertraline concentration, while CYP2B6 explained < 1%. The dose-normalized concentration was highest among CYP2C19 poor and intermediate metabolizers that were also CYP2B6 poor or intermediate metabolizers (Figure 1).

Interpretation, Conclusion or Significance: This is the first study to evaluate the combined effect of CYP2C19 and CYP2B6 phenotypes on sertraline exposure in pediatric patients. Like in adults, youth who are poor or intermediate metabolizers for both enzymes have increased sertraline exposure. These results support the Clinical Pharmacogenetics Implementation Consortium recommendations for CYP2C19 and CYP2B6-related reductions in sertraline dose or slower titration.

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