Sophie Fischer-Holzhausen, Styliani Fragki, Pavel Balazki, Raphaëlle Lesage , Leonie Lautz, Marco Siccardi, Alexander Kulesza, Stephan Schaller
ESQlabs GmbH
Introduction/Objectives: The Open Systems Pharmacology (OSP) Suite, with its two mechanistic modeling and simulation software solutions PK-Sim® and MoBi®, as well as an R-Framework, comprises a comprehensive solution for Physiologically Based Kinetic (PBK) and Quantitative Systems modeling in pharmacology and toxicology (QSP/T) [1]. Modeling and simulation of PBK models allow for investigating an organism’s exposure to xenobiotics via a mechanistic description of absorption, distribution, excretion, and metabolism (ADME). This enables the prediction of the pharmacokinetics/toxicokinetics (PK/TK) in different species and populations.
Pregnant women are potentially exposed to various chemicals/medications, which bear the risk of significant consequences for the development of the fetus. Although it is often not feasible to acquire direct measurements during pregnancy, the understanding of exposure in pregnant women and fetuses is essential to minimize toxicological risks.
Considering these limitations, in silico methods, such as Pregnancy PBK (p-PBK) models, represent promising approaches to fill gaps in our understanding. p-PBK models integrate physiological and anatomical changes during pregnancy and, thereby, can help predict PK/TK changes during the different pregnancy stages [3].
Cross-species extrapolation, e.g. using data from rat pregnancy models, can be used in cross-species de-risking in non-clinical drug development by extrapolating and predicting cross-species differences in PK/TK resulting from species-specific physiology and anatomy [3]. Such an approach is currently unavailable for p-PBK models as part of the OSP suite. Therefore, we are expanding the OSP model library with a rat pregnancy model.
Objectives:
- Build a maternal-fetal PBK model for rats by expanding the PK-Sim® rat model with pregnancy-specific compartments and parameters congruent to the detail of the existing human pregnancy model [4].
- Verify the rat p-PBK model by comparing its predicted maternal and fetal exposure with data from measurements in rats.
Methods: To construct the rat p-PBK model, the human p-PBK model that includes all pregnancy-specific compartments (uterus, placenta, fetus with organ sub-compartments, breast tissue, amniotic fluid, umbilical cord) [4] is used as a template. Translation into a rat model is achieved by adapting the parameters of the human model. The physiological and anatomical changes during pregnancy are informed with data from a literature search. Pregnancy-specific physiological changes, e.g. the increase in blood volume, are considered by the model and captured by time-dependent functions.
The model performance is assessed by the model’s capability to predict maternal and fetal exposure.
Establishing a p-PBK model for a given compound is done in a two-step procedure [5]:
- A PBK model for non-pregnant rats is established and evaluated.
- The non-pregnant model (model from the first step) is expanded by the pregnancy-specific compartments and physiology. The expanded model is also verified.
Results: As a result of our literature research, the physiological and anatomical changes during pregnancy can be informed for 10 of the dam’s model compartments, including the breast, placenta and uterus. For the fetus, sufficient data is available to describe the development of at least 8 fetal compartments, including the brain, the kidney and the liver, between day 6 and day 22 of gestation. We curated the available literature regarding potential compounds for model validation and concluded that our set of validation compounds includes the herbicide Atrazine and the drug Theophylline.
We expect our model to adequately predict the maternal plasma concentration, concentration in amniotic fluid and the fetal exposure for our validation compounds, supported by goodness-of-fit plots.
Conclusions: The extension of the OSP model library by a rat pregnancy PBK model, allows for the investigation of xenobiotic exposure in mother and fetus during rat pregnancy. The availability of such a model as part of the OSP suite enables cross-species extrapolation from rat to human in the case of pregnancy. It consequently allows for better model-based risk assessment in this special population.
References:
[1] Lippert, Jörg, et al. CPT: pharmacometrics & systems pharmacology 8.12 (2019): 878.
[2] Thépaut, E., et al. Computational Toxicology (2023): 100282.
[3] Thiel, Christoph, et al. Journal of pharmaceutical sciences 104.1 (2015): 191-206.
[4] Liu, Xiaomei I., et al. Clinical pharmacokinetics 63.1 (2024): 69-78.
[5] Dallmann, André, et al. Clinical pharmacokinetics 56 (2017): 1525-1541.
Reference: PAGE 32 (2024) Abstr 11100 [www.page-meeting.org/?abstract=11100]
Poster: Methodology - Other topics