Physiologically-based pharmacokinetic model of in vitro porcine ear skin permeation for drug delivery research.

In silico techniques, such as physiologically based pharmacokinetic modeling (PBKP), are recently gaining importance. Computational methods in drug discovery and development and the generic drugs industry enhance research effectiveness by saving time and money and avoiding ethical issues. One key advantage is the ability to conduct toxicology studies without risking harm to living beings. This study aimed to repurpose the multi-phase multi-layer mechanistic dermal absorption (MPML MechDermA) PBPK model for simulation permeation through porcine ear skin under in vitro conditions. The work was divided into four steps: (1) the development of a pig ear skin model based on a previously collected dataset; (2) testing the model's ability to discriminate permeation between pig ear, human abdomen, and human back skin; (3) development of a caffeine permeation model; and (4) testing the caffeine model's performance against in vitro generated data sourced from the scientific literature. Data from 31 manuscripts were used for the development of the pig skin model. Based on these data, values specific to pig skin were found for 22 parameters of the MPML MechDermA model. The model was able to discriminate permeation between pig and human skin. A caffeine model was developed and used to simulate seven experiments identified in the literature. The model's performance was assessed by comparing simulated to observed results. Based on a visual check, all simulations were considered acceptable, whereas three out of seven experiments met the twofold difference criterion. The variability of the experimental data was considered the biggest challenge for reliable model assessment.

Data set of fraction unbound values in the in vitro incubations for metabolic studies for better prediction of human clearance.

In vitro-in vivo extrapolation is a commonly applied technique for liver clearance prediction. Various in vitro models are available such as hepatocytes, human liver microsomes, or recombinant cytochromes P450. According to the free drug theory, only the unbound fraction (fu) of a chemical can undergo metabolic changes. Therefore, to ensure the reliability of predictions, both specific and nonspecific binding in the model should be accounted. However, the fraction unbound in the experiment is often not reported. The study aimed to provide a detailed repository of the literature data on the compound's fu value in various in vitro systems used for drug metabolism evaluation and corresponding human plasma binding levels. Data on the free fraction in plasma and different in vitro models were supplemented with the following information: the experimental method used for the assessment of the degree of drug binding, protein or cell concentration in the incubation, and other experimental conditions, if different from the standard ones, species, reference to the source publication, and the author's name and date of publication. In total, we collected 129 literature studies on 1425 different compounds. The provided data set can be used as a reference for scientists involved in pharmacokinetic/physiologically based pharmacokinetic modelling as well as researchers interested in Quantitative Structure-Activity Relationship models for the prediction of fraction unbound based on compound structure. Database URL: https://data.mendeley.com/datasets/3bs5526htd/1.

An open-access data set of pig skin anatomy and physiology for modelling purposes.

The use of animal as opposed to human skin for in vitro permeation testing (IVPT) is an alternative, which can reduce logistical and economic issues. However, this surrogate also has ethical considerations and may not provide an accurate estimation of dermal absorption in humans due to physiological differences. The current project aimed to provide a detailed repository for the anatomical and physiological parameters of porcine skin, with the aim of parametrizing the Multi-phase Multi-layer Mechanistic Dermal Absorption (MPML MechDermA) Model in the Simcyp Simulator. The MPML MechDermA Model is a physiologically based pharmacokinetic (PBPK) model that accounts for the physiology and geometry of skin in a mechanistic mathematical modelling framework. The database provided herein contains information on 14 parameters related to porcine skin anatomy and physiology, namely, skin surface pH, number of stratum corneum (SC) layers, SC thickness, corneocyte thickness, corneocyte dimensions (length and width), volume fraction of water in corneocyte (where SC is divided into four parts with different water contents), intercellular lipid thickness, viable epidermis thickness, dermis thickness, hair follicle and hair shaft diameter, hair follicle depth and hair follicle density. The collected parameters can be used to parameterize PBPK models, which could be further utilized to bridge the gap between animal and human studies with interspecies extrapolation or to predict dermatokinetic properties typically assessed in IVPT experiments. Database URL: https://data.mendeley.com/datasets/mwz9xv4cpd/1.

Open-access database of literature derived drug-related Torsade de Pointes cases.

Since an introduction of an ICH guidance in 2005, no new drugs were withdrawn from the market because of the causation of Torsade de Pointes (TdP). However, the risk of TdP is still a concern for marketed drugs. TdP is a type of polymorphic ventricular tachycardia which may lead to sudden cardiac death. QT/QTc interval prolongation is considered a sensitive, but not specific biomarker. To improve the effectiveness of studies' workflow related to TdP risk prediction we created an extensive, structured, open-access database of drug-related TdP cases. PubMed, Google Scholar bibliographic databases, and the Internet, via the Google search engine, were searched to identify eligible reports. A total of 424 papers with a description of 634 case reports and observational studies were included. Each paper was manually examined and listed with up to 53 variables related to patient/population characteristics, general health parameters, used drugs, laboratory measurements, ECG results, clinical management, and its outcomes, as well as suspected drug's properties and its FDA adverse reaction reports. The presented database may be considered as an extension of the recently developed and published database of drug cardiac safety-related information, part of the tox-portal project providing resources for cardiac toxicity assessment.