Andre Dallmann (1), Ibrahim Ince (2), Michaela Meyer (2), Thomas Eissing (2), Georg Hempel (1)
(1) University of Münster, Münster, Germany, (2) Bayer Technology Services, Systems Pharmacology CV, Leverkusen, Germany
Objectives: The goal of this study is to validate a physiologically-based pharmacokinetic (PBPK) model for the prediction of pharmacokinetics (PK) of small molecule drugs in pregnant women at different stages of pregnancy.
Methods: Based on a recent literature review on anatomical and physiological changes during pregnancy [1], a pregnancy population PBPK model has been developed using PK-Sim®/MoBi® [2]. In this model, the standard model structure of an adult woman was extended by 9 physiological compartments. These compartments are either specific to pregnancy (e.g. placenta and fetus) or become of specific relevance during pregnancy (uterus and breasts). To ensure a smooth transition from the non-pregnant to the pregnant state, organs and blood flows at the onset of pregnancy were scaled to non-pregnant levels. Populations of pregnant women were created using the organ scaling approach implemented in PK-Sim® [3]. The pregnancy population PBPK model was applied to predict the PK of multiple drugs at different stages of pregnancy. Prediction results were evaluated by comparison with experimentally observed literature data.
Results: The pregnancy population PBPK model successfully predicted the PK of all drugs at different stages of pregnancy. Compared to the non-pregnant state, maximum clearance changes of renally cleared drugs were observed in the early 2nd trimester with an increase of approximately 50%. The differences declined towards delivery, approximating values comparable to non-pregnant clearance levels. No changes in the activity of renal transporters involved in the clearance were necessary to correctly predict the experimentally observed PK. This indicates that the activity of these transporters remains essentially constant throughout pregnancy.
Conclusions: We successfully developed and validated a pregnancy population PBPK model at different stages of gestation for multiple small molecule drugs. PK changes in pregnant women could be fully attributed to pregnancy-related changes in relevant physiological parameters such as kidney volume and perfusion. Ultimately, this model can be applied to investigate in silico the PK of small molecule drugs and help design dosages e.g. for clinical trials in this vulnerable special population.
References:
[1] Dallmann, A., 2015, PAGE 24, Abstr 3456.
[2] Eissing, T. et al. (2011). A computational systems biology software platform for multiscale modeling and simulation: integrating whole-body physiology, disease biology, and molecular reaction networks. Frontiers in physiology 2: 1–10.
[3] Willmann, S. et al. (2007). Development of a physiology-based whole-body population model for assessing the influence of individual variability on the pharmacokinetics of drugs. Journal of pharmacokinetics and pharmacodynamics 34(3): 401–431.
Reference: PAGE 25 (2016) Abstr 5852 [www.page-meeting.org/?abstract=5852]
Poster: Drug/Disease modeling - Absorption & PBPK