Within this repository, we distribute the physiologically-based whole-body models for pregnant individuals published in [1,2,3,4,5,6,7]. Additionally, this repository contains the refined passive transports building block which was used to build pregnancy PBPK models with different unbound drug fractions in maternal and fetal organism as described in [8] as well as the in silico cotyledon perfusion model presented in [9].
The pregnancy (and postpartum) PBPK model for amoxicillin published in [10] can be found here.
The pregnancy model structure comprises per default 27 compartments, including nine pregnancy-specific compartments as shown in the schema below.
The pregnancy PBPK models published in [1,2,3,4,5,6,7] are provided as ready-to-use MoBi® and PK-Sim® projects (subfolder Models). Evaluation of these model is described in the following publications:
- Cefazolin, cefuroxime and cefradine model evaluation is described in [2]
- Caffeine, midazolam, nifedipine, metoprolol, ondansetron, granisetron, diazepam and metronidazole model evaluation is described in [3]
- Acyclovir and emtricitabine model evaluation is described in [4]
- Dolutegravir and raltegravir model evaluation is described in [5]
- Acetaminophen model evaluation is described in [6,7,9]
The subfolder BuildingBlocks contains the MoBi® building blocks for spatial structure and passive transports in pregnant individuals. Those building blocks can be used in MoBi® to build new substance models (see below).
Note that the building block PassiveTransport_PregnantWoman.pkml includes the drug's fraction unbound as global parameter for both the maternal and fetal organism, i.e. differential protein binding in mother and fetus cannot be modeled with this building block.
The pkml file PassiveTransport_PregnantWoman_with-fetal-fu.pkml (subfolder BuildingBlocks) is a refined building block where the drug's fraction unbound was separately implemented in the maternal and fetal organism as described in [8].
When setting up a pregnancy PBPK model using this building block, the fetal fraction unbound needs to be added as new parameter called Fetal Fraction unbound (plasma, reference value) to the drug's parameter list in the Molecule building block as shown below:
The in silico cotyledon perfusion model presented in [9] is provided as MoBi® file (subfolder CotyledonPerfusionModel).
Currently, simulations based on pregnant individuals cannot be built up directly in PK-Sim® (due to the fact that e.g. for the protein model structure not all required data was collected).
Steps 3 to 5 are performed in PK-Sim®.
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If a (MoBi®) pregnancy model is available in
pkmlformat, go to the step 3 -
If a (MoBi®) pregnancy model is available in
mbp3format (MoBi® project): open it in MoBi®, select simulation of interest and save it inpkmlformat -
Create an individual using the population
Pregnant (Dallmann et al. 2017)Please note that in PK-Sim®, the fertilization age (FA) is defined via the individual’s age, with 30 years corresponding to a FA of 0 weeks (i.e. just prior to conception). Hence, a pregnant woman with a FA of 38 weeks is defined using an age of 30.75 years.
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Create a pregnancy population with the required settings based on the individual above
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Import (MoBi®) pregnancy model in
pkmlformat and combine it with created population building block as described in the OSP Suite manual (Ch. 21.2 Importing Individual and Population Simulation)
The procedure is described in a comprehensive tutorial.
The physiology is based on the PBPK model implemented in PK-Sim® version 6.0. The MoBi® project files were created in version 6.0.
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We encourage contribution to the Open Systems Pharmacology community. Before getting started please read the contribution guidelines. If you are contributing code, please be familiar with the coding standard.
The model code is distributed under the GPLv2 License.