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Pharmacokinetics of the interaction of icenticaftor (QBW251) with multiple substrates
No full textIcenticaftor (QBW251) is an orally administered potentiator of the cystic fibrosis transmembrane conductance regulator that is being developed as add-on therapy for the treatment of patients with chronic obstructive pulmonary disease and chronic bronchitis. A drug-drug interaction (DDI) study was conducted to evaluate the effect of icenticaftor on the pharmacokinetics (PK) of a 5 probe cytochrome P450 (CYP) substrate cocktail; this was guided by in vitro studies in human hepatocytes and liver microsomes. A second DDI study investigated the effect of icenticaftor on the PK and pharmacodynamics (PD) of a monophasic oral contraceptive (OC) containing ethinyl estradiol (EE) and levonorgestrel (LVG) in premenopausal healthy female subjects. The static mechanistic DDI assessment indicated that icenticaftor may induce the metabolic clearance of co-medications metabolized by CYP3A4 and potentially CYP2C; icenticaftor may also inhibit the metabolic clearance of co-medications metabolized by CYP1A2, CYP2B6, and CYP3A4/5. In the CYP substrate cocktail DDI study, icenticaftor 300 mg twice daily (b.i.d.) moderately inhibited CYP1A2 and CYP2C19. As expected from the results of the in vitro studies, weak induction was observed for CYP3A4 and CYP2C8. In the OC DDI study, co administration of icenticaftor 450 mg b.i.d. with monophasic OC containing 30 μg EE and 150 μg LVG once daily reduced the plasma exposure of both components by approximately 50% and led to increased levels of follicle-stimulating hormone and luteinizing hormone. These results provide valuable guidance for the use of icenticaftor in patients taking concomitant medications that are substrates of CYP enzymes or those using OCs
Protecting-Group-Free Mechanosynthesis of Amides from Hydroxycarboxylic Acids
No full textMechanochemical methods for assembling carbon-nitrogen bonds play a central role in the ongoing green chemistry-driven renovation of organic synthesis.However, there is a paucity of reports addressing chemoselective issues in these transformations, such as the tolerance of unmasked hydroxyl groups. Screening of various amide coupling conditions revealed 1 ethyl 3 (3 dimethylaminopropyl)carbodiimide (EDC) in combination with ethyl acetate as a liquid-assisted grinding (LAG) solvent as the most selective amide coupler, delivering 76–94% yields of the respective amide products from unprotected hydroxycarboxylic acids. Boc-protected tyrosine and serine with unmasked OH functionalities were successfully involved in peptide couplings
Identification of Acyl-Protein Thioesterase-1 as a Polysorbate-Degrading Host Cell Protein in a Monoclonal Antibody Formulation Using Activity-Based Protein Profiling
No full textPolysorbate (PS) degradation in monoclonal antibody (mAb) formulations poses a significant challenge in the biopharmaceutical industry. PS maintains protein stability during drug product's shelf life but is vulnerable to breakdown by low-abundance residual host cell proteins (HCPs), particularly hydrolytic enzymes such as lipases and esterases. In this study, we used activity-based protein profiling (ABPP) coupled with mass spectrometry to identify acyl-protein thioesterase-1 (APT-1) as a polysorbate-degrading HCP in one case of mAb formulation with stability problems. We validated the role of APT1 by matching the polysorbate degradation fingerprint in the mAb formulation with that of a recombinant APT1 protein. Furthermore, we found an agreement between APT1 levels and PS degradation rates in the mAb formulation, and we successfully halted PS degradation using APT1-specific inhibitors ML348 and ML211. APT1 was found to co-purify with a specific mAb via hitchhiking mechanism. Our work provides a streamlined approach to identifying critical HCPs in PS degradation, supporting quality-by-design principles in pharmaceutical development
Challenges for the Discovery of Non-Covalent WRN Helicase Inhibitors.
No full textThe Werner Syndrome RecQ helicase (WRN) is a synthetic lethal target of interest for the treatment of cancers with microsatellite instability (MSI). Different hit finding approaches were initially tested. The identification of WRN inhibitors proved challenging due to a high propensity for artefacts via protein interference, i. e., hits inhibiting WRN enzymatic activities through multiple, unspecific mechanisms. Previously published WRN Helicase inhibitors (ML216, NSC19630 or NSC617145) were characterized in an extensive set of biochemical and biophysical assays and could be ruled out as specific WRN helicase probes. More innovative screening strategies need to be developed for successful drug discovery of non-covalent WRN helicase inhibitors
The impact of earth-abundant metals as a replacement for Pd in cross coupling reactions
No full textSubstitution from one metal catalyst to another is not as straightforward and simply justified by the availability and/or cost of the metals. Extensive life cycle assessment was performed to that the commonly held view that use of earth-abundant metals, and mainly Ni, are replacements for palladium in cross coupling reactions, and Suzuki-Miyaura couplings, in particular an incomplete assessment of the entire picture. This notion unfortunately derives from the standpoint of cost, and to some degree, the relative natural abundance of each metal. However, a more realistic appreciation emerges when far more reaction parameters involved in the chemistry are considered. Such an analysis unequivocally points to the major impact on climate change brought on by use of organic solvents, while the metal itself may play a subordinate role. Clearly, this study reveals that various materials can contribute in various ways to the overall carbon footprint. Hence, a more detailed analysis is required
First-in-human safety, tolerability, and pharmacokinetic results of DFV890, an oral low-molecular-weight NLRP3 inhibitor.
No full textThis first-in-human study evaluated the safety, tolerability, single- and multiple-dose pharmacokinetic profiles with dietary influence, and pharmacodynamics (PD) of DFV890, an oral NLRP3 inhibitor, in healthy participants. In total, 122 participants were enrolled into a three-part trial including single and 2-week multiple ascending oral doses (SAD and MAD, respectively) of DFV890, and were randomized (3:1) to DFV890 or placebo (SAD [3-600 mg] and MAD [fasted: 10-200 mg, once-daily or fed: 25 and 50 mg, twice-daily]). DFV890 was generally well-tolerated. Neither deaths nor serious adverse events were reported. A less than dose-proportional increase in exposure was observed with the initially used crystalline suspension (3-300 mg); however, an adjusted suspension formulation using spray-dried dispersion (SDD; 100-600 mg) confirmed dose-proportional increase in exposure. Relative bioavailability between crystalline suspension and tablets, and food effect were evaluated at 100 mg. Under fasting conditions, Cmax of the tablet yielded 78% compared with the crystalline suspension, and both formulations showed comparable AUC. The fed condition led to a 2.05- and 1.49-fold increase in Cmax and AUC0-last compared with the fasting condition. The median IC50 and IC90 for ex-vivo lipopolysaccharide-stimulated interleukin IL-1β release inhibition (PD) were 61 (90% CI: 50, 70) and 1340 ng/mL (90% CI: 1190, 1490). Crystalline tablets of 100 mg once-daily or 25 mg twice-daily were sufficient to maintain ~90% of the IL-1β release inhibition over 24 h at steady state. Data support dose and formulation selection for further development in diseases, in which an overactivated NLRP3 represents the underlying pathophysiology
One-pot synthesis of substituted amides from nitriles under mild reaction conditions in aqueous surfactant TPGS-750-M
No full textA copper-catalyzed amide bond synthesis is described under micellar aqueous reaction conditions with THF as
co-solvent. By using commercially available copper iodide catalyst, various amides were efficiently obtained
from a wide range of nitriles and aryl iodides. Aryls, heterocycles, and aliphatic amides were obtained in
moderate to excellent yields. Through optimization of the parameters, the process showed to be simple, scalable,
and sustainable. A Scale-up to 2 kg was performed of the hydration reaction supporting an API intermediate
synthesis
A minimal metadata set (MNMS) to repurpose non-clinical in vivo data for biomedical research
No full textBiomedical research is experiencing a data explosion, yet the accumulation of vast
quantities of data alone does not guarantee a primary objective for science: building
upon existing knowledge. Data collections that lack appropriate metadata cannot be
fully interrogated or integrated into new research projects, leading to wasted resources
and missed opportunities for data repurposing. This issue is particularly acute for
research using animals, where concerns around data reproducibility and ensuring
animal welfare are paramount. To address this, we propose a minimal metadata set
(MNMS) designed to enable repurposing of in vivo data. MNMS builds into an existing
validated guideline for reporting in vivo data (ARRIVE 2.0) and contributes to making in
vivo data FAIR compliant. Scenarios where MNMS can be deployed in diverse
research environments are presented, highlighting opportunities and challenges for
data repurposing at different scales. We conclude with a ‘call for action’ to key
stakeholders in biomedical research to adopt and deploy MNMS to accelerate both the
advancement of knowledge and the betterment of animal welfare
Recovery Animals in Toxicology Studies: An Innovation and Quality Consortium Perspective on Best Practices With Case Study Examples.
No full textThe inclusion of recovery animals in nonclinical safety studies that support clinical trials is undertaken with a wide diversity of approaches even while operating under harmonized regulatory guidance. While empirical evaluation of reversibility may enhance the overall nonclinical risk assessment, there are often overlooked opportunities to reduce recovery animal use by leveraging robust scientific and regulatory information. In the past, there were several attempts to benchmark recovery practices; however, recommendations have not been consistently applied across the pharmaceutical industry. A working group (WG) sponsored by the 3Rs Translational and Predictive Sciences Leadership Group of the IQ Consortium conducted a survey of current industry practice related to the evaluation of reversibility/recovery in repeat dose toxicity studies. Discussion among the WG representatives included member company strategies and case studies that highlight challenges and opportunities for continuous refinements in the use of recovery animals. The case studies presented in this paper demonstrate increasing alignment with the Society of Toxicologic Pathology recommendations (2013) towards (1) excluding recovery phase cohorts by default (include only when scientifically justified), (2) minimizing the number of recovery groups (e.g., control and one dose level), and (3) excluding controls in the recovery cohort by leveraging external and/or dosing phase data. Recovery group exclusion and decisions regarding the timing of reversibility evaluation may be driven by indication, modality, and/or other scientific or strategic factors using a weight of evidence approach. The results and recommendations discussed present opportunities to further decrease animal use without impacting the quality of human risk assessment