DOI: 10.5061/dryad.6djh9w1fv
title: Comparison of physiologically based pharmacokinetic modeling platforms for developmental neurotoxicity in vitro to in vivo extrapolation

description: This study describes an in vitro to in vivo extrapolation (IVIVE) approach
 to derive human-relevant administered equivalent doses based on chemical
 partitioning into developmental neurotoxicity (DNT) target organs during
 the critical period of brain development. Three physiologically
 based pharmacokinetic (PBPK) modeling platforms were evaluated for their
 suitability for this DNT-IVIVE approach. This dataset includes the model
 code for the two open-source platforms used for this approach- the U.S.
 EPA's R package, httk, and PK-Sim from Open Systems Pharmacology.
description: PBPK modeling was performed in batch mode in each platform using
 a pregnancy model at 15 gestation weeks (GW) and 24GW. For modeling of
 infants, a standard PBPK model was run at 2 weeks and 6 months of age for
 each platform; for httk, this was the preliminary brain—adipose model
 described in Unnikrishnan et al. (2024) (Unnikrishnan. et al. in prep).
 The individual for simulation was created based on age for PK-Sim, which
 accounts for ontogeny. As httk does not consider ontogeny, age was set in
 httk by body weight using the GastroPlus (Simulations Plus) default
 weights for a 2 week and 6 month-old male, which were 3.7 kg and 8.29 kg,
 respectively. Chemical exposure was modeled as a single oral bolus of 1
 mg/kg body weight and was simulated for a 24-hour period. As the maximum
 number of integration steps that GastroPlus can run in batch mode is 500,
 the integration time interval was divided into 500 steps for all platforms
 to ensure equivalent granularity across platforms for estimation of the
 maximal concentration (C<sub>max</sub>). To
 implement this as a mid-throughput approach, PBPK modeling was conducted
 in batched mode. For httk, the R code was written to allow for batched
 modeling using both the pregnancy and brain—adipose models. Several
 chemicals would not run due to falling outside httk’s applicability
 domain. Therefore, these chemicals were forced to run using the command,
 “physchem.exclude = FALSE” or “class.exclude = FALSE.” While PK-Sim is
 typically run using a GUI, the GUI does not allow for batched modeling.
 Therefore, code was written in R to perform batched modeling for PK-Sim.
 The R code for both httk and PK-Sim is freely available here on Dryad, as
 well as on GitHub (https://github.com/esqLABS/pregnancy-neonates-batch-run/tree/master). Values for C<sub>max</sub> were derived for DNT-relevant compartments—fetal, fetal venous, and maternal plasma at 15GW and 24GW, brain and plasma at 2w and 6m, and fetal brain at 15GW and 24GW in httk. To allow for comparison between models, code was written in Python to compute a single effective fetal compartment concentration by volume-averaging the concentrations of the fetal sub compartments (code is available through this Dryad repository and at https://github.com/esqLABS/pregnancy-neonates-batch-run/tree/master).
description: # Acute exposure batch PBK simulations for pregnancy and neonates ##
 Project description The files housed here were created for the manuscript
 "Comparison of physiologically based pharmacokinetic modeling
 platforms for developmental neurotoxicity in vitro to in vivo
 extrapolation." In this work, an in vitro to in vivo extrapolation
 (IVIVE) approach for developmental neurotoxicity (DNT) was developed using
 physiologically based pharmacokinetic (PBPK) modeling. The included files
 were used for modeling in two of the three PBPK models used in this
 publication- PK-Sim and httk. Modeling was performed in batch for neonates
 (2 weeks and 6 months) and pregnancy (GW 15 and 24) for oral exposure. ##
 Description of the project *PK-Sim* This is a R project (Pregnancy and
 Pediatric batch run.Rproj) that uses R environment (renv). The files
 .gitignore, .Rprofile and renv.lock are all files related to renv or git.
 This R project requires the installation of ospsuiteR package. To do so,
 use: install.packages("remotes") 
 remotes::install_github("Open-Systems-Pharmacology/OSPSuite-R@*release") This will install the package and its dependencies. Remaining packages, from CRAN, can be installed by running ren::status() renv::restore() The file Neonate and Pregnancy sim function.R has the workflow to make the simulations for the different ages, partition coefficients and get the different outputs. From the chemicals, only MW, logP, Fu, hepatic clearance (/min), SMILES, and ionization (pKa and type ionization) are needed. An example file with the physicochemical properties of the chemicals can be seen in test_batch_2. If you have a new chemical list to run, design the .csv identically to this test_batch_2.csv and replace the name of the new chemicals file in line 8 of the "Neonate and Pregnancy sim function.R". The file Run batch function.R contains the code to run the simulations and where options relative to the dose, partition coefficient and individuals can be selected. It can also be selected how oral permeability (Pint) and tissue permeability values are as calculated. By default these parameters are calculated with the OSP internal QSAR. We added options to run with a very high oral permeability and/or very high tissue permeability to assume 100% oral bioavailability as is the default in the httk model. The aim is that we can run the simulations without permeability being a limited rate. Mind that for chemicals with very low Fub , effective permeability might still be limiting. *httk* Three code files are provided to run httk and process the outputs. These files include the script used to run the pregnancy PBPK model (FetalPBTKhttk.R), the standard model at infant timepoints (PedPBTKhttk.R), and the Python script used for calculation and analysis of httk outputs (httkDataProcessing.ipynb).