Etienne Weisskopf (1), Monia Guidi (1,2), Céline J Fischer (3), Myriam Bickle Graz (3), Etienne Beaufils (4), Kim An Nguyen (5,6), Mathilde Morisod Harari (7), Sylvie Rouiller (8), Sophie Rothenburger (9), Pascal Gaucherand (4), Behrouz Kassai-Koupai (6), Cristina Borradori Tolsa (10), Manuella Epiney (11), Jean-Francois Tolsa (3), Yvan Vial (12), Jean-Michel Hascoët (13), Olivier Claris (5,14), Chin B Eap (1, 15), Alice Panchaud* (1, 16), Chantal Csajka* (1, 2)
(1) School of Pharmaceutical Sciences, University of Geneva and University of Lausanne, Geneva, Switzerland (2) Service of Clinical Pharmacology, Lausanne University Hospital, Lausanne, Switzerland (3) Clinic of Neonatology, Lausanne University Hospital, Lausanne, Switzerland (4) Department of Obstetrics, Hospices Civils de Lyon, Lyon, France (5) Department of Neonatology, Hospices Civils de Lyon, Lyon, France (6) Department of Pharmacotoxicology, CHU Lyon, Lyon, France (7) Division of Child and Adolescent Psychiatry, Lausanne University Hospital, Lausanne, Switzerland (8) Service of Gynecology and Obstetrics, Ensemble hospitalier de la Côte, Morges, Switzerland (9) Department of Obstetrics and Gynecology, Maternité, CHRU Nancy, Nancy, France (10) Division of Child Development and Growth, Geneva University Hospital, Geneva, Switzerland (11) Department of Gynecology and Obstetrics, Geneva University Hospital, Geneva, Switzerland (12) Department of Gynecology, Obstetrics and Genetics, Lausanne University Hospit
Objectives: Worldwide about 10% of pregnant women and women who have just given birth experience a mental disorder, primarily depression. If left untreated, depression have been associated with adverse outcomes for the mother, the infant and their family environment, such as reduced maternal sensitivity and involvement in caregiving, and child emotional or behavioral difficulties. Escitalopram figures among the most frequently prescribed drugs for the treatment of depression in pregnant and breastfeeding women. Available information on exposure to escitalopram during the perinatal period and its excretion into breast milk is based on heterogeneous and incomplete data. The aim of the study was to better characterize the exposure to escitalopram and its metabolite in maternal blood and breast milk. The model was used to quantify the potential risks associated with the use of this medication during breastfeeding.
Methods: The study population was composed of women taking escitalopram or racemic citalopram stemming from a multicenter prospective cohort study enrolling pregnant women under treatment with serotonin reuptake inhibitors (SSRI) and willing to breastfeed. First, a structural model was built for escitalopram (SCIT) in plasma using a one compartment model with first order absorption and elimination in NONMEM®. Then, drug breast milk concentrations were added to the basic model and described by estimating milk-to-plasma ratios (MPR). The effect of different influential covariates such as age, bodyweight, CYP2C19, 2D6 and 3A4/5 genotypes (categorized according to the phenotypic activity) or milk fat content and time after delivery on drug pharmacokinetics was tested. Finally, drug exposure of a suckling child through breast milk was predicted by simulating 5’000 mother-infants pairs under various conditions of maternal characteristics and milk consumption (11±3 feedings per day range 6 and 18 times/day, assuming a typical milk volume of 150 mg/kg/day). The relative infant dose (RID), that is equivalent to the ratio of drug dose ingested by an exclusively breastfed infant with the weight-adjusted maternal dose, was calculated for each mother-infant pair.
Results: The study enrolled 33 patients under escitalopram or racemic citalopram who provided 80 blood and 104 milk samples. Mean SCIT clearance was 32.3 L/h with a between-subject variability (CV%) of 31% and an apparent volume of distribution of 1590 L. Poor metabolizers of CYP2C19 showed a significant 51% decrease in SCIT clearance compared to the other genetic groups. The other genetic polymorphisms did not show any influence on SCIT or SDCIT pharmacokinetics. SCIT was characterized by a MPR of 1.9, while an increased milk fat content was significantly associated with an increased drug transfer into breast milk (+28% for SCIT when fat amount doubled from 3.1 to 6.2 g/100 ml). Drug concentrations was slightly higher 1 month after delivery than compared to labor/early postpartum. Simulations suggest that the average RID of an exclusively breastfed infant after 10 mg escitalopram is 3.5% (from 0.8% to 12.7%). RID would increase mostly in mothers who are PM for CYP2C19 but remained low (average RID 6% from 3% to 17 %).
Conclusions: Escitalopram showed moderate between-subject variability in blood concentrations, partially explained by genetic polymorphisms in CYP2C19. Milk concentrations were similarly variable and mainly influenced by the milk fat content in addition to genetic polymorphism. The limited exposure to escitalopram through breast milk, as expected based on previous incomplete data, could be confirmed. These findings provide reassurance with a good level of certainty for clinicians and pregnant women successfully treated with escitalopram or racemic citalopram.
Reference: PAGE 27 (2018) Abstr 8677 [www.page-meeting.org/?abstract=8677]
Poster: Drug/Disease Modelling - Safety