Anaëlle Monfort1, Chin B. Eap2,3,4,5, Nicolas Ansermot5, Severine Crettol5, Céline J. Fischer Fumeaux6, Myriam Bickle Graz6, Mathilde Morisod Harari7, Étienne Weisskopf2, Jean-Michel Hascöet8, Olivier Claris9,10, Manuella Epiney11, Chantal Csajka2,3,4, Alice Panchaud1,12, Monia Guidi2,4,13
1Service of Pharmacy, Lausanne University Hospital and University of Lausanne, 2Center for Research and Innovation in Clinical Pharmaceutical Sciences, University Hospital and University of Lausanne, 3School of pharmaceutical Sciences, University of Geneva, 4Institute of pharmaceutical Sciences of Western Switzerland, University of Geneva and University of Lausanne, 5Unit of Pharmacogenetics and Clinical Psychopharmacology, Department of Psychiatry, Lausanne University Hospital, 6Clinic of Neonatology, Department Mother-Woman-Child, Lausanne University Hospital and Lausanne University, 7Division of Child and Adolescent Psychiatry, Lausanne University Hospital, 8Department of Neonatology, Maternité Régionale, Université de Lorraine, 9Department of Neonatology, Hospices Civils de Lyon, 10Claude Bernard University, EA4129, 11Department of Women, Child and Adolescent, Geneva University Hospital, , 12Institute of Primary Health Care (BIHAM), University of Bern, 13Service of Clinical Pharmacology, Lausanne University Hospital and University of Lausanne
Introduction/Objectives: Paroxetine is a selective serotonin reuptake inhibitor commonly used to treat mental health conditions, including in pregnant and breastfeeding women (1, 2). Although available data suggest that only small amounts of paroxetine transfer into cord blood and breast milk, substantial interindividual variability has been reported (3, 4). This study aimed to develop a population pharmacokinetic (popPK) model to characterize the pharmacokinetics of paroxetine during the perinatal period, quantify interindividual variability and identify its sources. Additionally, the study sought to assess infant exposure in silico through placenta and breast milk under various conditions. Methods: Pregnant women receiving paroxetine were enrolled in the multicenter prospective cohort study “SSRI-Breast Milk Study” (ClinicalTrial.gov http://clinicaltrials.gov/show/NCT01796132) conducted in Switzerland and France. Data collection included demographic, genetic, and environmental factors such as maternal weight, age, moment of sampling and type of milk collected, along with maternal plasma, breast milk and cord blood samples. Paired maternal plasma and cord blood samples were collected on the day of delivery, while paired maternal plasma and breast milk samples were obtained during the first week postpartum and between 4 and 6 weeks postpartum. At each time point, both foremilk and hindmilk samples were collected. Paroxetine concentrations were quantified using a validated liquid chromatography-coupled to mass spectrometry method. A popPK model for paroxetine concentrations in maternal plasma was first developed using NONMEM, comparing different compartmental models and absorption and elimination processes. A breast milk compartment was then incorporated, using either a scaling factor between plasma and milk concentration profiles (assumed to reflect the milk-to-plasma ratio (MPR)) or transfer rates assuming a fixed milk volume of 0.125 L. Similarly, a fetal compartment was added to the central compartment to describe cord blood concentrations, using either transfer rates with an assumed negligible fetal volume or a scaling factor termed the cord-to-plasma ratio (CPR). Covariate analysis was performed following the classical popPK workflow to identify factors influencing paroxetine pharmacokinetics. Results: Twenty-four women treated with paroxetine provided 51 maternal plasma, 60 breast milk and 23 cord blood samples. A three-compartment model with linear absorption and elimination best described paroxetine concentrations in maternal plasma, cord blood and breast milk, with interindividual variability (IIV) associated with paroxetine clearance (CL). The typical paroxetine volume of distribution was estimated at 704 L, with a CL of 62.7 L/h and an associated IIV of 71%. The absorption rate constant (ka) was fixed at 0.908 to prevent identifiability issues. The breast milk compartment was linked to the plasma compartment using transfer rates (kPlasma Milk = 0.059 and kMilk Plasma = 0.52), as this approach yielded a better data description compared to the MPR-based model. For cord blood concentrations, the CPR method was preferred with an estimated CPR of 0.42. Maternal weight was the only significant covariate affecting CL, with a 53% reduction in CL for every 10 kg decrease in maternal weight, reducing both intra- and interindividual variabilities by at least 5%. Conclusions: A three-compartment popPK model was successfully developed to describe paroxetine pharmacokinetics in women with mental health conditions during the perinatal period. This model confirms high interindividual variability in paroxetine concentrations in pregnant and breastfeeding women. Maternal body weight is one of the covariates that explain this high interindividual variability and reflects changes in drug pharmacokinetics following the end of pregnancy. The low transfer rate from maternal plasma to breast milk suggests minimal transfer of paroxetine into breast milk. Finally, this model provides a framework for simulating maternal plasma, breast milk, and cord blood concentrations to assess maternal and infant exposure to paroxetine, supporting risk assessment during the perinatal period.
(1) Molenaar NM, Bais B, Lambregtse-van den Berg MP, Mulder CL, Howell EA, Fox NS, Rommel AS, Bergink V, Kamperman AM. The international prevalence of antidepressant use before, during, and after pregnancy: A systematic review and meta-analysis of timing, type of prescriptions and geographical variability. J Affect Disord. 2020 Mar 1;264:82-89. doi: 10.1016/j.jad.2019.12.014. Epub 2019 Dec 9. PMID: 31846905. (2) Wisner KL, Parry BL, Piontek CM. Clinical practice. Postpartum depression. N Engl J Med. 2002 Jul 18;347(3):194-9. doi: 10.1056/NEJMcp011542. PMID: 12124409. (3) Drugs and Lactation Database (LactMed®) [Internet]. Bethesda (MD): National Institute of Child Health and Human Development; 2006-. Paroxetine. [Updated 2025 Feb 15]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK501190/ (4) Schoretsanitis G, Westin AA, Stingl JC, Deligiannidis KM, Paulzen M, Spigset O. Antidepressant transfer into amniotic fluid, umbilical cord blood & breast milk: A systematic review & combined analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2021 Apr 20;107:110228. doi: 10.1016/j.pnpbp.2020.110228. Epub 2021 Jan 2. PMID: 33358964; PMCID: PMC7882033.
Reference: PAGE 33 (2025) Abstr 11582 [www.page-meeting.org/?abstract=11582]
Poster: Drug/Disease Modelling - Safety