Utility of life stage-specific chemical risk assessments based on New Approach Methodologies (NAMs).

The safety assessments for chemicals targeted for use or expected to be exposed to specific life stages, including infancy, childhood, pregnancy and lactation, and geriatrics, need to account for extrapolation of data from healthy adults to these populations to assess their human health risk. However, often adequate and relevant toxicity or pharmacokinetic (PK) data of chemicals in specific life stages are not available. For such chemicals, New Approach Methodologies (NAMs), such as physiologically based pharmacokinetic (PBPK) modeling, biologically based dose response (BBDR) modeling, in vitro to in vivo extrapolation (IVIVE), etc. can be used to understand the variability of exposure and effects of chemicals in specific life stages and assess their associated risk. A life stage specific PBPK model incorporates the physiological and biochemical changes associated with each life stage and simulates their impact on the absorption, distribution, metabolism, and elimination (ADME) of these chemicals. In our review, we summarize the parameterization of life stage models based on New Approach Methodologies (NAMs) and discuss case studies that highlight the utility of a life stage based PBPK modeling for risk assessment. In addition, we discuss the utility of artificial intelligence (AI)/machine learning (ML) and other computational models, such as those based on in vitro data, as tools for estimation of relevant physiological or physicochemical parameters and selection of model. We also discuss existing gaps in the available toxicological datasets and current challenges that need to be overcome to expand the utility of NAMs for life stage-specific chemical risk assessment.

Prediction of physicochemical and pharmacokinetic properties of botanical constituents by computational models.

Botanicals contain complex mixtures of chemicals most of which lack pharmacokinetic data in humans. Since physicochemical and pharmacokinetic properties dictate the in vivo exposure of botanical constituents, these parameters greatly impact the pharmacological and toxicological effects of botanicals in consumer products. This study sought to use computational (i.e., in silico) models, including quantitative structure-activity relationships (QSAR) and physiologically based pharmacokinetic (PBPK) modeling, to predict properties of botanical constituents. One hundred and three major constituents (e.g., withanolides, mitragynine, and yohimbine) in 13 botanicals (e.g., ashwagandha, kratom, and yohimbe) were investigated. The predicted properties included biopharmaceutical classification system (BCS) classes based on aqueous solubility and permeability, oral absorption, liver microsomal clearance, oral bioavailability, and others. Over half of these constituents fell into BCS classes I and II at dose levels no greater than 100 mg per day, indicating high permeability and absorption (%Fa > 75%) in the gastrointestinal tract. However, some constituents such as glycosides in ashwagandha and Asian ginseng showed low bioavailability after oral administration due to poor absorption (BCS classes III and IV, %Fa < 40%). These in silico results fill data gaps for botanical constituents and could guide future safety studies. For example, the predicted human plasma concentrations may help select concentrations for in vitro toxicity testing. Additionally, the in silico data could be used in tiered or batteries of assays to assess the safety of botanical products. For example, highly absorbed botanical constituents indicate potential high exposure in the body, which could lead to toxic effects.

An Overview of Physiologically-Based Pharmacokinetic Models for Forensic Science.

A physiologically-based pharmacokinetic (PBPK) model represents the structural components of the body with physiologically relevant compartments connected via blood flow rates described by mathematical equations to determine drug disposition. PBPK models are used in the pharmaceutical sector for drug development, precision medicine, and the chemical industry to predict safe levels of exposure during the registration of chemical substances. However, one area of application where PBPK models have been scarcely used is forensic science. In this review, we give an overview of PBPK models successfully developed for several illicit drugs and environmental chemicals that could be applied for forensic interpretation, highlighting the gaps, uncertainties, and limitations.

Physiologically based pharmacokinetic (PBPK) modeling of RNAi therapeutics: Opportunities and challenges.

Physiologically based pharmacokinetic (PBPK) modeling is a powerful tool with many demonstrated applications in various phases of drug development and regulatory review. RNA interference (RNAi)-based therapeutics are a class of drugs that have unique pharmacokinetic properties and mechanisms of action. With an increasing number of RNAi therapeutics in the pipeline and reaching the market, there is a considerable amount of active research in this area requiring a multidisciplinary approach. The application of PBPK models for RNAi therapeutics is in its infancy and its utility to facilitate the development of this new class of drugs is yet to be fully evaluated. From this perspective, we briefly discuss some of the current computational modeling approaches used in support of efficient development and approval of RNAi therapeutics. Considerations for PBPK model development are highlighted both in a relative context between small molecules and large molecules such as monoclonal antibodies and as it applies to RNAi therapeutics. In addition, the prospects for drawing upon other recognized avenues of PBPK modeling and some of the foreseeable challenges in PBPK model development for these chemical modalities are briefly discussed. Finally, an exploration of the potential application of PBPK model development for RNAi therapeutics is provided. We hope these preliminary thoughts will help initiate a dialogue between scientists in the relevant sectors to examine the value of PBPK modeling for RNAi therapeutics. Such evaluations could help standardize the practice in the future and support appropriate guidance development for strengthening the RNAi therapeutics development program.

Structure and decomposition energies of high-energy open-chain carbon-nitrogen compounds N(x)C(2).

Molecules and ions consisting entirely or predominantly of nitrogen are of interest because of their energy release properties. Such molecules can decompose into N(2), a process that is very exothermic. Following a study predicting the stability properties of isomers of open-chain N(4)C(2), the current study involves calculations on a series of open-chain carbon-nitrogen molecules. Molecules with the general formulas N(x)C(2) are studied to determine their structure and bonding, as well as their energy release capabilities. Theoretical calculations are carried out on this series of molecules to determine geometries and heats of formation. The MP2 method is used for geometry optimizations and vibrational frequencies, with single energies calculated with coupled-cluster theory (CCSD(T)). Energetic and structural trends are calculated and discussed.

Stability and Dissociation Energies of Open-Chain N4C2.

Complex forms of nitrogen are of interest due to their potential as high-energy materials. Many forms of nitrogen, including open-chain and cage molecules, have been studied previously. While many all-nitrogen molecules Nx have been shown to be too unstable for high-energy applications, it has been shown that certain heteroatoms (including carbon) can stabilize a nitrogen structure. A molecule that is not 100% nitrogen will be less energetic, but that energy loss is a tradeoff for the improved stability. In this study, open-chain N4C2 (70% nitrogen by mass) isomers are studied by theoretical calculations to determine isomer stability and dissociation energies. Calculations are carried out with density functional theory (PBE1PBE), perturbation theory (MP2), and coupled-cluster theory (CCSD(T)). Trends in stability of the molecules are calculated and discussed.