Development of a mechanistic ex vivo placental perfusion model...

Development of a Mechanistic ex vivo Placental Perfusion Model for Chemicals’ Transport PBPK Simulations

Elias Zgheib 1*, Céline Brohcot 1, Khaled Abduljalil 2

1 Certara France

2 Certara UK Ltd.

Ex vivo human placental perfusion is a valuable and ethically sound technique to study the transplacental transfer of drugs and nutrients. By using human placental tissue, this method preserves native physiological function and enables precise control of experimental variables such as flow rate, pH, and protein binding. It thus provides human-relevant kinetic parameters, including transplacental diffusion and elimination constants, essential for understanding foetal exposure. However, high inter-laboratory variability currently limits data comparability and model qualification. In this work, we developed a comprehensive mechanistic model that unifies and extends previously published placental perfusion models (1–3). The model integrates additional structural and mechanistic features, for each of the source models, including representation of maternal and foetal vascular pathways, non-perfused tissue, unbound fractions in distinct compartments, and active influx/efflux transport across both microvillus and basal membranes. This structure allows separation of physiological parameters from experimental design and compound dependent parameters, which has the advantage to ease quantification of key compound-specific parameters. Model validation was conducted using several compounds (e.g., antipyrine, metformin, digoxin, morphine, and nicotine). The presented model demonstrates accurate prediction of concentration-time profiles in maternal, placental, and foetal compartments. Predictions were within 2-fold of the measured concentrations. Embarking on same set of physiological parameters across these experimental studies, while drug-specific kinetic parameters differ among compounds, reproduced observed data suggesting the model’s generalisability and facilitate its standardisation for regulatory acceptance. This framework thus enables standardised interpretation of perfusion studies across laboratories and compounds. This will ease integration of this model into the PBPK approach and consequently will enhance the prediction of foetal drug exposure and support quantitative risk assessment in drug development and toxicology.

References:

1. Ho H, Zhang S, Kurosawa K, Jiang B, Chiba K. In silico modeling for ex vivo placenta perfusion of nicotine. Front Pharmacol. 2024 Apr 12;15:1275467.

2. Kurosawa K, Chiba K, Noguchi S, Nishimura T, Tomi M. Development of a Pharmacokinetic Model of Transplacental Transfer of Metformin to Predict In Vivo Fetal Exposure. Drug Metab Dispos. 2020 Dec;48(12):1293–302.

3. Kurosawa K, Noguchi S, Nishimura T, Tomi M, Chiba K. Transplacental Pharmacokinetic Model of Digoxin Based on Ex Vivo Human Placental Perfusion Study. Drug Metab Dispos. 2022 Mar;50(3):287–98.

Keywords: « Ex vivo », « Transplacental transfer », « PBPK », « Maternal-Foetal PK », « Modelling ».