Developing a Physiologically-Based Pharmacokinetic Model Knowledgebase in Support of Provisional Model Construction

Abstract

Developing physiologically-based pharmacokinetic (PBPK) models for chemicals can be resource-intensive, as neither chemical-specific parameters nor in vivo pharmacokinetic data are easily available for model construction. Previously developed, well-parameterized, and thoroughly-vetted models can be a great resource for the construction of models pertaining to new chemicals. A PBPK knowledgebase was compiled and developed from existing PBPK-related articles and used to develop new models. From 2,039 PBPK-related articles published between 1977 and 2013, 307 unique chemicals were identified for use as the basis of our knowledgebase. Keywords related to species, gender, developmental stages, and organs were analyzed from the articles within the PBPK knowledgebase. A correlation matrix of the 307 chemicals in the PBPK knowledgebase was calculated based on pharmacokinetic-relevant molecular descriptors. Chemicals in the PBPK knowledgebase were ranked based on their correlation toward ethylbenzene and gefitinib. Next, multiple chemicals were selected to represent exact matches, close analogues, or non-analogues of the target case study chemicals. Parameters, equations, or experimental data relevant to existing models for these chemicals and their analogues were used to construct new models, and model predictions were compared to observed values. This compiled knowledgebase provides a chemical structure-based approach for identifying PBPK models relevant to other chemical entities. Using suitable correlation metrics, we demonstrated that models of chemical analogues in the PBPK knowledgebase can guide the construction of PBPK models for other chemicals.

Modeling liver electrical conductivity during hypertonic injection

“…Several studies have performed mathematical models of the liver to computationally assess the pharmacokinetic behavior of a defined drug or chemical agent . These studies usually used the so‐called physiologically based pharmacokinetic (PBPK) models, which represent the anatomical and physiological structure of the organ by using interconnected fluidic compartments.…”

Next generation physiologically based kinetic (NG-PBK) models in support of regulatory decision making

“…A public repository is needed for PBK models that have been built and/or peer reviewed, and once this repository is developed, relevant documentation can be introduced from an independent peer review to support model credibility. Such a repository is in line with the work reported in Lu et al, [36] and will allow for the curation of more case studies and the creation of libraries of ad hoc PBK models that could be used for training purposes. Additionally, this repository will facilitate risk assessment approaches applying PBK models and IVIVE, and communicate to decision makers more efficiently the current state of science regarding the use of animal-free models in regulatory applications.…”

“…For example, if a valid PBK model exists for chemical A (source chemical), and chemical B (target chemical) lacks any in vivo data and has been shown to be similar in structure to chemical A, then the same parameterised PBK model structure/code and in vivo data for chemical A can be used for chemical B. This read-across approach has been demonstrated by case studies applying the PBK Knowledgebase developed by Lu et al [36] . Alternatively, if parameterisation of the PBK model using available in vitro or in silico data for chemical B is possible, predictions can be compared to output from the model for chemical A based on in vivo data, in order to evaluate the PBK model for chemical B.…”

Fitting tissue chips and microphysiological systems into the grand scheme of medicine, biology, pharmacology, and toxicology

“…97,98 Ultimately, these types of analyses and their extension to physiologically based pharmacokinetics (PBPK) will be critical for the in vitro to in vivo extrapolation that will be necessary to relate TC and MPS homunculi studies to clinical trials in humans. 90,91,93,[99][100][101][102][103][104] These models may help address the volume problem in coupled-organ MPS. MPS/PKPD models will also be useful for predicting human response to multiple drugs, as this is difficult to do with animal experiments only.…”