Pharmacodynamic effects of semorinemab on plasma and CSF biomarkers of Alzheimer's disease pathophysiology.

Introduction: Semorinemab, an anti-tau monoclonal antibody, was assessed in two Phase II trials for Alzheimer's disease (AD). Plasma and cerebrospinal fluid (CSF) biomarkers provided insights into the drug's potential mechanism of action.

Methods: Qualified assays were used to measure biomarkers of tau, amyloidosis, glial activity, neuroinflammation, synaptic function, and neurodegeneration from participant samples in Tauriel (NCT03289143) and Lauriet (NCT03828747) Phase II trials.

Semorinemab Pharmacokinetics and The Effect on Plasma Total Tau Pharmacodynamics in Clinical Studies.

Background: Semorinemab is a monoclonal antibody that targets the N-terminal domain of the tau protein that is in clinical development for the treatment of Alzheimer's disease.

Objectives: To perform model-based evaluations of the observed pharmacokinetics in serum and the total plasma tau target-engagement dynamics from clinical studies evaluating semorinemab.

Design: The observed semorinemab pharmacokinetics and plasma tau target engagement from phase 1 and 2 clinical studies were modeled using a non-linear mixed effect target-mediated drug disposition model.

Integrating Dynamic in vitro Systems and Mechanistic Absorption Modeling: Case Study of Pralsetinib.

Dynamic in vitro absorption systems and mechanistic absorption modeling via PBPK have both shown promise in predicting human oral absorption, although these efforts have been largely separate; this work aimed to integrate knowledge from these approaches to investigate the oral absorption of a RET inhibitor, pralsetinib, with BCS Class II properties. Tiny-TIM (TIM B.V.

Understanding CYP3A4 and P-gp mediated drug-drug interactions through PBPK modeling - Case example of pralsetinib.

Pralsetinib, a potent and selective inhibitor of oncogenic RET fusion and RET mutant proteins, is a substrate of the drug metabolizing enzyme CYP3A4 and a substrate of the efflux transporter P-gp based on in vitro data. Therefore, its pharmacokinetics (PKs) may be affected by co-administration of potent CYP3A4 inhibitors and inducers, P-gp inhibitors, and combined CYP3A4 and P-gp inhibitors. With the frequent overlap between CYP3A4 and P-gp substrates/inhibitors, pralsetinib is a challenging and representative example of the need to more quantitatively characterize transporter-enzyme interplay.

Factors contributing to the nonlinear pharmacokinetics of astegolimab: a close examination of potential causes.

This paper describes a case study of an antibody therapeutic targeting a membrane-bound receptor, also present in systemic circulation, as a soluble receptor. During phase I studies of astegolimab, nonlinear pharmacokinetics (PKs) were observed. We investigated the potential contribution of antidrug antibodies, target-mediated drug disposition and assay format.

Randomized Phase II Study of the Safety and Efficacy of Semorinemab in Participants With Mild-to-Moderate Alzheimer Disease: Lauriet.

Background And Objectives: Accumulation of tau pathology in Alzheimer disease (AD) correlates with cognitive decline. Anti-tau immunotherapies were proposed as potential interventions in AD. While antibodies targeting N-terminal tau failed to demonstrate clinical efficacy in prodromal-to-mild AD, their utility at other disease stages was not evaluated in prior studies.

Department Wide Validation in Digital Pathology-Experience from an Academic Teaching Hospital Using the UK Royal College of Pathologists' Guidance.

Aim: we describe our experience of validating departmental pathologists for digital pathology reporting, based on the UK Royal College of Pathologists (RCPath) "Best Practice Recommendations for Implementing Digital Pathology (DP)," at a large academic teaching hospital that scans 100% of its surgical workload. We focus on Stage 2 of validation (prospective experience) prior to full validation sign-off.

Methods And Results: twenty histopathologists completed Stage 1 of the validation process and subsequently completed Stage 2 validation, prospectively reporting a total of 3777 cases covering eight specialities.

Streamlining Food Effect Assessment - Are Repeated Food Effect Studies Needed? An IQ Analysis.

Current regulatory guidelines on drug-food interactions recommend an early assessment of food effect to inform clinical dosing instructions, as well as a pivotal food effect study on the to-be-marketed formulation if different from that used in earlier trials. Study waivers are currently only granted for BCS class 1 drugs. Thus, repeated food effect studies are prevalent in clinical development, with the initial evaluation conducted as early as the first-in-human studies.

Modeling Alzheimer's disease progression utilizing clinical trial and ADNI data to predict longitudinal trajectory of CDR-SB.

There is strong interest in developing predictive models to better understand individual heterogeneity and disease progression in Alzheimer's disease (AD). We have built upon previous longitudinal AD progression models, using a nonlinear, mixed-effect modeling approach to predict Clinical Dementia Rating Scale - Sum of Boxes (CDR-SB) progression. Data from the Alzheimer's Disease Neuroimaging Initiative (observational study) and placebo arms from four interventional trials (N = 1093) were used for model building.

Longitudinal Exposure-Response Modeling of Multiple Indicators of Alzheimer's Disease Progression.

Background: Progression in Alzheimer's disease manifests as changes in multiple biomarker, cognitive, and functional endpoints. Disease progression modeling can be used to integrate these multiple measures into a synthesized metric of where a patient lies within the disease spectrum, allowing for a more dynamic measure over the range of the disease.

Objectives: This study aimed to combine modeling techniques from psychometric research (e.

A comprehensive regulatory and industry review of modeling and simulation practices in oncology clinical drug development.

Exposure-response (E-R) analyses are an integral component in the development of oncology products. Characterizing the relationship between drug exposure metrics and response allows the sponsor to use modeling and simulation to address both internal and external drug development questions (e.g.

Exploring the Use of a Kinetic pH Calculation to Correct the ACAT Model with a Single Stomach Compartment Setting: Impact of Stomach Setting on Food Effect Prediction for Basic Compounds.

Advanced compartmental absorption and transit (ACAT) based computational models have become increasingly popular in the industry for predicting oral drug product performance. However, due to its complexity, some compromises have been made in practice, and the stomach is often assigned as a single compartment. Although this assignment worked generally, it may not be sufficient to reflect the complexity of the gastric environment under certain conditions.

Concentration QTc analysis of giredestrant: Overcoming QT/heart rate confounding in the presence of drug-induced heart rate changes.

Concentration-QTc (C-QTc) analysis has become a common approach for evaluating proarrhythmic risk and delayed cardiac repolarization of oncology drug candidates. Significant heart rate (HR) change has been associated with certain classes of oncology drugs and can result in over- or underestimation of the true QT prolongation risk. Because oncology early clinical trials typically lack a placebo control arm or time-matched, treatment-free baseline electrocardiogram collection, significant HR change brings additional challenges to C-QTc analysis in the oncology setting.

Belvarafenib penetrates the BBB and shows potent antitumor activity in a murine melanoma brain metastasis model.

Brain metastasis is a common complication in melanoma patients with BRAF and NRAS mutations and has a poor prognosis. Although BRAF inhibitors are clinically approved, their poor brain penetration limits their efficacy in brain metastasis. Thus, melanoma brain metastasis still requires better treatment.

Quantitative systems pharmacology model of the amyloid pathway in Alzheimer's disease: Insights into the therapeutic mechanisms of clinical candidates.

Despite considerable investment into potential therapeutic approaches for Alzheimer's disease (AD), currently approved treatment options are limited. Predictive modeling using quantitative systems pharmacology (QSP) can be used to guide the design of clinical trials in AD. This study developed a QSP model representing amyloid beta (Aβ) pathophysiology in AD.

Elucidating a Potential Mechanism of Permeability Enhancer Sodium N-[8-(2-hydroxybenzoyl) amino] Caprylate in Rats: Evidence of Lymphatic Absorption of Cyanocobalamin using the Mesenteric Lymph Duct Cannulated Rat.

Oral administration is the most popular and convenient route for drug delivery, yet the success of oral drug delivery is dependent on the ADME properties of the drug. Among those ADME properties, permeability is considered one of the key attributes for successful oral drug absorption. Hence, the utilization of permeability enhancers to improve drug oral absorption is an important area of research in drug delivery.

Evaluating the Safety and Efficacy of Crenezumab vs Placebo in Adults With Early Alzheimer Disease: Two Phase 3 Randomized Placebo-Controlled Trials.

Importance: Alzheimer disease (AD), a neurodegenerative disease characterized by β-amyloid plaques and τ tangles in the brain, represents an unmet medical need with no fully approved therapeutics to modify disease progression.

Objective: To investigate the safety and efficacy of crenezumab, a humanized monoclonal immunoglobulin G4 antibody targeting β-amyloid oligomers, in participants with prodromal to mild (early) AD.

Design, Setting, And Participants: Two phase 3 multicenter randomized double-blind placebo-controlled parallel-group efficacy and safety studies of crenezumab in participants with early AD, CREAD and CREAD2, were initiated in 2016 and 2017, respectively, and were designed to evaluate the efficacy and safety of crenezumab in participants with early AD.

Phase 2 randomized clinical trial of astegolimab in patients with moderate to severe atopic dermatitis.

Background: The binding of IL-33 to its receptor ST2 (alias of IL1RL1) leads to the release of inflammatory mediators and may play a role in the pathogenesis of atopic dermatitis. Astegolimab is a fully human, IgG mAb that binds to ST2 and inhibits IL-33 signaling.

Objectives: This study sought to assess the efficacy, safety, and pharmacokinetics of astegolimab in patients with atopic dermatitis.

Safety and Efficacy of Semorinemab in Individuals With Prodromal to Mild Alzheimer Disease: A Randomized Clinical Trial.

Importance: Neurofibrillary tangles composed of aggregated tau protein are one of the neuropathological hallmarks of Alzheimer disease (AD) and correlate with clinical disease severity. Monoclonal antibodies targeting tau may have the potential to ameliorate AD progression by slowing or stopping the spread and/or accumulation of pathological tau.

Objective: To evaluate the safety and efficacy of the monoclonal anti-tau antibody semorinemab in prodromal to mild AD.

The Use of Digital Pathology and Artificial Intelligence in Histopathological Diagnostic Assessment of Prostate Cancer: A Survey of Prostate Cancer UK Supporters.

There has been particular interest in the deployment of digital pathology (DP) and artificial intelligence (AI) in the diagnosis of prostate cancer, but little is known about the views of the public on their use. Prostate Cancer UK supporters were invited to an online survey which included quantitative and qualitative questions exploring views on the use of DP and AI in histopathological assessment. A total of 1276 responses to the survey were analysed (response rate 12.

Evaluating the IVIVC by Combining Tiny-tim Outputs and Compartmental PK Model to Predict Oral Exposure for Different Formulations of Ibuprofen.

Nowadays, the ever-increasing costs of research and development in the pharmaceutical industry have created a big demand for predicting the performances of drug candidates. Of those, the desire to establish an in vitro-in vivo correlation (IVIVC) to better predict the oral drug exposure for different drug products is a growing need. Once a robust IVIVC is established, the performance of different drug products can be predicted and selected for testing in clinical trials with greater confidence.

Population Pharmacokinetics and Exposure-Response Relationships of Astegolimab in Patients With Severe Asthma.

Astegolimab is a fully human immunoglobulin G2 monoclonal antibody that binds to the ST2 receptor and blocks the interleukin-33 signaling. It was evaluated in patients with uncontrolled severe asthma in the phase 2b study (Zenyatta) at doses of 70, 210, and 490 mg subcutaneously every 4 weeks for 52 weeks. This work aimed to characterize astegolimab pharmacokinetics, identify influential covariates contributing to its interindividual variability, and make a descriptive assessment of the exposure-response relationships.

Safety, Tolerability, and Pharmacokinetics of High-Volume Subcutaneous Crenezumab, With and Without Recombinant Human Hyaluronidase in Healthy Volunteers.

Compared with intravenous formulations, subcutaneous (s.c.) formulations of therapeutic monoclonal antibodies may provide increased patient access and more convenient administration options, although historically high-volume s.

Population repeated time-to-event analysis of exacerbations in asthma patients: A novel approach for predicting asthma exacerbations based on biomarkers, spirometry, and diaries/questionnaires.

Identification of covariates, including biomarkers, spirometry, and diaries/questionnaires, that predict asthma exacerbations would allow better clinical predictions, shorter phase II trials and inform decisions on phase III design, and/or initiation (go/no-go). The objective of this work was to characterize asthma-exacerbation hazard as a function of baseline and time-varying covariates. A repeated time-to-event (RTTE) model for exacerbations was developed using data from a 52-week phase IIb trial, including 502 patients with asthma randomized to placebo or 70 mg, 210 mg, or 490 mg astegolimab every 4 weeks.

Utilizing Tiny-TIM to Assess the Effect of Acid-Reducing Agents on the Absorption of Orally Administered Drugs.

Acid-reducing agents (ARAs) are the most commonly used medicines to treat patients with gastric acid-related disorders. ARA administration results in an elevation of intragastric pH and eases symptoms such as acid reflux. However, this effect could also lead to a reduction in the absorption of some co-administered oral medications (i.