Mass spectrometry for clinical bioanalysis without chromatographic separation: bioequivalence for bupropion and its metabolites.

Background: High-throughput solid-phase extraction coupled with tandem mass spectrometry (HT-SPE-MS/MS) is an automated sample delivery system to mass spectrometry that operates without chromatographic separation. The typical analysis time per sample using this platform is 10-30 s. While the HT-SPE-MS/MS system has demonstrated efficacy for in vitro assays, its application to the analysis of biological samples from in vivo bioavailability and bioequivalence studies presents challenges due to the complexity of the sample matrix.

Raman spectroscopy as a tool to accelerate development of complex medicinal products.

Regulatory approval of complex generic drug products that are applied topically to treat skin disease can be challenging because a standard method to assess cutaneous pharmacokinetics in vivo is not available. As a result, expensive and prolonged clinical trials are often necessary, and this has proved to be a significant disincentive to generic product development and restrictive of patient access to more affordable medicines. Here Raman spectroscopy is used to quantify the relative spatiotemporal disposition of metronidazole (a drug used to treat rosacea) within the skin and proximal to its site of pharmacological action.

Chromoblastomycosis and phaeohyphomycotic abscess-associated hospitalizations, United States, 2016-2021.

Background: Chromoblastomycosis and phaeohyphomycotic abscesses are infections of the skin and subcutaneous tissues caused by dematiaceous fungi; more rarely, phaeohyphomycotic brain abscesses can occur. The epidemiology and clinical outcomes of chromoblastomycosis and phaeohyphomycotic abscesses are not well-understood in the United States.

Methodology/ Principal Findings: We used data from the Healthcare Cost and Utilization Project's National Inpatient Sample to obtain yearly national estimates of chromoblastomycosis and phaeohyphomycotic abscess-associated hospitalizations.

Analysis by Age, Sex, Race, and Ethnicity of Participants in Clinical Trials Supporting Recently Approved Novel Therapies.

Trial populations that are representative of the intended population for therapies build evidence supporting the generalizability of results to the intended population and improve adoption of novel therapies upon approval. We evaluated the demographic composition of trial populations in 62 pivotal studies supporting approval of novel therapies for human immunodeficiency virus, migraines, multiple sclerosis, and type 2 diabetes. Enrollment at all sites, US sites, and sites outside the United States was evaluated relative to US prevalence.

R Value-Based Criteria Outperform Alkaline Phosphatase Less than Twice Normal in Identifying Hy's Law Cases in Clinical Trials.

Background: It is unknown whether nR value [(ALT or AST/ULN) ÷ (AP/ULN)] ≥ 5 is better than alkaline phosphatase less than twice the upper limit of normal (AP < 2x ULN) in identifying hepatocellular drug-induced liver injury (HC DILI) consistent with Hy's law in clinical trials.

Objective: We aimed to compare nR value ≥ 5 and AP < 2x ULN in clinical trial DILI cases with ALT or AST ≥ 3x ULN and total bilirubin (TB) > 2x ULN.

Methods: We retrospectively categorized clinical trial, DILI cases from July 2020 to April 2024 with ALT or AST ≥ 3x ULN and jaundice as meeting nR value ≥ 5, AP < 2x ULN, both, or neither.

New approach methodologies for assessing developmental toxicity of pharmaceuticals: Case Examples and Future Directions.

Several new approach methodologies (NAMs) for developmental toxicity (Dev Tox) testing are being used by pharmaceutical companies for derisking or for exploring Dev Tox mechanisms. Regulatory adoption of these NAMs-based approaches as being adequate for Dev Tox risk assessment has been more challenging, due, in part, to dynamic changes in the conceptus and placenta throughout development and the impact of the pharmaceutical on the mother's physiology, which may also have an embryo-fetal impact. Still, there is currently a recognition by Health Authorities that there are certain contexts-of-use under which Dev Tox NAMs can provide information that is adequate to inform risk.

A metagenomic analysis coupled with oligotrophic enrichment approach for detecting specified microorganisms in potable groundwater samples.

In pharmaceutical manufacturing, there is a significant need for the detection and identification of specified microorganisms (, complex (BCC), , and ), which are often missed or not identified by traditional culture-dependent methods. We employed a metagenomic analysis coupled with oligotrophic enrichment to identify specified microorganisms and evaluate tryptic soy broth (TSB) and 1/10 strength TSB for the recovery of specific microorganisms in potable groundwater samples. A total of 589-996 genera were identified in 12 water samples taken from a cold water fountain, with spp.

Quasi-3D Mechanistic Model for Predicting Eye Drop Distribution in the Human Tear Film.

Topical drug administration is a common method of delivering medications to the eye to treat various ocular conditions, including glaucoma, dry eye, and inflammation. Drug efficacy following topical administration, including the drug's distribution within the eye, absorption and elimination rates, and physiological responses can be predicted using physiologically based pharmacokinetic (PBPK) modeling. High-resolution computational models of the eye are desirable to improve simulations of drug delivery; however, these approaches can have long run times.

Innovative use of self-controlled methods for the evaluation of waning effectiveness of the COVID-19 monovalent third dose: comparison with a test-negative design.

Background: Waning vaccine effectiveness (VE) evaluations are affected by multiple biases, many of which could be implicitly adjusted by using self-controlled methods.

Methods: We used a self-controlled risk interval (SCRI) design to evaluate waning COVID-19 monovalent third dose effectiveness against laboratory-confirmed SARS-CoV-2 medically-attended infections (cases) and hospitalizations with COVID-19 discharge diagnosis among Veterans Health Administration enrollees who received a third dose 15 December 2021-31 August 2022. We used weeks 3-8 post-third dose as reference interval, representing the period of peak VE.

Overcoming Barriers to Developing and Implementing Novel Therapies for Hypertension.

Hypertension is the single most important modifiable risk factor for preventable disability and death worldwide and disproportionately affects socially disadvantaged populations. We face a paradox-blood pressure control is low and recent trends suggest it is even declining, despite the availability of inexpensive and effective therapies. A variety of barriers on the system, patient, and healthcare provider side hinder effective drug-based risk factor management.

Nonclinical Human Cardiac New Approach Methodologies (NAMs) Predict Vanoxerine-Induced Proarrhythmic Potential.

New approach methodologies (NAMs), including microphysiological systems (MPSs), can recapitulate structural and functional complexities of organs. Vanoxerine was reported to induce cardiac adverse events, including torsade de points (TdP), in a Phase III clinical trial. Despite earlier nonclinical animal models and Phase I-II clinical trials, events of QT prolongation or proarrhythmia were not observed.

Non-Invasive Tests: Establishing efficacy for metabolic dysfunction associated steatohepatitis beyond the biopsy-current perspectives from the division of hepatology and nutrition, US Food and Drug Administration.

To support drug development for metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis, multiple stakeholders including patients, clinicians, and investigators have communicated a desire to move away from liver histology. FDA accelerated approval is based on a surrogate endpoint (such as liver histology) that has less definitive evidence tying it to the clinical endpoint (such as death or liver transplant) but nonetheless is considered reasonably likely to predict clinical benefit -- a reasonably likely surrogate endpoint (RLSE). This communication is intended to provide some of the regulatory considerations on adopting non-invasive tests in lieu of liver histology as a RLSE in drug development for MASH.

Application of Lactation Physiologically Based Pharmacokinetic Modeling to Predict Milk Exposure of Passively Diffused Drugs.

Physiologically based pharmacokinetic (PBPK) models have gained interest as a tool for predicting drug transfer to human milk and assessing the exposure levels in infants. Our group previously developed an integrated lactation PBPK model framework to understand the transfer of drugs into milk and the resulting exposure in infants. As a part of the framework, the current paper focuses on performance of lactation PBPK models to predict maternal plasma and milk concentrations for drugs that are not substrates of P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) transporters-atenolol, escitalopram, and alprazolam.

US Food and Drug Administration Approval Summary: Inavolisib With Palbociclib and Fulvestrant for Endocrine-Resistant, -Mutated, Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative, Locally Advanced or Metastatic Breast Cancer.

Purpose: The US Food and Drug Administration (FDA) approved inavolisib with palbociclib and fulvestrant for adults with endocrine-resistant, -mutated, hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer (MBC), as detected by an FDA-approved test, FoundationOne Liquid CDx assay, after recurrence on or after completing adjuvant endocrine therapy.

Patients And Methods: Approval was based on INAVO120, a randomized, double-blind, placebo-controlled trial in 325 patients with endocrine-resistant, -mutated, hormone receptor-positive, HER2-negative, locally advanced or MBC. Patients were randomly assigned (1:1) to either inavolisib (n = 161) or placebo (n = 164) in combination with palbociclib and fulvestrant.

The Current Landscape of Repurposed Drugs for Fungal Neglected Tropical Diseases.

Purpose Of Review: Eumycetoma, chromoblastomycosis, and sporotrichosis are three of only four fungal infections recognized as Neglected Tropical Diseases (NTDs) by the World Health Organization. They are a significant source of morbidity in subtropical and tropical regions of the Americas, Africa, and Asia. There are very few treatments approved for these diseases.

Multi-laboratory comparisons of manual patch clamp hERG data generated using standardized protocols and following ICH S7B Q&A 2.1 best practices.

Acute block of hERG channels is the most common mechanism underlying drug-induced QT prolongation and potentially fatal Torsade de Pointes arrhythmia. Updates to ICH E14 Q&As now allow for using negative nonclinical data, including hERG, to support QT risk assessment in late-stage clinical development. To interpret the hERG results, understanding hERG assay reproducibility or hERG data variability is pivotal.

Pregnancy reduces COVID-19 vaccine immunity against novel variants.

Pregnant women are at heightened risk for severe outcomes from infectious diseases like COVID-19, yet were not included in initial vaccine trials, which may contribute to low booster uptake (15% or lower). We explored the serological and cellular responses to COVID-19 mRNA booster vaccines (i.e.

Interagency Collaboration for Patient-Centered Antibacterial Drug Development.

This manuscript presents key advances of the Antibacterial Resistance Leadership Group (ARLG) Innovations Task Force, a collaboration focused on improving endpoints for registrational trials of antibacterial drugs, including health-related quality-of-life measures, for common acute infections. This group includes members from the United States Food and Drug Administration, National Institutes of Health, academia, industry, and patient representatives to amplify patient voices and ensure that the endpoints are meaningful to how patients feel, function, and survive.

Novel Pharmacokinetic Bridging Strategy for Locally Acting Intravitreal Drug Products.

A clinical development program for follow-on locally acting intravitreal drug products typically includes a comparative efficacy study. Pharmacokinetic assessment is often considered of limited value because systemic exposure is low and/or not predictive of efficacy at the site of action. In this commentary, we evaluated the relevance of pharmacokinetics for locally acting intravitreal large molecule drug products.

The Plasma Membrane may Serve as a Drug Depot to Drive the Extreme Potency of Fentanyl.

The drug overdose crisis in the United States is driven largely by the ultrapotent synthetic (UPS) opioid fentanyl; however, fentanyl's extreme potency is poorly understood. Here we used state-of-the-art molecular dynamics simulations and experiments to test a hypothesis that fentanyl's extreme potency is driven by its ability to partition into the plasma membrane, creating a drug reservoir near the receptor. The estimated effective permeability of fentanyl at pH 7.

Longitudinal graphics of patient-reported physical function in patients treated for hematologic malignancies.

Background: The US Food and Drug Administration (FDA) released a draft guidance document detailing core patient-reported outcomes in cancer clinical trials, including physical function (PF). The objectives of this study were to develop analytic methods and visualizations of patient-reported PF in patients with cancer.

Methods: We applied an estimand framework to a patient-reported tolerability endpoint to develop data summaries cross-sectionally and over time, along with visualizations.