A population pharmacokinetic model for sertraline in depressive patients during the perinatal period: prediction of infant drug exposure through placenta and human milk
Anaëlle Monfort (1), Evelina Cardoso (2), Chin B. Eap (3-6), Céline J. Fischer Fumeaux (7), Myriam Bickle Graz (7), Mathilde Morisod Harari (8), Étienne Weisskopf (3), Jean-Michel Hascöet (9), Olivier Claris (10,11), Manuella Epiney (12), Grégoire Leclair (1), Ema Ferreira (1), Chantal Csajka (3-5), Alice Panchaud (2,13), Monia Guidi (2,14)
(1) Faculty of Pharmacy, Université de Montréal, Canada, (2) Service of Pharmacy, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland, (3) Center for Research and Innovation in Clinical Pharmaceutical Sciences, University Hospital and University of Lausanne, Lausanne, Switzerland, (4) School of pharmaceutical Sciences, University of Geneva, Geneva, Switzerland, (5) Institute of pharmaceutical Sciences of Western Switzerland, University of Geneva and University of Lausanne, Lausanne and Geneva, Switzerland, (6) Unit of Pharmacogenetics and Clinical Psychopharmacology, Department of Psychiatry, Lausanne University Hospital, Lausanne, Switzerland, (7) Clinic of Neonatology, Department Woman-Mother-Child, Lausanne University Hospital and Lausanne University, Lausanne, Switzerland, (8) Division of Child and Adolescent Psychiatry, Lausanne University Hospital, Lausanne, Switzerland, (9) Department of Neonatology, Maternité Régionale, Université de Lorraine, Nancy, France, (10) Department of Neonatology, Hospices Civils de Lyon, Lyon, France, (11) Claude Bernard University, P2S 4129, Lyon, France, (12) Department of Women, Child and Adolescent, Geneva University Hospital, Geneva, Switzerland, (13) Institute of Primary Health Care (BIHAM), University of Bern, Bern, Switzerland, (14) Service of Clinical Pharmacology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
Introduction/Objectives: Depression affects around 10% of women during the perinatal period [1]. Sertraline, a selective serotonin reuptake inhibitor, is one of the most prescribed drugs for depression in both pregnant and breastfeeding women [2]. According to the limited available data, only small amounts of sertraline are transferred into human milk, yet with a large amount of unexplained interindividual variability (IIV) [3]. The aims of this study were to describe the pharmacokinetics of sertraline in depressive women during the perinatal period, to quantify its IIV while identifying the underlying factors responsible for such variability with the goal of better understanding the transfer of sertraline to the fetus and into human milk.
Methods: Pregnant women treated with sertraline were enrolled in the multicenter prospective cohort study “SSRI-Breast Milk Study” (ClinicalTrial.gov http://clinicaltrials.gov/show/NCT01796132) conducted in Switzerland and France. Demographic, genetic, and environmental information such as weight, age, CY2C19 and CYP2D6 predicted phenotype and moment of sampling, as well as maternal plasma, cord blood and milk samples were collected. Sertraline was quantified in all samples using a validated liquid chromatography-coupled to mass spectrometry method while fat, proteins, carbohydrates, and calories were measured in milk samples using a Human Milk Analyzer.
A population pharmacokinetic (popPK) base model for sertraline concentrations in maternal plasma was first built comparing several compartmental models and absorption processes using NONMEM. Drug concentrations in human milk were then included in the model through an additional compartment estimating the milk-to-plasma ratio (MPR). Finally, a fetal compartment of negligible volume was linked to the central compartment to describe cord blood concentrations. Several covariates were tested for significance in the complete base maternal plasma, cord blood and milk model. Ultimately, final model-based simulations on 10 000 women allowed predicting infant drug exposure through placenta and human milk under various conditions and after doses between 25 and 150 mg/day. Simulated milk concentrations were used to estimate the daily infant dosage. The latter was, then, used to calculate the relative infant dose, i.e., the percentage of the weight-adjusted maternal dose ingested by the newborn through breast milk, and the cumulative dose of sertraline that a newborn would ingest with an exclusive breastfeeding over 6 months.
Results: Thirty-eight women treated with sertraline provided 89 maternal plasma, 29 cord blood and 107 milk samples. A three-compartment model with linear absorption and elimination best described maternal plasma, cord blood and milk concentrations, with IIV associated with sertraline clearance (CL). Typical sertraline MPR was 1.42 and CL was 119 L/h with IIV of 30%. The CL was reduced by 42% in cytochrome P450 2C19 poor metabolizers compared to intermediate, extensive, or ultra-rapid metabolizers. Increased milk fat content was significantly associated with an increased MPR (+93% when fat amount doubled from 2.59 to 5.18 g/100 mL). Simulations suggested that the median daily infant dosage after a 50 mg maternal daily dose of sertraline would be 0.007 mg/kg/day, which represents 0.9% of the weight-adjusted maternal dose. Over a 6-month period and with the maximum daily maternal dose of 150 mg, an exclusively breastfed infant whose mother is a CYP2C19 poor metabolizer would ingest a sertraline median cumulative dose of 28.8 mg (range 2.9-138.1 mg). Conversely, if the mother is one of the other CYP2C19 metabolizers, her infant would ingest a sertraline median cumulative dose of 16.3 mg (range 1.5-90.6 mg). Finally, concentrations in cord blood could range from 1.5 to 41.5 ng/mL after maternal daily doses between 25 and 150 mg.
Conclusions: A three-compartment popPK model was successfully developed to describe the pharmacokinetics of sertraline in depressive women during the perinatal period. This study confirms the limited exposure to sertraline through human milk observed in previous studies and provides reassurance for sertraline intake during breastfeeding.
References:
[1] Gavin et al. (2005) Perinatal depression: A systematic review of prevalence and incidence
[2] Norris et al. (2013) Use of antidepressants during pregnancy and lactation
[3] https://www.ncbi.nlm.nih.gov/books/NBK501191/