Towards the understanding of the IVPT results variability-Development, verification and validation of the PBPK model of caffeine in vitro human skin permeation.

In the context of evaluating the safety and efficacy of dermal products, pharmacokinetic (PK) studies face considerable challenges, particularly concerning topically applied formulations. This underscores the necessity for alternative methods, such as in vitro permeation tests (IVPT) and physiologically based pharmacokinetic (PBPK) modelling, to better understand the dermal pharmacokinetics of a product. The purpose of this study was to modify, verify, and validate the PBPK model of caffeine permeation through human skin previously developed by Patel et al.

Mechanistic Model for Drug Release from PLGA-Based Biodegradable Implants for Release Testing: Development and Validation.

Several factors can affect drug release from polylactide coglycolide (PLGA)-based formulations, including polymer and drug properties, formulation components, manufacturing processes, and environmental or conditions. To achieve optimal release profiles for specific drug delivery applications, it is crucial to understand the mechanistic processes that determine drug release from PLGA-based formulations. In the current study, we developed a mechanistic model for the drug release of PLGA-based solid implants.

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.

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.

How PBPK Can Help to Understand Old Drugs and Inform their Dosing in Elderly: Amantadine Case Study.

Amantadine, despite being on the market for 55 years, has several unknown aspects of its pharmacokinetics especially related to the influence of covariates such as age, disease, or interactions linked to amantadine's renal elimination. As amantadine is used in Parkinson's disease and is considered a potential candidate in COVID treatment and other diseases, there is an unmet need for thorough understanding of its pharmacokinetic in special populations, such as the elderly. We aimed to mechanistically describe amantadine pharmacokinetics in healthy subjects and shed some light on the differences in drug behavior between healthy volunteers (18-65 years) and an elderly/geriatric population (65-98 years) using PBPK modeling and simulation.

Dataset of in vitro measured chemicals neurotoxicity.

To understand and describe neurotoxicity mechanistically, we must first understand the processes and responses that occur within neuronal cell systems after the administration of a chemical. The dataset we present is a collection of experimental results from the literature that comprises various neurotoxic endpoints in human-derived in vitro models, allowing for easy data analysis. Currently available and free databases such as the EPA's ToxCast, which focuses on forecasting toxic health risks, are created by collecting reports on cytotoxicity testing and creating mathematical fits that could help predict the effects of a given chemical on various types of cells.

Simulation of the Fasted Gastric Conditions and Their Variability to Elucidate Contrasting Properties of the Marketed Dabigatran Etexilate Pellet-Filled Capsules and Loose Pellets.

Variability of the gastrointestinal tract is rarely reflected in test protocols but often turns out to be crucial for the oral dosage form performance. In this study, we present a generation method of dissolution profiles accounting for the variability of fasted gastric conditions. The workflow featured 20 biopredictive tests within the physiological variability.

Development and verification of mechanistic vaginal absorption and metabolism model to predict systemic exposure after vaginal ring and gel application.

Aims: The current work describes the development of mechanistic vaginal absorption and metabolism model within Simcyp Simulator to predict systemic concentrations following vaginal application of ring and gel formulations.

Methods: Vaginal and cervix physiology parameters were incorporated in the model development. The study highlights the model assumptions including simulation results comparing systemic concentrations of 5 different compounds, namely, dapivirine, tenofovir, lidocaine, ethinylestradiol and etonogestrel, administered as vaginal ring or gel.

Can 3D Printed Tablets Be Bioequivalent and How to Test It: A PBPK Model Based Virtual Bioequivalence Study for Ropinirole Modified Release Tablets.

As the field of personalized dosing develops, the pharmaceutical manufacturing industry needs to offer flexibility in terms of tailoring the drug release and strength to the individual patient's needs. One of the promising tools which have such capacity is 3D printing technology. However, manufacturing small batches of drugs for each patient might lead to huge test burden, including the need to conduct bioequivalence trials of formulations to support the change of equipment or strength.

Applications of Modeling and Simulation Approaches in Support of Drug Product Development of Oral Dosage Forms and Locally Acting Drug Products: a Symposium Summary.

The number of modeling and simulation applications, including physiologically based pharmacokinetic (PBPK) models, physiologically based biopharmaceutics modeling (PBBM), and empirical models, has been constantly increasing along with the regulatory acceptance of these methodologies. While aiming at minimizing unnecessary human testing, these methodologies are used today to support the development and approval of novel drug products and generics. Modeling approaches are leveraged today for assessing drug-drug interaction, informing dose adjustments in renally or hepatically impaired patients, perform dose selection in pediatrics and pregnant women and diseased populations, and conduct biopharmaceutics-related assessments such as establish clinically relevant specifications for drug products and achieve quality assurance throughout the product life cycle.

A Rational Approach to Predicting Immediate Release Formulation Behavior in Multiple Gastric Motility Patterns: A Combination of a Biorelevant Apparatus, Design of Experiments, and Machine Learning.

Gastric mechanical stress often impacts drug dissolution from solid oral dosage forms, but in vitro experiments cannot recreate the substantial variability of gastric motility in a reasonable time. This study, for the first time, combines a novel dissolution apparatus with the design of experiments (DoE) and machine learning (ML) to overcome this obstacle. The workflow involves the testing of soft gelatin capsules in a set of fasted-state biorelevant dissolution experiments created with DoE.

3D printing combined with biopredictive dissolution and PBPK/PD modeling optimization and personalization of pharmacotherapy: Are we there yet?

Precision medicine requires selecting the appropriate dosage regimen for a patient using the right drug, at the right time. Model-Informed Precision Dosing (MIPD) is a concept suggesting utilization of model-based prediction methods for optimizing the treatment benefit-harm balance, based on individual characteristics of the patient, disease, treatment method, and other factors. Here, we discuss a theoretical workflow comprising several elements, beginning from the physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) models, through 3D printed tablets with the model proposed dose, information range and flow, and the patient themselves.

A novel physiologically based pharmacokinetic model of rectal absorption, evaluated and verified using clinical data on 10 rectally administered drugs.

We present a physiologically based pharmacokinetic (PBPK) model simulating systemic drug concentrations following administration to the human rectum. Rectum physiology is parameterized based on literature data. The model utilizes in vitro release (IVRT) profiles from which drug mass transfer through the rectal fluid and tissue and into the systemic circulation are predicted.

Data on ADME parameters of bisphenol A and its metabolites for use in physiologically based pharmacokinetic modelling.

The paper presents the collection of physicochemical parameters of bisphenol A (BPA) and its sulfate (BPAS) and glucuronide (BPAG) conjugates, accompanied by data characterizing their absorption, distribution, metabolism and excretion (ADME) behavior following oral administration of BPA. The data were collected from open literature sources and publicly available databases. Additionally, data calculated by using the MarvinSketch 18.

Artificial Intelligence That Predicts Sensitizing Potential of Cosmetic Ingredients with Accuracy Comparable to Animal and In Vitro Tests-How Does the Infotechnomics Compare to Other "Omics" in the Cosmetics Safety Assessment?

The aim of the current study was to develop an in silico model to predict the sensitizing potential of cosmetic ingredients based on their physicochemical characteristics and to compare the predictions with historical animal data and results from "omics"-based in vitro studies. An in silico model was developed with the use of WEKA machine learning software fed with physicochemical and structural descriptors of haptens and trained with data from published epidemiological studies compiled into estimated odds ratio (eOR) and estimated attributable risk (eAR) indices. The outcome classification was compared to the results of animal studies and in vitro tests.

In Vitro/In Vivo Translation of Synergistic Combination of MDM2 and MEK Inhibitors in Melanoma Using PBPK/PD Modelling: Part III.

The development of in vitro/in vivo translational methods and a clinical trial framework for synergistically acting drug combinations are needed to identify optimal therapeutic conditions with the most effective therapeutic strategies. We performed physiologically based pharmacokinetic-pharmacodynamic (PBPK/PD) modelling and virtual clinical trial simulations for siremadlin, trametinib, and their combination in a virtual representation of melanoma patients. In this study, we built PBPK/PD models based on data from in vitro absorption, distribution, metabolism, and excretion (ADME), and in vivo animals' pharmacokinetic-pharmacodynamic (PK/PD) and clinical data determined from the literature or estimated by the Simcyp simulator (version V21).

Physiologically based modelling of dermal absorption and kinetics of consumer-relevant chemicals: A case study with exposure to bisphenol A from thermal paper.

Bisphenol A (BPA) is one of the best studied industrial chemicals in terms of exposure, toxicity, and toxicokinetics. This renders it an ideal candidate to exploit the recent advancements in physiologically based pharmacokinetic (PBPK) modelling to support risk assessment of BPA specifically, and of other consumer-relevant hazardous chemicals in general. Using the exposure from thermal paper as a case scenario, this study employed the multi-phase multi-layer mechanistic dermal absorption (MPML MechDermA) model available in the Simcyp® Simulator to simulate the dermal toxicokinetics of BPA at local and systemic levels.

Mechanistic modeling of drug products applied to the skin: A workshop summary report.

The development of a generic drug product involves demonstrating that there is no significant difference in the rate and extent to which the active ingredient becomes available at the site of action, relative to the reference listed drug product. This remains challenging for many locally acting topical dermatological products because measuring the concentration of the active ingredient at the site of action in the skin may not be straightforward, and, in most instances, there are no established relationships between skin and plasma pharmacokinetic profiles. In recent years, the Office of Generic Drugs of the US Food and Drug Administration (FDA) established scientific research programs with the goal of enhancing patient access to high quality, affordable topical dermatological generics.

In Vitro/In Vivo Translation of Synergistic Combination of MDM2 and MEK Inhibitors in Melanoma Using PBPK/PD Modelling: Part I.

Translation of the synergy between the Siremadlin (MDM2 inhibitor) and Trametinib (MEK inhibitor) combination observed in vitro into in vivo synergistic efficacy in melanoma requires estimation of the interaction between these molecules at the pharmacokinetic (PK) and pharmacodynamic (PD) levels. The cytotoxicity of the Siremadlin and Trametinib combination was evaluated in vitro in melanoma A375 cells with MTS and RealTime-Glo assays. Analysis of the drug combination matrix was performed using Synergy and Synergyfinder packages.

In Vitro/In Vivo Translation of Synergistic Combination of MDM2 and MEK Inhibitors in Melanoma Using PBPK/PD Modelling: Part II.

The development of in vitro/in vivo translational methods for synergistically acting drug combinations is needed to identify the most effective therapeutic strategies. We performed PBPK/PD modelling for siremadlin, trametinib, and their combination at various dose levels and dosing schedules in an A375 xenografted mouse model (melanoma cells). In this study, we built models based on in vitro ADME and in vivo PK/PD data determined from the literature or estimated by the Simcyp Animal simulator (V21).

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.

Utilization of mechanistic modelling and simulation to analyse fenspiride proarrhythmic potency - Role of physiological and other non-drug related parameters.

What Is Known And Objective: Fenspiride, a drug that had been used for decades for the treatment of respiratory diseases, was recently withdrawn from the market due to the potential risk of QT prolongation and proarrhythmia. This is the first such withdrawal for many years and hence poses a question whether such risk could have been predicted and to what degree non-drug-specific parameters play a role in the reported QT prolongation and cases of TdP. The study aim was to test various 'what-if' scenarios to assess the influence of age, gender, heart rate, and plasma potassium concentration on QT interval prolongation due to various doses of fenspiride with the use of mechanistic mathematical modelling.

Modelling and simulation approaches to support formulation optimization, clinical development and regulatory assessment of the topically applied formulations - Nimesulide solution gel case study.

The objective of the study was to show how mechanistic modelling can be used to characterize the skin absorption of Nimesulide (NIM) in both in vitro systems and in vivo subjects. A basic PBPK model for oral absorption to characterize the systemic disposition of NIM and MPML MechDermA models for in vitro permeation and in vivo, topical absorption was developed and verified using published data. The developed models utilize drug physicochemical properties, formulation attributes and physiology information either collected from literature and/or from Simcyp databases (systems' data).

Mechanistic Modeling of In Vitro Skin Permeation and Extrapolation to In Vivo for Topically Applied Metronidazole Drug Products Using a Physiologically Based Pharmacokinetic Model.

Physiologically based pharmacokinetic (PBPK) modeling has increasingly been employed in dermal drug development and regulatory assessment, providing a framework to integrate relevant information including drug and drug product attributes, skin physiology parameters, and population variability. The current study aimed to develop a stepwise modeling workflow with knowledge gained from modeling in vitro skin permeation testing (IVPT) to describe in vivo exposure of metronidazole locally in the stratum corneum following topical application of complex semisolid drug products. The initial PBPK model of metronidazole in vitro skin permeation was developed using infinite and finite dose aqueous metronidazole solution.

Quality Control Dissolution Data Is Biopredictive for a Modified Release Ropinirole Formulation: Virtual Experiment with the Use of Re-Developed and Verified PBPK Model.

Physiologically based pharmacokinetic and absorption modeling are being used by industry and regulatory bodies to address various scientifically challenging questions. While there is high confidence in the prediction of exposure for the BCS class I drugs administered as immediate-release formulations, in the case of prolonged-release formulations, special attention should be given to the input dissolution data. Our goal was to develop and verify a PBPK model for a BCS class I compound, ropinirole, and check the biopredictiveness of the dissolution data for the prolonged-release formulation administered by Parkinson's patients.