The application of precision dosing in the use of sertraline throughout pregnancy for poor and ultrarapid metabolizer CYP 2C19 subjects: A virtual clinical trial pharmacokinetics study

Abstract

Sertraline is known to undergo changes in pharmacokinetics during pregnancy. CYP 2C19 has been implicated in the interindividual variation in clinical effect associated with sertraline activity. However, knowledge of suitable dose titrations during pregnancy and within CYP 2C19 phenotypes is lacking. A pharmacokinetic modeling virtual clinical trials approach was implemented to: (i) assess gestational changes in sertraline trough plasma concentrations for CYP 2C19 phenotypes, and (ii) identify appropriate dose titration strategies to stabilize sertraline levels within a defined therapeutic range throughout gestation. Sertraline trough plasma concentrations decreased throughout gestation, with maternal volume expansion and reduction in plasma albumin being identified as possible causative reasons. All CYP 2C19 phenotypes required a dose increase throughout gestation. For extensive metabolizer (EM) and ultrarapid metabolizer (UM) phenotypes, doses of 100–150 mg daily are required throughout gestation. For poor metabolizers (PM), 50 mg daily during trimester 1 followed by a dose of 100 mg daily in trimesters 2 and 3 are required.

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

“…However, pharmacokinetic data from prospective studies in pregnant women are rare and infrequently consider intrinsic variation in cytochromes activity. Importantly, 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). Phlebotomy performed during usual care permits opportunistic sampling, an approach that has been used to examine developmental pharmacokinetics of many medications-including SSRIs-in children (Girdwood et al, 2021).…”

“…Additionally, population PK studies may provide additional information regarding the pregnancy-related pharmacokinetic changes as they relate to variation in CYP phenotypes. These simulation studies also have the potential to examine the impact of dose changes which may normalize exposure related to pregnancy-related shifts in pharmacokinetic parameters and CYP phenotypes (Almurjan et al, 2020;Almurjan et al, 2021). While understanding the effects of this variation in SSRI pharmacokinetics and the underlying differences in pharmacokinetic genes on SSRI exposure in pregnancy is in its early stages, multiple applications can already be imagined.…”

“…Fewer than a dozen in vivo and modeling studies have examined SSRI pharmacokinetics in pregnant women (Heikkinen et al, 2002;Heikkinen et al, 2003;Freeman et al, 2008;Sit et al, 2008;Ververs et al, 2009;Sit et al, 2011;Westin et al, 2017), in addition to two modeling-based explorations of SSRI pharmacokinetics in pregnant women (Almurjan et al, 2020;Almurjan et al, 2021). To extend these findings and to illustrate how baseline phenotypic variation in CYP enzymes may affect pregnancy-associated changes in SSRI pharmacokinetics, we simulated escitalopram and fluoxetine concentrations at steady state during pregnancy and compared to a non-pregnant state across metabolizer phenotypes.…”

“…Recent studies suggest that some single nucleotide polymorphisms may decrease suppression of CYP2C19 expression and boost metabolism of some CYP2C19-metabolized SSRIs, including escitalopram and citalopram, and even alter improvement trajectories in escitalopram and citalopram-treated adults with depressive disorders (Qin et al, 2020). Beyond these models, two population pharmacokinetic modeling studies previously examined pregnancy-related changes in paroxetine (Almurjan et al, 2020) and sertraline (Almurjan et al, 2021) concentrations with regard to CYP2D6 and CYP2C19 metabolizer status, respectively. These studies aimed to identify "appropriate dose titration strategies to stabilize" medication concentrations within therapeutic ranges during pregnancy.…”

“…Normal and ultrarapid metabolizers needed doses between 100 and 150 mg daily (throughout the pregnancy). However, poor metabolizers needed a dose of 50 mg daily during the first trimester and then required titration to 100 mg daily during the second and third trimester (Almurjan et al, 2021).…”