According to the US Census Bureau, there is a birth every eight seconds in the United States. Women frequently take prescription and over-the-counter drugs during pregnancy. Given the ubiquity of pregnancy and births, you’d think that there would be a robust understanding of the safety and efficacy of drugs in pregnant women. However, the vast majority of drugs are prescribed to pregnant women off-label—often scaling doses from the recommendations set for men or non-pregnant women—because of ethical concerns about performing clinical testing in this vulnerable population.
Physiological and absorption, distribution, metabolism, and excretion (ADME) changes during pregnancy can significantly affect pharmacokinetics (PK). This can lead to under-dosing, with lack of therapeutic effect, or over-dosing, with potential toxicity that endangers both mother and developing fetus. In this blog post, I’ll discuss how pharmacometrics and modeling approaches can be leveraged to identify drugs whose PK may be altered during pregnancy, guide rational study design, and support dosing recommendations for pregnant women.
The current landscape for drug safety during pregnancy
Recent moves by the US FDA and European Medicines Agency are requiring that post-marketing studies be conducted into the effects of drugs in pregnancy where there is a high likelihood of use in women of child-bearing age. The challenge for pharmaceutical companies is not only to determine appropriate initial dosing levels – which will vary depending on the stage of pregnancy – but also account for the time-related changes in drug exposure that may occur over an extended study period. As the physiological and biological changes that occur during pregnancy are well-studied, using physiologically-based pharmacokinetic (PBPK) modeling and simulation to study pharmacokinetics is an intuitive solution.
Using modeling and simulation to study maternal-fetal drug disposition
My Certara colleagues developed a full PBPK pregnancy model which has been implemented in the Simcyp Simulator and tested for its ability to simulate how drug concentrations change over time. The model reflects the progression of pregnancy through changes such as body weight, tissue blood flow, blood and plasma volume, feto-placenta volume, CYP450 enzymatic activity, renal function, and serum albumin levels. In validation studies, good agreement was found between simulated and observed maternal exposure of caffeine, metoprolol and midazolam, three compounds which undergo hepatic metabolism by three different enzyme pathways (CYP1A2, CYP2D6 and CYP3A4).
Appropriate dosing for drugs with narrow safety windows is critical in order to avoid adverse effects that may occur with only slight alterations in clearance levels. The Simcyp model is a major advance on previous pregnancy models as it is the first to consider time-dependent factors at any stage of pregnancy. This provides drug developers and the regulatory agencies with a more versatile tool to understand compound-specific changes in drug exposure throughout pregnancy and aid in the planning and design of clinical trials in pregnant women.
PBPK modeling and simulation is increasingly featuring in submissions for regulatory approval, gaining widespread acceptance for its role in optimizing study design, identifying worst-case scenarios for further investigation and informing dosage recommendations and labeling. PBPK models for pregnancy are not only relevant for the development of drugs specifically for pregnancy-related conditions but can also potentially assist with the dose adjustment decisions required to preserve the safety and efficacy of other therapies which are beneficial to expectant mothers. PBPK modeling and simulation also offers the possibility to assess fetal exposure to drugs, one of the major determinants in assessing the benefit versus risk associated with the treatment.
Ready to learn more about PBPK modeling?
If you’d like a more in-depth look at the issues surrounding applying pharmacometrics approaches for pregnancy, please read this paper that I wrote with Amin Rostami in the Annual Review of Pharmacology and Toxicology. You also might be interested in watching a webinar that Dr. Rostami gave with Dr. Brahim Achour on how new LC-MS techniques in quantitative proteomics are transforming the approach to quantitative pharmacology and in vitro-in vivo extrapolation (IVIVE) for PBPK models. I hope that you’ll check it out and let me know what you think in the comments!