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.
Highlights
Depression throughout pregnancy is known to affect up to 20% of women (Fisher et al, 2012; Vigod et al, 2016), fewer than 20% of pregnant women will receive suitable treatment (Byatt et al, 2016; Geier et al, 2015)
The median trough plasma concentration decreased by 17.2% (EM, p < 0.001), 14.4% (PM, p < 0.05), and 20% (UM, p < 0.001) by week 30 when compared to baseline (Figure 4) (Supplementary Materials: Section 3 Table S2)
Confounding the use of sertraline in pregnancy is the gestational alterations in maternal CYP 2C19 activity, which has been determined to decrease by 62% and 68% during trimesters 2 and 3, respectively (McGready, Stepniewska, Edstein, et al, 2003; McGready, Stepniewska, Seaton, et al, 2003; Ward et al, 1991)
Summary
Depression throughout pregnancy is known to affect up to 20% of women (Fisher et al, 2012; Vigod et al, 2016), fewer than 20% of pregnant women will receive suitable treatment (Byatt et al, 2016; Geier et al, 2015). The risk of untreated depression is important given that death associated with suicide can affect one in every 25 women aged 20–35 years, from conception through to the postnatal period Antenatal depression is a major risk factor for developing postnatal depression (McAllister‐Williams et al, 2017). A key strategy in the management of moderate‐to‐severe depression is the use of selective serotonin reuptake inhibitors (SSRIs) as first‐line agents and which include sertraline, citalopram, fluoxetine, paroxetine, and fluvoxamine
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