Extension of a pregnancy physiologically-based pharmacokinetic model for renally cleared drugs to the postpartum period
Andre Dallmann (1), Anneke Himstedt (1), Ibrahim Ince (2), Juri Solodenko (2), Thomas Eissing (2), Georg Hempel (1)
(1) University of Münster, Münster, Germany, (2) Systems Pharmacology and Medicine, Bayer AG, Leverkusen, Germany
Objectives: The objective of this study is to extend a pregnancy physiologically-based pharmacokinetic (PBPK) model to the postpartum period and verify it for the prediction of pharmacokinetics (PK) of renally cleared drugs.
Methods: A systematic literature search was carried out to collect study data on anatomical and physiological changes in the postpartum period. Collected data were quality appraised and compiled in a database if they met predefined inclusion criteria. Using a previously described approach [1], mathematical functions were fitted to the collected data to describe anatomical and physiological dynamics observed in the postpartum period. These functions were combined with previously reported functions for pregnancy-dependant changes [1,2] and implemented in PK-Sim and MoBi as part of the Open Systems Pharmacology Suite [3,4]. Finally, a PBPK model was developed to predict the disposition of a predominantly renally cleared drug, amoxicillin, in late pregnancy and in early postpartum period on the first day after delivery. PK predictions were verified using in vivo data from the literature.
Results: The literature search yielded 105 studies with 1096 anatomical and physiological data on 3742 women in the postpartum period. The PBPK model for amoxicillin successfully predicted the altered disposition of amoxicillin during pregnancy and in the postpartum period. PK parameters were also adequately predicted by the PBPK model showing a significantly higher clearance in pregnancy and a somewhat lower, albeit still elevated, clearance on the first day after delivery compared to the non-pregnant level.
Conclusions: A set of mathematical functions describing anatomical and physiological changes during the postpartum period was developed and coupled to a previously presented pregnancy PBPK model. This allows the longitudinal description of anatomical and physiological changes observed between the onset of pregnancy and eventual restoration of pre-pregnant levels in the late postpartum period. A subsequently developed PBPK model successfully predicted observed amoxicillin disposition in late pregnancy and early postpartum period. Ultimately, such a model could be applied to investigate in silico the PK of drugs in the postpartum period including potential drug transfer to the neonate via breast-feeding.
References:
[1] Dallmann, A, et al. Gestation-specific changes in the anatomy and physiology of healthy pregnant women: An extended repository of model parameters for physiologically based pharmacokinetic modeling in pregnancy. [submitted for publication]
[2] Dallmann, A, et al. Physiologically based pharmacokinetic modeling of renally cleared drugs in pregnant women. [submitted for publication]
[3] 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.
[4] www.open-systems-pharmacology.org
