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.

Keywords: PBPK; pharmacokinetics; phenotype; pregnancy; sertraline.