Selective Serotonin Reuptake Inhibitor Pharmacokinetics During Pregnancy: Clinical and Research Implications.

Ethan A Poweleit,Sarah A Novotny,Margaret A Cinibulk,Laura B Ramsey,Jeffrey R Strawn,Melissa Wagner-Schuman

doi:10.3389/fphar.2022.833217

Abstract

Pregnancy and associated physiologic changes affect the pharmacokinetics of many medications, including selective serotonin reuptake inhibitors—the first-line pharmacologic interventions for depressive and anxiety disorders. During pregnancy, SSRIs exhibit extensive pharmacokinetic variability that may influence their tolerability and efficacy. Specifically, compared to non-pregnant women, the activity of cytochrome P450 (CYP) enzymes that metabolize SSRIs drastically changes (e.g., decreased CYP2C19 activity and increased CYP2D6 activity). This perspective examines the impact of pharmacokinetic genes—related to CYP activity on SSRI pharmacokinetics during pregnancy. Through a simulation-based approach, plasma concentrations for SSRIs metabolized primarily by CYP2C19 (e.g., escitalopram) and CYP2D6 (e.g., fluoxetine) are examined and the implications for dosing and future research are discussed.

Highlights

Selective Serotonin Reuptake Inhibitors (SSRIs) are commonly used to treat depression and anxiety across the lifespan, including during pregnancy (Mesches et al, 2020)
Pregnancy is associated with induction of many enzymes, including CYP2D6, CYP2C9 and these shifts subtend differences in selective serotonin reuptake inhibitor. ↓ (SSRI) metabolism during pregnancy
Several approaches may address the dearth of pharmacokinetic data in pregnancy and extend model-based recommendations that have been developed for sertraline and paroxetine (Almurjan et al, 2020; Almurjan et al, 2021)

Summary

INTRODUCTION

Selective Serotonin Reuptake Inhibitors (SSRIs) are commonly used to treat depression and anxiety across the lifespan, including during pregnancy (Mesches et al, 2020). Our simulations reflect differences in escitalopram and fluoxetine pharmacokinetics while accounting for each drug’s primary metabolizing enzyme (CYP2C19 and CYP2D6, respectively), in addition to changes in total body weight and creatinine clearance While this perspective precludes extensive physiological-based pharmacokinetic modeling that account for additional parameters that are relevant during pregnancy, these simulations reveal significant heterogeneity in SSRI concentrations due to CYP enzymes. Models accounting for multiple CYP enzymes involved in the metabolic pathway of these medications, among other pertinent parameters, are needed to further understand the complexity of SSRI pharmacokinetics during pregnancy (Betcher and George, 2020) This may be important in some specific populations and, as an example, in Chinese individuals, CYP2C19 poor metabolizers had a mean 46% increase in fluoxetine CMAX and similar increases

CONCLUSION AND FUTURE DIRECTIONS

Findings

DATA AVAILABILITY STATEMENT