Review of QSAR Models and Software Tools for predicting Biokinetic Properties

In the assessment of industrial chemicals, cosmetic ingredients, and active substances in pesticides and biocides, metabolites and degradates are rarely tested for their toxicologcal effects in mammals. In the interests of animal welfare and cost-effectiveness, alternatives to animal testing are needed in the evaluation of these types of chemicals. In this report we review the current status of various types of in silico estimation methods for Absorption, Distribution, Metabolism and Excretion (ADME) properties, which are often important in discriminating between the toxicological profiles of parent compounds and their metabolites/degradation products. The review was performed in a broad sense, with emphasis on QSARs and rule-based approaches and their applicability to estimation of oral bioavailability, human intestinal absorption, blood-brain barrier penetration, plasma protein binding, metabolism and. This revealed a vast and rapidly growing literature and a range of software tools. While it is difficult to give firm conclusions on the applicability of such tools, it is clear that many have been developed with pharmaceutical applications in mind, and as such may not be applicable to other types of chemicals (this would require further research investigation). On the other hand, a range of predictive methodologies have been explored and found promising, so there is merit in pursuing their applicability in the assessment of other types of chemicals and products. Many of the software tools are not transparent in terms of their predictive algorithms or underlying datasets. However, the literature identifies a set of commonly used descriptors that have been found useful in ADME prediction, so further research and model development activities could be based on such studies.JRC.DG.I.6-Systems toxicolog

Data-driven modeling of the bicalutamide dissolution from powder systems

Low solubility of active pharmaceutical compounds (APIs) remains an important challenge in dosage form development process. In the manuscript, empirical models were developed and analyzed in order to predict dissolution of bicalutamide (BCL) from solid dispersion with various carriers. BCL was chosen as an example of a poor watersoluble API. Two separate datasets were created: one from literature data and another based on in-house experimental data. Computational experiments were conducted using artificial intelligence tools based on machine learning (AI/ML) with a plethora of techniques including artificial neural networks, decision trees, rule-based systems, and evolutionary computations. The latter resulting in classical mathematical equations provided models characterized by the lowest prediction error. In-house data turned out to be more homogeneous, as well as formulations were more extensively characterized than literature-based data. Thus, in-house data resulted in better models than literature-based data set. Among the other covariates, the best model uses for prediction of BCL dissolution profile the transmittance from IR spectrum at 1260 cm−1 wavenumber. Ab initio modeling–based in silico simulations were conducted to reveal potential BCL–excipients interaction. All crucial variables were selected automatically by AI/ML tools and resulted in reasonably simple and yet predictive models suitable for application in Quality by Design (QbD) approaches. Presented data-driven model development using AI/ML could be useful in various problems in the field of pharmaceutical technology, resulting in both predictive and investigational tools revealing new knowledge

The Use of Computational Methods in the Toxicological Assessment of Chemicals in Food: Current Status and Future Prospects

A wide range of chemicals are intentionally added to, or unintentially found in, food products, often in very small amounts. Depending on the situation, the experimental data needed to complete a dietary risk assessment, which is the scientific basis for protecting human health, may not be available or obtainable, for reasons of cost, time and animal welfare. For example, toxicity data are often lacking for the metabolites and degradation products of pesticide active ingredients. There is therefore an interest in the development and application of efficient and effective non-animal methods for assessing chemical toxicity, including Quantitative Structure-Activity Relationship (QSAR) models and related computational methods. This report gives an overview of how computational methods are currently used in the field of food safety by national regulatory bodies, international advisory organisations and the food industry. On the basis of an international survey, a comprehensive literature review and a detailed QSAR analysis, a range of recommendations are made with the long-term aim of promoting the judicious use of suitable QSAR methods. The current status of QSAR methods is reviewed not only for toxicological endpoints relevant to dietary risk assessment, but also for Absorption, Distribution, Metabolism and Excretion (ADME) properties, which are often important in discriminating between the toxicological profiles of parent compounds and their reaction products. By referring to the concept of the Threshold of Toxicological Concern (TTC), the risk assessment context in which QSAR methods can be expected to be used is also discussed. This Joint Research Centre (JRC) Reference Report provides a summary and update of the findings obtained in a study carried out by the JRC under the terms of a contract awarded by the European Food Safety Authority (EFSA).JRC.DG.I.6-Systems toxicolog

A review of the current state of the art of physiologically-based tests for measuring human dermal in vitro bioavailability of polycyclic aromatic hydrocarbons (PAH) in soil

Polycyclic Aromatic Hydrocarbons are classed as Persistent Organic Pollutants, a large group of compounds that share similar characteristics. They are lipophilic, resistant to degradation in the environment and harmful to human and environmental health. Soil has been identified as the primary reservoir for Polycyclic Aromatic Hydrocarbons in the United Kingdom. This study reviews the literature associated with, or is relevant to, the measurement and modelling of dermal absorption of Polycyclic Aromatic Hydrocarbons from soils. The literature illustrates the use of in vivo, in vitro and in silico methods from a wide variety of scientific disciplines including occupational and environmental exposure, medical, pharmaceutical and cosmetic research and associated mathematical modelling. The review identifies a number of practical shortcomings which must be addressed if dermal bioavailability tests are to be applied to laboratory analysis of contaminated soils for human health risk assessment

Readings in Advanced Pharmacokinetics

This book, “Readings in Advanced Pharmacokinetics - Theory, Methods and Applications”, covers up to date information and practical topics related to the study of drug pharmacokinetics in humans and in animals. The book is designed to offer scientists, clinicians and researchers a choice to logically build their knowledge in pharmacokinetics from basic concepts to advanced applications. This book is organized into two sections. The first section discusses advanced theories that include a wide range of topics; from bioequivalence studies, pharmacogenomics in relation to pharmacokinetics, computer based simulation concepts to drug interactions of herbal medicines and veterinary pharmacokinetics. The second section advances theory to practice offering several examples of methods and applications in advanced pharmacokinetics

Exploiting the Metabolism of the Gut Microbiome as a Vehicle for Targeted Drug Delivery to the Colon

The prevalence of colon-associated diseases has increased significantly over the past several decades, as evidenced by accumulated literature on conditions such as Crohn’s disease, irritable bowel syndrome, colorectal cancer, and ulcerative colitis. Developing therapeutics for these diseases is challenging due to physiological barriers of the colon, systemic side effects, and the intestinal environment. Therefore, in a search for novel methods to overcome some of these problems, researchers discovered that microbial metabolism by gut microbiotia offers a potential method for targeted drug delivery This overview highlights several drug delivery systems used to modulate the microbiota and improve colon-targeted drug delivery. This technology will be important in developing a new generation of therapies which harness the metabolism of the human gut microflora

Population pharmacokinetic modelling to address the gaps in knowledge of commonly used HIV and TB drugs in children

The epidemiology of HIV and TB are overlapping, particularly in sub-Saharan Africa, and TB infection remains common in HIV-positive children. The combined administration of anti-tubercular and antiretroviral therapies(ART) may lead to drug-drug interactions potentially needing to be addressed with the adjustment of doses. This thesis assessed the pharmacokinetics of abacavir and ethambutol and evaluated the influence of covariates such as age and concomitant medication on the PK parameters across different studies using nonlinear mixed-effects modelling. The models developed were used to estimate area under the concentration-time curve (AUC) and maximum concentrations (Cmax) achieved with the currently-recommended weight-adjusted doses. A web-based paediatric dosing tool, which is meant to be used as a first step in the design of clinical trials for paediatric dosing was also developed. The model describing the pharmacokinetics of abacavir found: a) abacavir exposure to be 18.4% larger (CI:7.50-32.2) after the first dose of ART compared to abacavir co-treated with standard lopinavir/ritonavir for over 7 days, possibly indicating that clearance is induced with time on ART, b) malnourished HIV infected children had much higher exposures but this effect waned with a half-life of 12.2 (CI: 9.87-16.8) days as children stayed on nutritional rehabilitation and recovered, c). during co-administration of rifampicin-containing antituberculosis treatment and super-boosted lopinavir/ritonavir, abacavir exposure was decreased by 29.4% (CI: 24.3-35.8), d) children receiving efavirenz had 12.1% (CI: 2.57-20.1) increased abacavir clearance compared to standard lopinavir/ritonavir. The effects did not result in abacavir exposures lower or higher than those reported in adults and are not likely to be clinically important. The ethambutol model found lower concentrations than those reported in adults. The predicted ethambutol median (IQR) Cmax was 1.66 (1.21-2.15) mg/L for children on ethambutol with or without ART (excluding super-boosted lopinavir/ritonavir) and 0.882 (0.669-1.28) mg/L for children on ethambutol with super-boosted lopinavir/ritonavir, these are below the lower limit of the recommended Cmax range of 2 mg/L. During co-administration with super-boosted lopinavir, ethambutol exposure was decreased by 32% (CI: 23.8-38.9), likely due to drug-drug interaction involving absorption, metabolism or elimination. Bioavailability was decreased in children who were administered ethambutol in a crushed form, with an estimate decrease of 30.8% at birth, and an increase of 9.6% for each year of age up to 3.2 years where bioavailability was now similar to children taking EMB full tablet. The developed paediatric dosing tool contains two major sections. a) the ‘generic module’ which uses allometric scaling -based predictions to explore the expected AUC for a generic drug, b) the ‘drug-specific module’ which can simulate entire pharmacokinetic profiles (concentration over time after dose) by using a drug-specific population pharmacokinetic model. In summary, under the current weight-adjusted doses, abacavir exposure remained within the adult recommended levels. Ethambutol dose adjustment would be required in order to achieve adult exposures. A web-based paediatric dosing tool that uses allometric scaling -based predictions as well as drug specific predictions based on published pharmacokinetic models was successfully developed