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Pharmacogenetically-informed dosing may normalize SSRI exposure in teens

Adolescents with slower CYP2C19 metabolism had greater maximum blood concentration and exposure to both sertraline and escitalopram, according to data published in Journal of Child and Adolescent Psychopharmacology.

“In adults with reduced CYP2C19 metabolism, plasma escitalopram concentrations are higher than those in patients with normal CYP2C19 metabolism — putting these patients at higher risk of [selective serotonin reuptake inhibitor]-related side effects,” Jeffrey Strawn, MD, of the University of Cincinnati department of psychiatry and behavioral neuroscience, and colleagues wrote.

“Accumulating data raise the possibility that CYP2C19-guided dosing could decrease SSRI-related adverse events, potentially hasten time to response, and increase the magnitude of response in youth with depressive and anxiety disorders.”

Using pharmacokinetic modeling, the researchers modeled SSRI dosing across CYP2C19 phenotypes to compare SSRI exposure and maximum blood concentration (C_max) and examined pharmacogenomically-informed dosing strategies that allowed for similar drug exposure across all CYP2C19 phenotypes in teenagers. They used pharmacokinetic parameters in CYP2C19 phenotype groups and previously reported pediatric data for escitalopram and sertraline to model exposure and C_max as well as determine CYP2C19-guided dosing strategies.

Strawn and colleagues found higher C_max levels and exposure to both SSRIs in modeled adolescents who were slower than normal CYP2C19 metabolizers. In contrast, C_max levels and exposure to SSRIs were lower in teens with higher CYP2C19 activity compared with normal CYP2C19 metabolizers treated with either SSRI.

The study revealed that poor metabolizers receiving escitalopram required 10 mg per day and ultra-rapid metabolizers required 30 mg per day to reach an exposure equivalent to 20 mg per day in a normal metabolizer. For simulated teenagers receiving sertraline, poor metabolizers needed 100 mg per day to achieve exposure to and C_max similar to normal metabolizers receiving 150 mg per day, while rapid and ultra-rapid metabolizers needed 200 mg per day.

In addition, ultra-rapid metabolizers required twice daily escitalopram dosing to reach comparable trough levels and exposure to normal metabolizers, according to the study.

“These findings raise the possibility that minimizing CYP2C19-related variability in exposure and clearance might decrease concentration-dependent adverse effects in adolescents who require treatment with sertraline or escitalopram,” Strawn and colleagues wrote.

“Ultimately, moving beyond the ‘one size fits all’ approach to pharmacogenetically-guided dosing may enhance antidepressant treatment response, safety, and tolerability in youth,” they continued. “However, to answer the question, ‘Can refining current antidepressant dosing strategies increase treatment response and reduce side effect burden?’ we require prospective trials that compare pharmacogenetically-guided dosing strategies with standard approaches.” – by Savannah Demko

Disclosure: Strawn reports numerous relevant financial disclosures; please see the study for his and all other authors’ relevant financial disclosures.