A high-throughput micro-scale workflow to quantify molecularly dissolved drug concentrations under solubilizing conditions.

Physiological and artificial solubilizing agents usually enhance apparent solubility of poorly soluble drugs, and in many cases also oral drug exposure. However, exposure may decrease in cases where micellization reduces the molecularly dissolved drug fraction, overriding the solubility advantage. While this information is critical to accurately anticipate the effect of drug micellization on oral absorption, the experimental determination of molecularly dissolved drug concentrations is complex and time consuming.

Using molecularly dissolved drug concentrations in PBBMs improves the prediction of oral absorption from supersaturating formulations.

Predicting the absorption of drugs from enabling formulations is still challenging due to the limited capabilities of standard physiologically based biopharmaceutics models (PBBMs) to capture complex absorption processes. Amongst others, it is often assumed that both, molecularly and apparently dissolved drug in the gastrointestinal lumen are prone to absorption. A recently introduced method for measuring concentrations of molecularly dissolved drug in a dynamic in vitro dissolution setup using microdialysis has opened new opportunities to test this hypothesis and refine mechanistic PBBM approaches.

Combining in vitro dissolution/permeation with microdialysis sampling: Capabilities and limitations for biopharmaceutical assessments of supersaturating drug formulations.

Many novel small drug molecules are poorly water-soluble and thus, enabling drug formulations may be required to ensure sufficient absorption upon oral administration. Biopharmaceutical assessment and absorption prediction of enabling formulations, however, remains challenging. Combined in vitro dissolution/permeation (D/P) assays have gained increasing interest since they may provide a more realistic formulation ranking based on the drug permeation profiles from different formulations as compared to conventional dissolution, which captures both readily permeable and not readily permeable fractions of "dissolved" drug.

Discovery of Novel Allosteric EGFR L858R Inhibitors for the Treatment of Non-Small-Cell Lung Cancer as a Single Agent or in Combination with Osimertinib.

Addressing resistance to third-generation EGFR TKIs such as osimertinib via the EGFR mutation remains a highly unmet need in EGFR-driven non-small-cell lung cancer (NSCLC). Herein, we present the discovery of the allosteric EGFR inhibitor , a novel fourth-generation inhibitor to overcome EGFR-mediated resistance in patients harboring the activating EGFR mutation. exhibits an improved potency compared to previous allosteric EGFR inhibitors.

Biopredictive capability assessment of two dissolution/permeation assays, µFLUX™ and PermeaLoop™, using supersaturating formulations of Posaconazole.

The majority of new drug entities exhibits poor water solubility and therefore enabling formulations are often needed to ensure sufficient in vivo bioavailability upon oral administration. Several in vitro tools have been proposed for biopredictive screening of such drug formulations to facilitate formulation development. Among these, combined dissolution/permeation (D/P) assays have gained increasing interest in recent years, since they are presumed to better predict the absorption behavior as compared to single-compartment dissolution assays.

Chemical, Analytical and Pharmacokinetic Characterisation of RO7304898, an API Consisting of Two Rapidly Interconverting Diastereoisomers.

Purpose: Exploration of the chemical, analytical and pharmacokinetic properties of the API, RO7304898, an allosteric EGFR inhibitor, intended to be developed as a mixture of two rapidly interconverting diastereoisomers with composition ratio of approximately 1:1.

Methods: Assessment of diastereoisomer stereochemistry, interconversion rates, binding to EGFR protein, metabolic stability and in vivo PK in Wistar-Han rats was conducted.

Results: The two diastereoisomers of the API undergo fast interconversion at physiologically relevant pH and direct EGFR binding studies revealed diastereoisomer B to be the active moiety.

Microdialysis and nanofiltration allow to distinguish molecularly dissolved from colloid-associated drug concentrations during biomimetic dissolution testing of supersaturating formulations.

Many new drug entities are poorly water-soluble and thus require solubility-enhancing formulations to ensure sufficient bioavailability. On the other hand, it is more and more accepted that not all "dissolved" states of a drug contribute equally to enhanced absorption, i.e.

Preclinical Characterization of a Next-Generation Brain Permeable, Paradox Breaker BRAF Inhibitor.

Purpose: Disease progression in BRAF V600E/K positive melanomas to approved BRAF/MEK inhibitor therapies is associated with the development of resistance mediated by RAF dimer inducing mechanisms. Moreover, progressing disease after BRAFi/MEKi frequently involves brain metastasis. Here we present the development of a novel BRAF inhibitor (Compound Ia) designed to address the limitations of available BRAFi/MEKi.

Fundamental aspects of DMPK optimization of targeted protein degraders.

Targeted protein degraders are an emerging modality. Their properties fall outside the traditional small-molecule property space and are in the 'beyond rule of 5' space. Consequently, drug discovery programs focused on developing orally bioavailable degraders are expected to face complex drug metabolism and pharmacokinetics (DMPK) challenges compared with traditional small molecules.

Development of a Unified Dissolution and Precipitation Model and Its Use for the Prediction of Oral Drug Absorption.

Drug absorption is a complex process involving dissolution and precipitation, along with other kinetic processes. The purpose of this work was to (1) establish an in vitro methodology to study dissolution and precipitation in early stages of drug development where low compound consumption and high throughput are necessary, (2) develop a mathematical model for a mechanistic explanation of generated in vitro dissolution and precipitation data, and (3) extrapolate in vitro data to in vivo situations using physiologically based models to predict oral drug absorption. Small-scale pH-shift studies were performed in biorelevant media to monitor the precipitation of a set of poorly soluble weak bases.

Interactions between iron(III)-hydroxide polymaltose complex and commonly used drugs / simulations and in vitro studies.

Under physiological conditions, ferric ions are essentially insoluble because of the formation of polynuclear hydroxo-bridged complexes. Ferrous ions are more soluble but may produce hydroxyl radicals on reaction with hydrogen peroxide. Chelation of ferric and ferrous ions with organic ligands may prevent these undesirable reactions.