Andre Dallmann (1), Ibrahim Ince (2), Michaela Meyer (2), Kirstin Thelen (2), Stefan Willmann (2), Thomas Eissing (2), Georg Hempel (1)
(1) University of Münster, Münster, Germany, (2) Systems Pharmacology CV, Bayer Technology Services GmbH, Leverkusen, Germany
Objectives: The goal of this study is to develop a physiologically-based pharmacokinetic (PBPK) model for the prediction of pharmacokinetics (PK) of small molecule drugs in healthy Caucasian pregnant women from conception until term.
Methods: A systematic literature search was carried out to identify and collect study data on pregnancy-related changes of anatomical, physiological, and functional parameters to establish a PBPK population model for healthy Caucasian pregnant woman. Each study was quality appraised and the data were extracted if the study met the inclusion criteria. The extracted data were further analysed and compiled in a database. A set of mathematical functions was fitted to the data and the best performing function was selected based on numerical and visual diagnostics together with literature support. The mathematical functions were implemented in PK-Sim®/MoBi® [1] and the pre-existing PBPK model structure for healthy Caucasian adult women was extended by pregnancy-relevant compartments to create a prototype whole-body PBPK population model for pregnant women.
Results: The literature search yielded 279 studies with 9409 anatomical, physiological, and functional data on 430 507 healthy Caucasian pregnant women. These data comprised information on 28 out of 50 parameters. Rich data were found for many relevant parameters such as cardiac output, placental volume, and uterine arterial blood flow. Parameters for which minimal or no data could be found, such as brain or bone volume, were set to the values of non-pregnant women and were kept constant throughout pregnancy. The mathematical functions were selected based on numerical and visual diagnostics and described the time-related changes adequately. They were implemented in a prototype whole-body PBPK population model for healthy Caucasian pregnant women.
Conclusions: A set of mathematical functions describing changes in anatomical, physiological, and functional parameters throughout the course of pregnancy is developed and implemented in a longitudinal and time-varying prototype whole-body PBPK model for healthy Caucasian pregnant woman. Ultimately, this model could be applied to investigate in silico the PK of small molecule drugs in this vulnerable special population.
References:
[1] Eissing T, et al.. A computational systems biology software platform for multiscale modeling and simulation: integrating whole-body physiology, disease biology, and molecular reaction networks. Frontiers in physiology 2011;2:1-10.
Reference: PAGE 24 (2015) Abstr 3456 [www.page-meeting.org/?abstract=3456]
Poster: Methodology - Other topics