(S-113) Population pharmacokinetic analysis of sertraline in pregnant individuals

Silvia Illamola – University of Minnesota; Marc Kalin – University of Wisconsin School of Medicine; Michael Evans – University of Minnesota; Catherine Sherwin – Wright State University Boonshoft School of Medicine; Costantine Maged – The Ohio State University; Zachary Stowe – University of Wisconsin; Angela Birnbaum – University of Minnesota

Objectives: Depression affects up to 20% of individuals during pregnancy and postpartum (PP) [1]. Sertraline, the most commonly prescribed selective serotonin reuptake inhibitor (SSRI) during pregnancy [2], is metabolized to N-desmethylsertraline (DMS), which is responsible for 5-10% of the pharmacological effect. Physiological changes during pregnancy can affect the pharmacokinetics (PK) of drugs, thus leading to unpredictable changes in response. The goal of this study was to characterize sertraline PK throughout pregnancy and PP in individuals with depression and identify factors that impact sertraline PK.

Methods: The Women’s Mental Health Program (WMHP) collected data from an observational study with inclusion criteria of individuals (18 – 46 years) with a depression diagnosis, on a stable dose of sertraline before sampling ≥ 7 days, planning pregnancy, or < 16 weeks of gestation. Exclusion criteria included a non-verified maternal daily dose (mg/day), dose before sampling > 36 hours, or missing/not clinically interpretable data (i.e., < 0h). Data were collected at 4-8 weeks intervals, delivery, and through 12 months PP. Baseline measures included demographics and vital characteristics (e.g., weight, height). Sertraline and DMS concentrations, and psychometric measures (i.e., HRSD-17, BDI, EPDS, CGI) were measured at all visits. Obstetrical/neonatal outcomes (e.g., low birth weight, small for gestational age) were also collected at birth. A population pharmacokinetic (popPK) model using non-linear mixed-effects modelling (NONMEM®) was developed.

Results: 993 sertraline (median [range] 49 ng/mL [2 – 588]) and DMS concentrations (median [range] 125 ng/mL [2 – 2003]) from 215 pregnant individuals (222 pregnancies) (median 34 years), were included: 3.4% before pregnancy, 12.7% during the first, 25.4% second, and 20.3% third trimester, and 38.2% in the PP period. The median sertraline daily dose was 100 mg (range 12.5-300). After fixing the absorption rate constant (ka) and volume of distribution (Vd), a one-compartment model with proportional error fit the data, including inter-individual variability (IIV) on clearance (48.0%), with a clearance rate of 179 L/hr. No available covariates were deemed to have a significant effect on the PK parameters. Bootstrap indicated that estimates of the fixed and random effects in the final model were estimated with good precision. Model evaluation, performed through pc-VPC, showed consistency with the observed data.

Conclusions: The parent sertraline model showed good agreement with observed data and will be used in the development of a sertraline metabolite model, that will be used to predict exposure measures (e.g. area-under-the concentration curve) to characterize the exposure-response relationship between sertraline exposure and maternal/neonatal outcomes. The long-term goal is to provide information to derive optimized dosing strategies to improve sertraline treatment in pregnant women with depression.

Citations: [1] Pawluski JL. Arch Womens Ment Health. 2019,22(3):407-8;
[2] Andrade SE et al. Arch Womens Ment Health. 2016;19(6):969-77.

Keywords: population pharmacokinetics, antidepressants, pregnancy, pharmacometrics