depressive disorders

Cytochrome P4502C19 (CYP2C19) is a highly polymorphic gene that encodes an enzyme that metabolizes escitalopram and sertraline, two selective serotonin reuptake inhibitors (SSRIs); that are FDA approved for pediatric use and commonly used to treat anxiety and depressive disorders in youth.
Using pharmacokinetic (PK) models in adolescents; they sought to model SSRI dosing across CYP2C19 phenotypes to compare SSRI exposure (area under the curve, AUC) and maximum concentration (Cmax); evaluate the impact of b.i.d. dosing (in rapid metabolizers [RM] and ultrarapid metabolizers [UM]) on SSRI exposure and Cmax; determine pharmacogenomically-informed dosing strategies to provide similar exposure across CYP2C19 phenotypes in adolescents.

The slower metabolizers

Using PK parameters in CYP2C19 phenotype groups and previously reported pediatric PK data; for escitalopram and sertraline, they modeled exposure (AUC0–24) and Cmax and determined CYP2C19-guided dosing strategies. Compared with normal CYP2C19 metabolizers treated with either escitalopram or sertraline; Cmax and AUC024 higher in slower metabolizers and lower in patients with increased CYP2C19 activity, although the magnitude of these differences was more pronounced for escitalopram than for sertraline.

For escitalopram, poor metabolizers (PMs) require 10 mg/day and UMs require 30 mg/day to achieve an exposure that is equivalent to 20 mg/day in a normal metabolizer (NM). For sertraline, to achieve AUC0–24 and Cmax similar to NMs receiving 150 mg/day, PMs require 100 mg/day; whereas a dose of 200 mg/day was required in rapid and UMs. For UMs, b.i.d. escitalopram dosing was necessary to achieve comparable trough levels and exposure to NMs.

This simulation study raises the possibility that achieving similar escitalopram and sertraline plasma concentrations; could require dose adjustments in CYP2C19 poor metabolizers and UMs; although the magnitude of these differences; more pronounced for escitalopram than for sertraline. However, prospective trials of pharmacogenomically guided dosing in the pediatric population are needed to extend the findings of these modeling studies.

The antidepressant exposure

This is one of only several studies to pharmacokinetically model antidepressant exposure in youth and the first to evaluate PGx derived phenotypes on these models. They observed that slower CYP2C19 metabolizers had greater Cmax and exposure to both sertraline and escitalopram. Furthermore, our models suggest that CYP2C19-informed dosing could normalize; sertraline and escitalopram exposure in adolescents.
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. With regard to the parameter estimates described herein; the results are generally consistent with the extant steady state PK data in adolescents and shed light on some of the variability of the experimentally determined PK parameters in prior studies.