Cell-Based Assays to Detect Innate Immune Response Modulating Impurities: Application to Biosimilar Insulin.

Characterizing and mitigating factors that impact product immunogenicity can aid in risk assessment and/or managing risk following manufacturing changes. For follow-on products that have the same indication, patient population, and active product ingredient, the residual immunogenicity risk resides predominantly on differences in product and process related impurities. Characterizing differences in innate immune modulating impurities (IIRMI), which could act as adjuvants by activating local antigen presenting cells (APCs), can inform the immunogenicity risk assessment potentially reducing the need for clinical trials.

Downregulation of IRF7-mediated type-I interferon response by LmCen parasites is necessary for protective immunity.

Leishmaniasis is a tropical disease caused by Leishmania parasites and currently has no licensed vaccines. We developed a dermotropic Leishmania major centrin gene-deleted strain (LmCen) as a live attenuated vaccine. Recent studies have shown that type I interferons (IFNs) play important roles in immunity to parasitic and viral pathogens.

Enhancing pharmacogenomic data accessibility and drug safety with large language models: a case study with Llama3.1.

Pharmacogenomics (PGx) holds the promise of personalizing medical treatments based on individual genetic profiles, thereby enhancing drug efficacy and safety. However, the current landscape of PGx research is hindered by fragmented data sources, time-consuming manual data extraction processes, and the need for comprehensive and up-to-date information. This study aims to address these challenges by evaluating the ability of Large Language Models (LLMs), specifically Llama3.

Advancing rare disease measurement through the Rare Disease Clinical Outcome Assessment Consortium.

There is a significant unmet need to develop and evaluate new treatments for people living with one of approximately 8000 rare diseases. Well-known difficulties in conducting clinical trials (e.g.

The incorporation of MALDI mass spectrometry imaging in studies to identify markers of toxicity following opioid exposures in mouse fetuses.

Introduction: In 2015, the FDA released a Drug Safety Communication regarding a possible link between opioid exposure during early pregnancy and an increased risk of fetal neural tube defects (NTDs). At the time, the indications for opioid use during pregnancy were not changed due to incomplete maternal toxicity data and limitations in human and animal studies. To assess these knowledge gaps, largescale animal studies are ongoing; however, state-of-the-art technologies have emerged as promising tools to assess otherwise non-standard endpoints.

Independent FDA Analyses of Nirmatrelvir/Ritonavir Resistance in the Phase 2/3 Trials EPIC-HR and EPIC-SR.

Background: PAXLOVID consists of nirmatrelvir, an inhibitor of SARS-CoV-2 main protease (Mpro), copackaged with ritonavir, a pharmacokinetic enhancer. Nirmatrelvir/ritonavir received emergency use authorization in the United States in 2021 and was approved in 2023. However, there is limited published information on SARS-CoV-2 clinical resistance to nirmatrelvir/ritonavir.

Current State and New Horizons in Applications of Physiologically Based Biopharmaceutics Modeling (PBBM): A Workshop Report.

This report summarizes the proceedings for Day 3 of the workshop titled "". This day focused on the current and future drug product quality applications of PBBM from the innovator and generic industries as well as the regulatory agencies perspectives. The presentations, which included several case studies, covered the applications of PBBM in generic drug product development, applications of virtual bioequivalence trials to support formulation bridging and the utility of absorption modeling in clinical pharmacology assessments.

Communicating therapeutic indication information in direct-to-consumer television ads for prescription cancer drugs: Exploring the effect of dual-modality presentations.

Objective: The rise in direct-to-consumer (DTC) ads for cancer drugs, which often have complex indications, raises concerns about consumer misunderstanding. A drug's indication must clearly convey its condition(s) of use, which may include elements such as the approved patient population, second-line treatment status, and whether it is adjunctive or concomitant therapy. The study examines whether the modality used to communicate the drug's indication in DTC television ads affects consumers' recognition, recall, and comprehension.

Effect of "In Use" Administration on Topical Product Metamorphosis and Skin Permeation of Acyclovir Creams: Implications for Bioequivalence.

Purpose: Typical clinical "in use" conditions for topical semisolids involve their application as a thin film, often with rubbing that can induce metamorphic stress. Yet, product quality and performance tests often characterize the manufactured product, and may not consider product metamorphosis (e.g.

FDA Approval Summary: Nalmefene Nasal Spray for the Emergency Treatment of Known or Suspected Opioid Overdose.

On May 22, 2023, the United States Food and Drug Administration approved the first nalmefene hydrochloride nasal spray for the emergency treatment of known or suspected opioid overdose in adults and pediatric patients 12 years of age and older. This approval of a new prescription nalmefene hydrochloride nasal spray adds to the available opioid reversal options for hospitals, communities, harm reduction groups, and emergency responders. Due to the life-threatening nature of opioid overdose, conducting randomized, well-controlled clinical efficacy trials in the target patient population is neither ethical nor feasible.

In vitro and in vivo characterization of Invega Sustenna® (paliperidone palmitate long-acting injectable suspension).

The aim of this study was to comprehensively characterize paliperidone palmitate (PP) long-acting suspension (Invega Sustenna®) through reverse engineering. We developed a series of analytical methods to assess critical quality attributes of four batches of Invega Sustenna®. The size distributions of the four batches of suspensions were measured using laser diffraction, and variations in the D50 and D90 parameters were observed.

Untargeted metabolomics and lipidomics in COVID-19 patient plasma reveals disease severity biomarkers.

Introduction: Coronavirus disease 2019 (COVID-19) has widely varying clinical severity. Currently, no single marker or panel of markers is considered standard of care for prediction of COVID-19 disease progression. The goal of this study is to gain mechanistic insights at the molecular level and to discover predictive biomarkers of severity of infection and outcomes among COVID-19 patients.

Detecting features of antibody structure through their mediator-accessible redox activities.

Protein function relies on sequence, folding and post-translational modification and molecular measurements are commonly used to reveal these structural features. Here, we report an alternative approach that represents these molecular features as readily measurable electronic patterns and validate this experimental approach by detecting structural perturbations commonly encountered during protein biomanufacturing. We studied a monoclonal antibody standard (from the National Institute of Standards and Technology) and focused on the electronic detection of variants that have undergone interchain disulfide bond reduction and methionine oxidation.

Regulatory Impact of Selected U.S. FDA Postmarketing Safety Registries Conducted for Drugs Used to Treat Inflammatory or Autoimmune Conditions.

Purpose: Assess the regulatory impact of selected FDA postmarketing safety registries on drug product labeling updates.

Methods: Postmarketing safety studies were identified in internal record repositories for the Center for Drug Evaluation and Research, U.S.

Reverse engineering of Onivyde® - Irinotecan liposome injection.

Onivyde® is an intravenous irinotecan liposomal injection approved by the FDA for the treatment of gemcitabine-refractory metastatic adenocarcinoma of the pancreas in combination with fluorouracil and leucovorin. In the Onivyde® formulation, irinotecan is encapsulated in the inner compartment of the liposome using sucrose octasulfate as a trapping agent, and stabilized by a pegylated lipid membrane, resulting in prolonged circulation in the body. Due to its complex formulation design, there is limited information available regarding the critical quality attributes (CQAs) of Onivyde® and suitable methods for evaluating these attributes.

A Meta-Analysis of the Safety and Immunogenicity of Pharmacokinetic Similarity Studies and Comparative Clinical Studies.

A biosimilar clinical development program generally includes a pharmacokinetic similarity study and a comparative clinical study. Since both types of studies assess safety and immunogenicity, it is important to evaluate the role of each in determining whether there are any meaningful differences between the proposed biosimilar products and the reference products. We conducted a systematic review and meta-analysis of the safety and immunogenicity data from pharmacokinetic similarity studies and comparative clinical studies, using a database of approved monoclonal antibody and fusion protein biosimilars.

Antipsychotics and Risk of Acute Respiratory Failure in U.S. Medicare Beneficiaries with Chronic Obstructive Pulmonary Disease.

Importance: Acute respiratory failure (ARF) associated with antipsychotic use has been documented through case reports and population-based studies.

Objective: To assess whether the recent use of antipsychotics is associated with an increased risk of ARF in U.S.

Modernizing multiple myeloma clinical trial eligibility to improve equity and inclusivity by hematological parameters.

In the United States, Black people experience multiple myeloma (MM) at a frequency that is more than double that of White people and experience much higher rates of mortality. Despite bearing a disproportionate impact of both MM incidence and mortality, Black patients are significantly underrepresented in most MM clinical trials. This is in part because Black patients experience a higher prevalence of hemoglobinopathies and Duffy-null phenotype, which affect hemoglobin and neutrophil levels, respectively, potentially excluding patients from clinical trials.

Exploration of the potential impact of batch-to-batch variability on the establishment of pharmacokinetic bioequivalence for inhalation powder drug products.

Batch-to-batch variability in inhalation powder has been identified as a potential challenge in the development of generic versions. This study explored the impact of batch-to-batch variability on the probability of establishing pharmacokinetic (PK) bioequivalence (BE) in a two-sequence, two-period (2 × 2) crossover study. A model-based parametric simulation approach was employed, incorporating batch-to-batch variability through the relative bioavailability (RBA) ratio.

A New Analytical Method for Quantifying Acid-End-Cap PLGA in Sub-Milligram Quantities.

Characterization of PLGA polymers used in FDA-approved drug products is critical for quality control and qualitative/quantitative (Q1/Q2) evaluation of potential generic formulations. Various techniques have been developed and used to characterize the molecular properties of PLGA polymers, such as molecular weight, molecular composition, and molecular structure. Commonly used techniques include gel permeation chromatography (GPC), nuclear magnetic resonance (NMR), semisolvent methods, and GPC-based intrinsic viscosity measurement.

Development and Validation of a Headspace GC-MS Method for Simultaneous Quantification of Antimicrobial Preservatives in Biopharmaceutical Peptide Formulations.

The four most used antimicrobial preservatives in biopharmaceutical parenteral formulations are phenol, meta-cresol, chlorobutanol, and benzyl alcohol. Preservatives are included in various combinations in biopharmaceuticals highlighting the importance of an analytical method to quantify the four preservatives simultaneously. A headspace GC-MS method was developed to quantify phenol, chlorobutanol, meta-cresol, and benzyl alcohol.