Gastrointestinal Bile Salt Concentrations in Healthy Adults Under Fasted and Fed Conditions: A Systematic Review and Meta-Analysis for Mechanistic Physiologically-Based Pharmacokinetic (PBPK) Modelling.

Bile salts are biosurfactants released into the intestinal lumen which play an important role in the solubilisation of fats and certain drugs. Their concentrations vary along the gastrointestinal tract (GIT). This is significant for implementation in physiologically based pharmacokinetic (PBPK) modelling to mechanistically capture drug absorption.

Optically Transparent Lead Halide Perovskite Polycrystalline Ceramics.

We utilize room-temperature uniaxial pressing at applied loads achievable with low-cost, laboratory-scale presses to fabricate freestanding CHNHPbX (X = Br, Cl) polycrystalline ceramics with millimeter thicknesses and optical transparency up to ∼70% in the infrared. As-fabricated perovskite ceramics can be produced with desirable form factors (i.e.

Physiologically Based Biopharmaceutics Model (PBBM) of Minimally Absorbed Locally Acting Drugs in the Gastrointestinal Tract-Case Study: Tenapanor.

A physiologically based biopharmaceutics model (PBBM) was developed to predict stool and urine sodium content in response to tenapanor administration in healthy subjects. Tenapanor is a minimally absorbed small molecule that inhibits the sodium/hydrogen isoform 3 exchanger (NHE3). It is used to treat irritable bowel syndrome with constipation (IBS-C).

Assessing Dose-Exposure-Response Relationships of Miltefosine in Adults and Children using Physiologically-Based Pharmacokinetic Modeling Approach.

Objectives: Miltefosine is the first and only oral medication to be successfully utilized as an antileishmanial agent. However, the drug is associated with differences in exposure patterns and cure rates among different population groups e.g.

Leveraging the use of in vitro and computational methods to support the development of enabling oral drug products: An InPharma commentary.

Due to the strong tendency towards poorly soluble drugs in modern development pipelines, enabling drug formulations such as amorphous solid dispersions, cyclodextrins, co-crystals and lipid-based formulations are frequently applied to solubilize or generate supersaturation in gastrointestinal fluids, thus enhancing oral drug absorption. Although many innovative in vitro and in silico tools have been introduced in recent years to aid development of enabling formulations, significant knowledge gaps still exist with respect to how best to implement them. As a result, the development strategy for enabling formulations varies considerably within the industry and many elements of empiricism remain.

Physiologically based pharmacokinetic modeling for development and applications of a virtual celiac disease population using felodipine as a model drug.

In celiac disease (CeD), gastrointestinal CYP3A4 abundance and morphology is affected by the severity of disease. Therefore, exposure to CYP3A4 substrates and extent of drug interactions is altered. A physiologically-based pharmacokinetic (PBPK) population for different severities of CeD was developed.

Non-specific binding of compounds in metabolism assays: a comparison of microsomal and hepatocyte binding in different species and an assessment of the accuracy of prediction models.

Non-specific binding in metabolism systems leads to an underestimation of the true intrinsic metabolic clearance of compounds being studied. Therefore binding needs to be accounted for when extrapolating data to predict the metabolic clearance of a compound. While techniques exist for experimentally determining the fraction of a compound unbound in metabolism systems, early in drug discovery programmes computational approaches are often used to estimate the binding in the system.

Developing Clinically Relevant Dissolution Specifications (CRDSs) for Oral Drug Products: Virtual Webinar Series.

A webinar series that was organised by the Academy of Pharmaceutical Sciences Biopharmaceutics focus group in 2021 focused on the challenges of developing clinically relevant dissolution specifications (CRDSs) for oral drug products. Industrial scientists, together with regulatory and academic scientists, came together through a series of six webinars, to discuss progress in the field, emerging trends, and areas for continued collaboration and harmonisation. Each webinar also hosted a Q&A session where participants could discuss the shared topic and information.

A Mechanistic Absorption and Disposition Model of Ritonavir to Predict Exposure and Drug-Drug Interaction Potential of CYP3A4/5 and CYP2D6 Substrates.

Background And Objectives: Due to health authority warnings and the recommended limited use of ketoconazole as a model inhibitor of cytochrome P450 (CYP) 3A4 in clinical drug-drug interaction (DDI) studies, there is a need to search for alternatives. Ritonavir is a strong inhibitor for CYP3A4/5-mediated DDIs and has been proposed as a suitable alternative to ketoconazole. It can also be used as a weak inhibitor for CYP2D6-mediated DDIs.

Artemisinin Cocrystals for Bioavailability Enhancement. Part 2: Bioavailability and Physiologically Based Pharmacokinetic Modeling.

We report the evaluation and prediction of the pharmacokinetic (PK) performance of artemisinin (ART) cocrystal formulations, that is, 1:1 artemisinin/orcinol (ART-ORC) and 2:1 artemisinin/resorcinol (ART-RES), using murine animal and physiologically based pharmacokinetic (PBPK) models. The efficacy of the ART cocrystal formulations along with the parent drug ART was tested in mice infected with . When given at the same dose, the ART cocrystal formulation showed a significant reduction in parasitaemia at day 4 after infection compared to ART alone.

Mechanistic PBPK Modelling to Predict the Advantage of the Salt Form of a Drug When Dosed with Acid Reducing Agents.

Acid reducing agents (ARAs) reduce the dissolution rate of weakly basic drugs in the stomach potentially leading to lower bioavailability. Formulating the API as a rapidly dissolving salt is one strategy employed to reduce the impact of ARAs on dissolution of such drugs. In the present work, a model drug was selected with an immediate release formulation of the free base dosed in both the absence and presence of the ARA famotidine.

Current status and future opportunities for incorporation of dissolution data in PBPK modeling for pharmaceutical development and regulatory applications: OrBiTo consortium commentary.

In vitro dissolution experiments are used to qualitatively assess the impact of formulation composition and process changes on the drug dosage form performance. However, the use of dissolution data to quantitatively predict changes in the absorption profile remains limited. Physiologically-based Pharmacokinetic(s) (PBPK) models facilitate incorporation of in vitro dissolution experiments into mechanistic oral absorption models to predict in vivo oral formulation performance, and verify if the drug product dissolution method is biopredictive or clinically relevant.

Biopharmaceutic Extrapolation (IVIV_E) Informed Physiologically-Based Pharmacokinetic Model of Ritonavir Norvir Tablet Absorption in Humans Under Fasted and Fed State Conditions.

Ritonavir is a well-known CYP3A4 and CYP2D6 enzyme inhibitor, frequently used to assess the drug-drug interaction (DDI) liability of susceptible drugs. It is also used as a pharmacokinetic booster to increase exposure to CYP3A4 substrates. This study aimed to develop a mechanistic absorption and disposition model to describe exposure to ritonavir following oral dosing of the commercial amorphous solid dispersion tablet, Norvir, under fasted and fed conditions.

Population-Based PBPK Model for the Prediction of Time-Variant Bile Salt Disposition within GI Luminal Fluids.

In vivo studies have shown cyclic bile salt (BS) outputs during fasting whereas higher amounts have been observed in fed states. This leads to fluctuations of intestinal BS concentrations ([BS]) that can affect the rate and extent of absorption of lipophilic drugs in particular. However, most PBPK models use fixed values of [BS] in fasted and fed states albeit with different values in different regions of the GI tract.

Combining biorelevant in vitro and in silico tools to investigate the in vivo performance of the amorphous solid dispersion formulation of etravirine in the fed state.

Introduction: In the development of bio-enabling formulations, innovative in vivo predictive tools to understand and predict the in vivo performance of such formulations are needed. Etravirine, a non-nucleoside reverse transcriptase inhibitor, is currently marketed as an amorphous solid dispersion (Intelence® tablets). The aims of this study were 1) to investigate and discuss the advantages of using biorelevant in vitro setups to simulate the in vivo performance of Intelence® 100 mg and 200 mg tablets in the fed state, 2) to build a Physiologically Based Pharmacokinetic (PBPK) model by combining experimental data and literature information with the commercially available in silico software Simcyp® Simulator V17.

Establishing virtual bioequivalence and clinically relevant specifications using in vitro biorelevant dissolution testing and physiologically-based population pharmacokinetic modeling. case example: Naproxen.

Background: Physiologically-based population pharmacokinetic modeling (popPBPK) coupled with in vitro biopharmaceutics tools such as biorelevant dissolution testing can serve as a powerful tool to establish virtual bioequivalence and set clinically relevant specifications. One of several applications of popPBPK modeling is in the emerging field of virtual bioequivalence (VBE), where it can be used to streamline drug development by implementing model-informed formulation design and to inform regulatory decision-making e.g.

Combining biorelevant in vitro and in silico tools to simulate and better understand the in vivo performance of a nano-sized formulation of aprepitant in the fasted and fed states.

Introduction: When developing bio-enabling formulations, innovative tools are required to understand and predict in vivo performance and may facilitate approval by regulatory authorities. EMEND® is an example of such a formulation, in which the active pharmaceutical ingredient, aprepitant, is nano-sized. The aims of this study were 1) to characterize the 80 mg and 125 mg EMEND® capsules in vitro using biorelevant tools, 2) to develop and parameterize a physiologically based pharmacokinetic (PBPK) model to simulate and better understand the in vivo performance of EMEND® capsules and 3) to assess which parameters primarily influence the in vivo performance of this formulation across the therapeutic dose range.

Danazol oral absorption modelling in the fasted dog: An example of mechanistic understanding of formulation effects on drug pharmacokinetics.

Oral bioavailability of poorly water soluble (BCS II) drugs like danazol can be minimal without the necessary formulation strategies. Availability of in vitro physicochemical and in vivo pharmacokinetic studies can be valuable when designing these strategies but cannot reveal the drug-formulation-gastrointestinal physiology interplay that impact the successful optimization of intestinal solubilization and resulting oral drug absorption. In silico mechanistic oral drug absorption models can serve as a tool for providing this important perspective and for integrating information generated across various in vivo and in vitro studies.

Biopharmaceutic IVIVE-Mechanistic Modeling of Single- and Two-Phase In Vitro Experiments to Obtain Drug-Specific Parameters for Incorporation Into PBPK Models.

The physiological relevance of single-phase (aqueous only) and 2-phase (aqueous and organic phase) in vitro dissolution experiments was compared by mechanistic modeling. For orally dosed dipyridamole, stepwise, sequential estimation/confirmation of biopharmaceutical parameters from in vitro solubility-dissolution data was followed, before applying them within a physiologically based pharmacokinetic (PBPK) model. The PBPK model predicted clinical dipyridamole luminal and plasma concentration profiles reasonably well for a range of doses only where the precipitation rate constant was derived from the 2-phase experiment.

In Silico Modeling Approach for the Evaluation of Gastrointestinal Dissolution, Supersaturation, and Precipitation of Posaconazole.

The aim of this study was to evaluate gastrointestinal (GI) dissolution, supersaturation, and precipitation of posaconazole, formulated as an acidified (pH 1.6) and neutral (pH 7.1) suspension.

Model-Based Analysis of Biopharmaceutic Experiments To Improve Mechanistic Oral Absorption Modeling: An Integrated in Vitro in Vivo Extrapolation Perspective Using Ketoconazole as a Model Drug.

Mechanistic modeling of in vitro data generated from metabolic enzyme systems (viz., liver microsomes, hepatocytes, rCYP enzymes, etc.) facilitates in vitro-in vivo extrapolation (IVIV_E) of metabolic clearance which plays a key role in the successful prediction of clearance in vivo within physiologically-based pharmacokinetic (PBPK) modeling.

Incorporation of the Time-Varying Postprandial Increase in Splanchnic Blood Flow into a PBPK Model to Predict the Effect of Food on the Pharmacokinetics of Orally Administered High-Extraction Drugs.

Following a meal, a transient increase in splanchnic blood flow occurs that can result in increased exposure to orally administered high-extraction drugs. Typically, physiologically based pharmacokinetic (PBPK) models have incorporated this increase in blood flow as a time-invariant fed/fasted ratio, but this approach is unable to explain the extent of increased drug exposure. A model for the time-varying increase in splanchnic blood flow following a moderate- to high-calorie meal (TV-Q ) was developed to describe the observed data for healthy individuals.

The Constraints, Construction, and Verification of a Strain-Specific Physiologically Based Pharmacokinetic Rat Model.

The use of in vitro-in vivo extrapolation (IVIVE) techniques, mechanistically incorporated within physiologically based pharmacokinetic (PBPK) models, can harness in vitro drug data and enhance understanding of in vivo pharmacokinetics. This study's objective was to develop a user-friendly rat (250 g, male Sprague-Dawley) IVIVE-linked PBPK model. A 13-compartment PBPK model including mechanistic absorption models was developed, with required system data (anatomical, physiological, and relevant IVIVE scaling factors) collated from literature and analyzed.