The Role of “Physiologically Based Pharmacokinetic Model (PBPK)” New Approach Methodology (NAM) in Pharmaceuticals and Environmental Chemical Risk Assessment

Abstract

Physiologically Based Pharmacokinetic (PBPK) models are mechanistic tools generally employed in the pharmaceutical industry and environmental health risk assessment. These models are recognized by regulatory authorities for predicting organ concentration–time profiles, pharmacokinetics and daily intake dose of xenobiotics. The extension of PBPK models to capture sensitive populations such as pediatric, geriatric, pregnant females, fetus, etc., and diseased populations such as those with renal impairment, liver cirrhosis, etc., is a must. However, the current modelling practices and existing models are not mature enough to confidently predict the risk in these populations. A multidisciplinary collaboration between clinicians, experimental and modeler scientist is vital to improve the physiology and calculation of biochemical parameters for integrating knowledge and refining existing PBPK models. Specific PBPK covering compartments such as cerebrospinal fluid and the hippocampus are required to gain mechanistic understanding about xenobiotic disposition in these sub-parts. The PBPK model assists in building quantitative adverse outcome pathways (qAOPs) for several endpoints such as developmental neurotoxicity (DNT), hepatotoxicity and cardiotoxicity. Machine learning algorithms can predict physicochemical parameters required to develop in silico models where experimental data are unavailable. Integrating machine learning with PBPK carries the potential to revolutionize the field of drug discovery and development and environmental risk. Overall, this review tried to summarize the recent developments in the in-silico models, building of qAOPs and use of machine learning for improving existing models, along with a regulatory perspective. This review can act as a guide for toxicologists who wish to build their careers in kinetic modeling.

Computational Pharmaceutics: A Comprehensive Review of Past Achievements, Present Applications, and Future Challenges

“…PBPK modeling plays a crucial role in predicting the pharmacokinetic/pharmacodynamic behavior of pharmaceutical formulations (Deepika & Kumar, 2023;Denninger et al, 2023;Elmokadem et al, 2023). By integrating in vitro dissolution data with PBPK tools, such as PK-Sim and GastroPlus®, accurate predictions of human pharmacokinetics can be achieved.…”

“…PBPK models aid in predicting organ concentration-time profiles, pharmacokinetics, and daily intake doses of xenobiotics (Conolly et al, 2023;Lancheros Porras et al, 2024). These models have been extended to encompass sensitive populations like pediatric, geriatric, and pregnant individuals, enhancing their applicability (Deepika & Kumar, 2023). PBPK modeling facilitates the development of quantitative adverse outcome pathways for various toxicological endpoints, such as developmental neurotoxicity and hepatotoxicity, contributing to toxicity assessments (Denninger et al, 2023).…”

Unraveling biomarkers of exposure for tenuazonic acid through urinary metabolomics

“…The trial’s design proposed in this study was applied for the first time by Vidal et al (2018) and provided pivotal insights into the metabolization of DON and its toxicokinetic properties ( Martins et al, 2019 ; Mengelers et al, 2019 ). The insights generated for TeA provide a foundation for subsequent research, including biomonitoring studies on different cohorts ( Gerding et al, 2015 ; Martins et al, 2022 ; Tesfamariam et al, 2022 ) and population based pharmacokinetic modelling ( Deepika & Kumar, 2023 ; Mengelers et al, 2019 ). The results obtained combined with population exposure data, offer a comprehensive toxicokinetic description that will set the basis for more accurate quantitative risk assessment ( Arcella et al, 2016 ; De Ruyck et al, 2020 ).…”

Physiologically Based Pharmacokinetic Modeling of Extracellular Vesicles

“…GastroPlus is a PBPK modeling software that is widely used in the pharmaceutical industry to predict the pharmacokinetics (PK) of drugs in various species, including humans, rats, dogs, and monkeys [ 113 , 114 ]. It can also simulate the PK of drugs after various routes of administration, such as oral, intravenous, transdermal, and inhalation [ 114 ]. GastroPlus is a closed source software and it’s developed by SimulationsPlus company.…”