Our research
What makes pharmacotherapy so challenging in pregnancy?
During pregnancy, the human body goes through remarkable changes. Almost every organ adjusts to support the growing baby. These dynamic physiology changes can also affect the concentration of medicines in the body, there are several mechanisms that play a role. Hormones rise early in pregnancy. This can slow down how quickly the stomach empties, meaning medicines taken by mouth may act later than expected. Nausea and vomiting can also reduce how much medicine is actually absorbed. At the same time, blood volume increases by up to 50%. Body water and body fat both increase. This means medicines may spread out differently in the body, some medications becoming more diluted, while others do not. The liver, which breaks down many medicines, may work faster for some drugs and slower for others. Also, the kidney function increases during pregnancy, clearing certain medicines more quickly.
Traditional dosing strategies, which often rely on adult data, ignore the profound physiological changes during pregnancy that alter how drugs are absorbed, distributed, metabolized, and excreted. Failing to account for these changes can lead to sub-therapeutic exposure or toxicity. Medication given to a pregnant subject can also reach the foetus. Therefore, when developing dosing recommendations for pregnant individuals, it is crucial to account for both exposure changes during pregnancy and potential foetal exposure.
How do we understand these exposure changes?
A rapidly emerging solution to understanding and predicting changes in drug exposure during pregnancy is the use of physiologically based pharmacokinetic (PBPK) modelling. PBPK modelling allows us to create a detailed virtual representation of the human body, simulating how a medicine is absorbed, distributed, metabolized, and eliminated. Our PBPK models are specifically adapted to reflect these pregnancy-related changes, ensuring that the predictions we make are as accurate as possible for this unique population.
In Project Madam, we also study how medicines cross the placenta. By using donated human placentas in a controlled laboratory setting, we can measure how much of a drug passes from mother to foetus. This information is integrated into our PBPK models to predict foetal drug exposure. Our goal is to create the most accurate virtual representation of pregnant physiology, allowing us to predict the exposure of both mother and foetus after medication intake.
So, what is model-informed dosing?
Once a PBPK model has been built and verified, it can be used to predict drug exposure and prospectively explore alternative dosing strategies. We evaluate different dosing regimens (e.g. dose amount or time between doses), but also different gestational age groups, since physiological changes continue throughout pregnancy. A dosing regimen is considered appropriate when it maintains drug levels within the therapeutic range; high enough to be effective, but low enough to avoid toxicity.
Model-informed dosing provides evidence to support dose selection. This is especially valuable in populations where clinical data are limited, such as pregnant women. Importantly, it does not replace clinical evidence. Final recommendations must also consider safety, effectiveness, and practical feasibility in the target population.
In project Madam, we perform PBPK studies to evaluate current antenatal dosing strategies and provide new dosing proposals that meet efficacy targets, while avoiding excessive peak exposures, to inform clinical practice.
In Project Madam, we perform PBPK studies to evaluate current antenatal dosing strategies and provide new dosing proposals that meet efficacy targets, while avoiding excessive peak exposures, to inform clinical practice.