AngioDynamics (United States)

ABSTRACTDespite significant investment, no effective disease‐modifying therapies for Alzheimer's disease (AD) have been developed to date. As understanding of the underlying causes of AD evolves, numerous animal models have been generated to study the disease. However, persistent therapeutic failures raise questions about the reasons for these shortcomings, including whether they stem from poor target selection and/or limitations in replicating key aspects of AD pathophysiology in animal models. In this study, a machine learning‐based workflow previously reported in the literature was modified and used to identify shared dysregulation in phenotype‐defining pathways across both animal models and human datasets—termed translatable pathways. This approach provided a framework for assessing the translational relevance of three widely used AD models: APP/PS1, 3×Tg, and 5×FAD, from hippocampal microarray data. The analysis suggested no translatable pathways in the APP/PS1 and 3×Tg preclinical models, whereas key pathways were identified in the 5×FAD (SREBP control of lipid synthesis and cytotoxic T‐lymphocyte pathways) model. Additionally, applying the workflow to publicly available microarray data from ibuprofen‐treated mice accurately predicted the clinical failure of ibuprofen for treating AD in human trials. This study highlights the importance of evaluating the translatability of animal models to human disease and provides a suitable framework for improving the selection of preclinical models in Alzheimer's research.

IntroductionBepirovirsen is a novel antisense oligonucleotide in development for chronic hepatitis B virus (HBV) infection therapy. Understanding the impact that clinical characteristics may have on bepirovirsen exposure is important for determining efficacious and well-tolerated dosing regimens. This analysis evaluated demographics and clinical characteristics associated with bepirovirsen exposure using a population pharmacokinetic (PK) analysis.MethodsPopulation PK analyses were conducted using pooled data from three phase 1/2 clinical studies (NCT03020745/NCT02981602/NCT04449029) to construct a structural PK model for bepirovirsen that adequately described plasma concentration–time profiles and identify covariates that affect systemic exposure. The final population PK model was used to simulate bepirovirsen exposure measures to inform exposures at different dose levels and within different subpopulations.ResultsBepirovirsen PK data were well-described by a linear, three-compartment model with first-order absorption and absorption delay. Chronic HBV infection status, body weight, and Asian versus non-Asian race were key covariates included in the final model. Visual inspection of correlation scatter plots confirmed general agreement between observed and predicted data from the studies. In simulations, bepirovirsen systemic exposure was dosed proportionally and predicted to be almost completely washed out by 12 weeks following the final 300-mg dose. Differences in body weight, Asian race, or disease status did not result in clinically relevant differences in exposure.ConclusionsThis analysis demonstrated that the linear three-compartmental model accurately described bepirovirsen PK data. The lack of clinically relevant differences seen in exposure indicate that dose adjustments are not recommended for bepirovirsen based on demographics or clinical characteristics.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40121-024-00980-9.

EDITORIAL article Front. Pharmacol., 12 April 2023Sec. Experimental Pharmacology and Drug Discovery Volume 14 - 2023 | https://doi.org/10.3389/fphar.2023.1184914

This open‐label, phase Ib study (NCT02346370) assessed the effect of pegvorhyaluronidase alfa (PVHA; PEGPH20) on the plasma pharmacokinetics (PKs) and safety of docetaxel in 15 patients with stage IIIB/IV non‐small cell lung cancer (NSCLC). The docetaxel PK profile from this study was consistent with simulations from a published docetaxel population PK model, and did not demonstrate an effect of PVHA on docetaxel PK. A maximum a posteriori Bayesian fit of the literature PK model to the docetaxel PK appeared unbiased. Adverse events (AEs) were generally consistent with previous reports for docetaxel monotherapy in NSCLC, except for higher incidence of musculoskeletal events, including myalgias, with PVHA plus docetaxel. The most common AEs were fatigue (87%), muscle spasms (60%), and myalgia (53%). Four patients experienced thromboembolic events (27%), three leading to treatment discontinuation. PVHA appeared to demonstrate an acceptable safety profile when given with docetaxel without significantly changing the plasma PK of docetaxel in patients with stage IIIB/IV NSCLC.

Irreversible electroporation (IRE) is a focal ablation methodology that involved generating brief, but intense, electric fields in a target tissue. These electric fields operate on the cell level to electrically perforate—or permeabilize—the cell membrane while maintaining the structural integrity of the extracellular components [12]. The development of IRE technology significantly improved the outcomes of patients with late-stage. A study investigating such outcomes found that the median survival of stage III pancreatic cancer patients rose from 6–13 to 24.9 months in a 200-person study following IRE treatment [31], roughly doubling patient posttreatment survival.

To evaluate the delayed effects of irreversible electroporation (IRE) ablation on nerves. The study was approved by the institutional animal care and use committee. CT-guided IRE-ablation (electric field per distance, 1,500 V/cm; pulse length, 70 μs; number of pulses, 90) of 6 sciatic nerves was performed in 6 pigs that were euthanized 2 months after ablation. The sciatic nerves were harvested immediately after euthanasia for histopathological evaluation. Sections from selected specimens were stained with haematoxylin and eosin (H&E), Masson's trichrome (MT) method for collagen, and immunohistochemistry was performed for S100 and neurofilaments (markers for Schwann cells and axons, respectively). All nerves showed a preserved endoneural architecture and presence of numerous small calibre axons associated with Schwann cell hyperplasia, consistent with axonal regeneration. A fibrous scar was observed in the adjacent muscle tissue, confirming ablation at the site examined. After IRE-ablation of nerves, the preservation of the architecture of the endoneurium and the proliferation of Schwann cells may enable axonal regeneration as demonstrated after 2 months in this study.