Drug Administration Research Articles

The role of regulatory agencies in public health emergencies: A critical review of global approaches and challenges

Regulatory agencies play a pivotal role in public health emergencies by ensuring that medical products, including vaccines, diagnostics, and therapeutics, are rapidly available while maintaining safety and efficacy standards. The COVID-19 pandemic, along with past crises such as the Ebola and Zika outbreaks, exposed both strengths and vulnerabilities in global regulatory frameworks. This paper critically reviews the role of regulatory agencies in public health emergencies, synthesizing existing literature to present new insights into their operational challenges and the reliance strategies employed to bridge capacity gaps. By examining case studies, such as the reliance on the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) by low- and middle-income countries (LMICs), this paper highlights the importance of global cooperation and reliance mechanisms in managing crises. Furthermore, it addresses challenges such as resource constraints, disparities in regulatory capacity, and ethical dilemmas faced when approving products based on limited data. The paper also explores the future direction of regulatory science, emphasizing the need for greater global regulatory convergence, capacity building, and the adoption of innovative digital tools. Ultimately, the paper argues that while reliance strategies are vital, long-term investment in national regulatory systems and global harmonization efforts are essential for a more equitable and effective response to future public health emergencies.

Zerlasiran—A Small-Interfering RNA Targeting Lipoprotein(a)

ImportanceElevated lipoprotein(a) increases the risk of atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis.ObjectiveTo evaluate the effects of zerlasiran, a small-interfering RNA targeting hepatic synthesis of apolipoprotein(a), on lipoprotein(a) serum concentration.Design, Setting, and ParticipantsA multicenter trial in patients with stable ASCVD with serum lipoprotein(a) concentrations greater than or equal to 125 nmol/L at 26 sites in Europe and South Africa between January 3, 2023, and April 27, 2023, with last follow-up on July 1, 2024.InterventionsParticipants randomized to receive a subcutaneous dose of placebo every 16 weeks for 3 doses (n = 23) or every 24 weeks for 2 doses (n = 24) or zerlasiran 450 mg every 24 weeks for 2 doses (n = 45), 300 mg every 16 weeks for 3 doses (n = 42), or 300 mg every 24 weeks for 2 doses (n = 44).Main Outcome and MeasuresThe primary outcome was the time-averaged percent change in lipoprotein(a) concentration from baseline to 36 weeks, with follow-up to 60 weeks.ResultsAmong 178 patients, mean (SD) age was 63.7 (9.4) years, 46 (25.8%) were female, with a median (IQR) baseline lipoprotein(a) concentration of 213 (177-282) nmol/L; 172 patients completed the trial. Compared with the pooled placebo group, the least-squares mean time-averaged percent change in lipoprotein(a) concentration from baseline to week 36 was −85.6% (95% CI, −90.9% to −80.3%), −82.8% (95% CI, −88.2% to −77.4%), and −81.3% (95% CI, −86.7% to −76.0%) for the 450 mg every 24 weeks, 300 mg every 16 weeks, and 300 mg every 24 weeks groups, respectively. Median (IQR) percent change in lipoprotein(a) concentration at week 36 was −94.5% (−97.3% to −84.2%) for the 450 mg every 24 weeks group, −96.4% (−97.7% to −92.3%) for the 300 mg every 16 weeks group, and −90.0% (−93.7% to −81.3%) for the 300 mg every 24 weeks group. The most common treatment-related adverse effects were injection site reactions, with mild pain occurring in 2.3% to 7.1% of participants in the first day following drug administration. There were 20 serious adverse events in 17 patients, none considered related to the study drug.ConclusionsZerlasiran was well-tolerated and reduced time-averaged lipoprotein(a) concentration by more than 80% during 36 weeks of treatment in patients with ASCVD.Trial RegistrationClinicalTrials.gov Identifier: NCT05537571

Dupilumab Demonstrates a Higher Likelihood of Achieving Improvements in Signs, Symptoms, and Quality of Life vs. Tralokinumab at Week 16: Results from a Bucher Indirect Treatment Comparison

Background: Dupilumab and tralokinumab are biologics approved by the US Food and Drug Administration (FDA) for the treatment of patients with moderate-to-severe atopic dermatitis (AD), aged ≥6 months and ≥12 years, respectively. Dupilumab and tralokinumab have demonstrated efficacy and safety in clinical trials. However, no direct head-to-head trials have been performed to compare the efficacy of dupilumab vs tralokinumab. The Bucher indirect treatment comparison (ITC) is a robust, placebo-adjusted, and accepted method to evaluate the relative efficacy of drugs in the absence of direct comparisons. The objective of this analysis was to report results from a Bucher ITC comparing the efficacy of dupilumab+topical corticosteroid (TCS) vs tralokinumab+TCS at Week 16. Methods: The placebo-adjusted Bucher ITC included published data from the two similarly designed phase 3 trials, LIBERTY AD CHRONOS (NCT02260986) and ECZTRA 3 (NCT03363854). For both studies, data from the 16-week period were used, employing non-responder imputation, with the following doses: 300mg dupilumab every 2 weeks (q2w)+TCS or placebo+TCS, and 300mg tralokinumab q2w+TCS or placebo+TCS. The evaluated endpoints included the proportions of patients achieving an Investigator’s Global Assessment score 0/1 (IGA 0/1; clear/almost clear), 75% and 90% improvements from baseline in Eczema Area and Severity Index (EASI-75 and EASI-90), ≥4-point improvement from baseline in the Peak Pruritus Numerical Rating Scale score (PP-NRS >4), and ≥4-point improvement from baseline in the Dermatology Life Quality Index (DLQI >4). The Bucher ITC with the frequentist approach was performed using R software (v 4.20; netmeta package) with a fixed-effect model. Results were reported as odds ratio (OR) with 95% confidence interval (CI). Results: A total of 801 patients (LIBERTY AD CHRONOS: placebo+TCS: 315; dupilumab+TCS: 106; ECZTRA 3: placebo+TCS: 127; tralokinumab+TCS: 253) were included in the Bucher ITC. Baseline disease characteristics indicated comparable severity between the two trial populations based on IGA and PP-NRS. However, CHRONOS showed slightly higher baseline EASI scores (median [Q1, Q3] score 30.9 [22.3, 41.6] vs. ECZTRA 3: 24.7 [18.4, 35.9]), while ECZTRA 3 showed slightly higher DLQI scores (median [Q1, Q3] score 18.0 [12.0, 23.0] vs. CHRONOS: 13.5 [8.0, 20.0]). Patients treated with dupilumab+TCS had a significantly higher likelihood of achieving IGA 0/1 (OR=2.49, 95%CI 1.24–5.00), EASI-75 (OR=3.21, 95%CI 1.66–6.19), EASI-90 (OR=2.92, 95%CI 1.41–6.02), PP-NRS ≥4 (OR=3.62, 95%CI 1.87–7.00), and DLQI ≥4 (OR=2.16, 95%CI 1.03–4.54) at Week 16 vs those treated with tralokinumab+TCS. Conclusions: A placebo-adjusted Bucher ITC showed that the likelihood of achieving improvements in signs, symptom, and quality of life is significantly higher for patients treated with dupilumab+TCS vs tralokinumab+TCS at Week 16.

Over-the-Counter Medication Abortion as a Strategy to Expand Access to Care

This Viewpoint discusses the growing body of evidence that indicates that mifepristone and misoprostol meet the US Food and Drug Administration’s criteria for over-the-counter sale.

Dermal and Systemic Pharmacokinetics of Oral DFD-29 (minocycline hydrochloride modified release capsules, 40 mg) vs Oral Doxycycline 40 mg in Healthy Subjects

Dermal and Systemic Pharmacokinetics of Oral DFD-29 (minocycline hydrochloride modified release capsules, 40 mg) vs Oral Doxycycline 40 mg in Healthy Subjects Adelaide A. Hebert, MD,1 Srinivas Sidgiddi, MD2 1UTHealth Houston McGovern Medical School, Houston, TX; 2Journey Medical Corporation, Scottsdale, AZ Introduction: A modified-release, low-dose formulation (DFD-29) of minocycline hydrochloride (HCl) is under investigation for the treatment of rosacea. This Phase 1 study compared the dermal and systemic pharmacokinetics of DFD-29 (minocycline HCl, 40 mg) and doxycycline 40 mg in healthy, adult subjects. Methods: This randomized, open-label, single-center, parallel-group study evaluated the systemic and dermal pharmacokinetics of once-daily administration of oral DFD-29 40 mg capsules or oral doxycycline 40 mg for 21 days in healthy adult volunteers. On Day 1, subjects received the assigned study drug under fasting conditions. Blood was sampled before drug administration, every 30 minutes for 4 hours, hourly for 4 hours, and 12 and 24 hours post dose. Dermal interstitial fluid (ISF) was sampled using three open-flow microperfusion probes before dosing, hourly for 8 hours, and at 11-12, 15-16, and 23-24 hours post dose. After discharge, subjects continued to take assigned study drug once daily through Day 21, when they returned to the center and underwent the same procedures as on Day 1. Safety was evaluated by monitoring adverse events (AEs), vital signs, and laboratory tests. Results: A total of 24 subjects were randomized and completed the study. On Day 1, mean plasma Cmax levels with DFD-29 (382.8 ng/mL) and doxycycline (405.9 ng/mL) were comparable (Pr > 0.716). By Day 21, mean plasma Cmax had nearly doubled with doxycycline but remained constant with DFD-29 (701.9 vs 337.7 ng/mL; Pr > 0.037). Mean plasma AUC was also significantly greater with doxycycline than with DFD-29 at Day 21 (6074.8 ng.hr/mL vs 3957.6 ng.hr/mL, Pr > 0.013). In contrast, mean dermal Cmax concentrations were numerically higher with DFD-29 (40 mg) than doxycycline at Day 1 (109.7 vs 81.5 ng/mL; Pr > 0.117) and Day 21 (125.7 vs 114.7 ng/mL; Pr > 0.681). The mean dermal AUC at Day 1 also was greater with DFD-29 than with doxycycline (1412.29 ng.hr/mL Vs 1088.55 ng.hr/mL, Pr > 0.213), and at Day 21 it was similar in the two groups (1604.77 ng.hr/mL for DFD-29 and 1573.63 ng.hr/mL for doxycycline, Pr > 0.954). Both DFD-29 and doxycycline 40 mg were well tolerated by the healthy volunteers. Conclusion: Minocycline from DFD-29 with its modified-release formulation provides higher dermal concentration than doxycycline from Day 1 onwards at a similar dose. The higher concentration from Day 1 at the site of action is expected to translate into a clinically meaningful impact in the treatment of patients with rosacea. This study and abstract are funded by Journey Medical Corporation.

Provider Burden Associated With Apremilast Adverse Events

Introduction: In December 2021, the US Food and Drug Administration (FDA) expanded its initial approval for apremilast to include moderate and severe cases of psoriasis. However, real-world epidemiology data regarding the use of apremilast, the influence of adverse events (AEs), and the burden of AEs on managing physicians, has been lacking. This retrospective, observational, multisite study aimed to describe real-world patient characteristics, AEs (including diarrhea, nausea, and headache), and healthcare provider-level burden associated with the psoriasis treatment apremilast in the US. Methods: Dermatologists abstracted medical record data for adults treated with apremilast on or after January 1, 2018, who had ≥3 months of data available. Dermatologist and patient characteristics, including demographics and clinical characteristics, AEs, and provider burden in managing AEs were summarized using descriptive statistics. Results: Forty-seven dermatologists nationwide responded to a survey and conducted a chart review of 308 patients. Dermatologists practiced in various US geographic regions. The most common practice setting was in a private community with 2 to 5 physicians (34.0%). Most patients were White (74.4%), non-Hispanic (86.0%), and male (55.2%). The mean age at diagnosis was 43.6 years (SD, 16.8 years). AEs occurred in 29.2% of patients, with the most common being diarrhea (16.2%), followed by nausea (13.6%) and headache (4.9%). Diarrhea mostly occurred ≤30 days into treatment (87.2%) and resulted in 1 additional office visit (39.5%) and 3 phone calls per patient to their providers (34.9%). Nausea mostly occurred within 30 days (70.2%) and resulted in 1 additional visit (29.7%) and 1 phone call per patient (35.1%). The burdens of managing both diarrhea and nausea were similar, although diarrhea resulted in more phone calls to the healthcare provider. Conclusion: Diarrhea and nausea were common and resulted in an additional time and resource burden on dermatologists and their staff. Future research on the AE burden on providers and patients related to apremilast is needed.

Methyl-Beta-Cyclodextrin Restores Aberrant Bone Morphogenetic Protein 2-Signaling in Bone Marrow Stromal Cells Obtained from Aged C57BL/6 Mice

During aging, disruptions in various signaling pathways become more common. Some older patients will exhibit irregular bone morphogenetic protein (BMP) signaling, which can lead to osteoporosis (OP)—a debilitating bone disease resulting from an imbalance between osteoblasts and osteoclasts. In 2002, the Food and Drug Administration (FDA) approved recombinant human BMP-2 (rhBMP-2) for use in spinal fusion surgeries as it is required for bone formation. However, complications with rhBMP-2 arose and primary osteoblasts from OP patients often fail to respond to BMP-2. Although patient samples are available for study, previous medical histories can impact results. Consequently, the C57BL/6 mouse line serves as a valuable model for studying OP and aging. We find that BMP receptor type Ia (BMPRIa) is upregulated in the bone marrow stromal cells (BMSCs) of 15-month-old mice, consistent with prior data. Furthermore, conjugating BMP-2 with Quantum Dots (QDot®s) allows effective binding to BMPRIa, creating a fluorescent tag for BMP-2. Furthermore, after treating BMSCs with methyl-β-cyclodextrin (MβCD), a disruptor of cellular endocytosis, BMP signaling is restored in 15-month-old mice, as shown by von Kossa assays. MβCD has the potential to restore BMPRIa function, and the BMP signaling pathway offers a promising avenue for future OP therapies.

Qualitative examination of US and Israeli adults' perceptions of IQOS advertising messages: modified exposure and risk statements, US FDA endorsement, and health warnings.

IQOS, a leading heated tobacco product, is advertised as less harmful than cigarettes and received US Food and Drug Administration (FDA) authorization for 'reduced exposure' advertising claims. Perceptions of advertising messages, including reduced exposure/risk claims, FDA endorsements, and health warning labels (HWLs), are understudied. Qualitative interviews (N=84) from US and Israeli adults (2022) examined perceptions of advertising messages, specifically: 1) scientific claims that switching completely from cigarettes to IQOS reduces 1a) chemical exposure and 1b) tobacco-related disease risk; 2) FDA endorsement of IQOS as a 2a) better choice for adult smokers and 2b) fundamentally different product (heat-not-burn); and 3) promoting IQOS as cigarette alternatives with a HWL pertaining to cigarettes. For half of participants, referencing scientific studies or the FDA enhanced credibility; some believed this implied unbiased, rigorous research. Half were skeptical due to lack of research-related details. Half interpreted message 1 (switching) to mean any substitution could be beneficial; half interpreted it as complete substitution was necessary. Most did not perceive differences between message 1a (reduced exposure) vs. 1b (reduced risk). Some believed message 2a (FDA endorsement, not targeting youth) demonstrated IQOS' social responsibility. Some interpreted message 2b (fundamentally different product) as risk reduction; others perceived no difference. The majority paraphrased messages using the terms 'safer', 'healthier', or 'less harmful'. For message 3 (safer alternative), some did not think the HWL applied to IQOS; some believed it promoted IQOS. Regulators and researchers must monitor harm reduction advertising messaging and take actions to prevent consumer misinterpretations. Philip Morris International's IQOS received US Food and Drug Administration (FDA) authorization for 'reduced exposure' advertising claims, which are often misinterpreted, and has exploited FDA authorization to promote IQOS globally. This qualitative study showed that most participants perceived no difference between reduced risk vs. exposure messages in IQOS ads, half believed that references to scientific studies or FDA enhanced credibility, some believed certain messages demonstrated IQOS' social responsibility, and some perceived warnings in IQOS ads to promote IQOS. Product ads using harm reduction messages must be monitored to inform efforts to prevent potentially harmful misinterpretations and mitigate negative population-level impacts.

A Novel Spectrofluorimetric Method for Vibegron in the Newly FDA Approved Pharmaceutical Formulation and in Human Plasma: Analytical QbD Strategy for Method Development and Optimization.

Vibegron is a novel selective beta-3 adrenergic receptor agonist molecule, recently approved by US Food and Drug Administration (FDA) in tablet pharmaceutical formulation for treating overactive bladder syndrome. Such formulation necessitates the development of a simple, fast and cost-effective methodology capable of assaying the drug in various real samples with high sensitivity. Herein, a facile and robust spectrofluorimetric method was introduced, for the first time, for vibegron quantification based on analytical quality-by-design approach. The method involves drug reaction with dansyl chloride at pH 9.8, as a smart approach to overcome the non-fluorescent nature of vibegron, giving a highly fluorescent yellow derivative measured at 514nm after being excited at 345nm. Plausible reaction scheme between the drug and dansyl chloride was elucidated through studying the differences in their infrared (IR) spectra. Variables affecting fluorescence intensities were carefully screened and rationally optimized via preliminary scouting studies and central composite design for accurate and robust results. Full International Council for Harmonisation (ICH) validation protocol was followed where linearity was achieved in range of 20.0-400.0 ng/mL with minimum detectability of 3.6 ng/mL. The proposed method expressed good capability in assaying the marketed dosage forms with no excipient inference. Finally, the high sensitivity of such method paved the way for extending its application to quantify vibegron in spiked human plasma at concentrations around its real human plasma concentrations for further bioavailability studies.

Pathology of doxorubicin-induced organopathies under different intravenous nicotinamide riboside administration modes

Doxorubicin (DOX) is a potent chemotherapeutic drug, but its clinical use is hindered by significant side effects on vital organs like the heart, kidneys, lungs, liver, and intestines. Currently, there is a lack of effective drugs that can provide simultaneous cardioprotection and organ protection during chemotherapy. Nicotinamide riboside (NR) holds promise as a pharmacological agent capable of offering comprehensive protection against the systemic toxicity caused by DOX. This study aimed to comprehensively evaluate the morphological characteristics of vital organs (heart, lungs, liver, kidneys) in Wistar rats with chronic doxorubicin-induced cardiomyopathy using various intravenous administration modes of NR as a protective agent. Sixty male SPF Wistar rats weighing 283 ± 22 g were divided into four groups: intact, control (DOX administered intraperitoneally), combined mode (the simultaneous use of DOX and NR) and preventive mode (the preliminary use of NR to realize the cumulative effect in cells, and its further joint use together with DOX) intravenous NR administration. Animal observation spanned two months after drug administration, followed by the collection of hearts, lungs, liver, and kidneys for morphological analysis. Echocardiographic assessment confirmed DOX cardiotoxicity. The study revealed that the hearts, kidneys and lungs exhibited more pronounced toxic effects of DOX compared to the liver. Both NR administration modes demonstrated protective effects, with the preventive regime showing the greatest efficacy in safeguarding vital organs.

Trends in complexity of single-agent and combination therapies for solid tumor cancers approved by the US Food and Drug Administration.

Many FDA-approved cancer therapies, whether as a multiagent combination or as a single agent, have demonstrated only modest clinical benefit. To investigate the drug development landscape, this analysis focuses on whether newly approved drugs are added to existing standards as combination therapy or replace a former drug as monotherapy. A retrospective analysis of package inserts and corresponding trials for the treatment of nonhematology solid tumor malignancies from January 2011 to December 2023 was conducted to categorize an approval as monotherapy or combination therapy. Drug characteristics, treatment indications, study design, approval history, and efficacy results were compared between the 2 cohorts. Among the 292 approval entries and 110 drugs, 193 (66.1%) were monotherapies and 99 (33.9%) were combinations. Combinations, when compared with monotherapies, were more frequently approved as regular than accelerated approval (85 [85.9%] vs 132 [68.4%], P <.01), in the first-line setting (66 [66.7%] vs 69 [35.8%], P <.01), and with overall survival as the criteria (49 [49.5%] vs 40 [20.7%], P <.01). Monotherapies were more likely to be novel drugs compared with combinations (80 [41.5%] vs 14 [14.1%] P <.01). Monotherapies were more likely to be small molecule targeted agents, while combinations were more likely to be immunotherapies (P <.02). There was no difference comparing the time-to-event endpoints and validated clinical benefit scale, but the median response rate of combinations (46%) was higher than monotherapies (34%, P <.01). Given that clinical benefit appears limited in combination therapy compared with monotherapy, drug development could focus on simplifying cancer therapies toward patient-centered paradigms.

Quality enhancement of potato chips through acrylamide mitigation and comparison with local potato chips in Bangladesh

Potato chips are popular and frequently consumed ready-to-eat food in the world. Acrylamide is a possible carcinogenic and neurotoxic compound formed in potato chips during heat processing, a public health concern. This study aimed to develop potato chips to mitigate acrylamide formation, followed by Food and Drug Administration (FDA) guidelines with some modifications. A total of 15 local chip samples were collected by a stratified random sampling method and were assessed for nutritional values, sensory attributes, microbial quality, and acrylamide levels. Acrylamide was extracted from potato chips using a novel activated charcoal method, then determined by the High- Performance Liquid Chromatography (HPLC) method and showed that only 40% of local potato chips were above the benchmark level established by the EU 2017/2158 (750 ppb) (parts per billion) and ranged from 461 ppb to 2129 ppb while in the developed chips it was not detected. The microbial results showed that the developed chips are safe according to Bangladesh Standards and Testing Institution (BSTI) standard, while the local chips contain total viable count (TVC) (&gt;104 ) and yeast-mold count in a significant amount (&gt;103 ). Sensory evaluation results showed that the developed potato chip samples had high ratings for all the evaluated attributes. From the nutritional point of view, fat content is lower while protein and fiber content is higher in developed potato chips. Moisture content is significantly higher in local potato chips than in developed potato chips, which is the major concern for microbial quality. As a result of the study's findings, acrylamide formation in potato chips was successfully mitigated by adhering to FDA modification guidelines without compromising quality, despite the fact that many locally produced potato chips are unfit for human consumption.

IDH1/2 Mutations in Cancer: Unifying Insights and Unlocking Therapeutic Potential for Chondrosarcoma.

Chondrosarcomas, a rare form of bone sarcomas with multiple subtypes, pose a pressing clinical challenge for patients with advanced or metastatic disease. The lack of US Food and Drug Administration (FDA)-approved medications underscores the urgent need for further research and development in this area. Patients and their families face challenges as there are no systemic therapeutic options available with substantial effectiveness. A significant number (50-80%) of chondrosarcomas have a mutation in the isocitrate dehydrogenase (IDH) genes. This review focuses on IDH-mediated pathogenesis and recent pharmacological advances with novel IDH inhibitors, explores their potential therapeutic value, and proposes potential future avenues for clinical trials combining IDH inhibitors with other systemic agents for chondrosarcomas.

Anxiety and depression among a community-recruited cohort of people who use methamphetamine: A longitudinal analysis.

This study (1) estimated changes in anxiety and depression throughout 3 years in a community-recruited cohort who use methamphetamine and (2) modelled whether these changes were associated with patterns of methamphetamine use or other time-varying or fixed covariates. We used a longitudinal analysis using data derived from surveys conducted between August 2016 and March 2020, set in metropolitan and rural locations in Victoria, Australia. Participants comprised a total of 849 adults with regular methamphetamine use history at baseline, recruited for the prospective VMAX study via snowball and respondent-driven sampling. Anxiety and depression symptoms were measured using the Generalized Anxiety Disorder (GAD)-7 and the Patient Health Questionnaire (PHQ)-9 instruments. Frequency of methamphetamine use was measured by self-reported number of days per week participants used any form of methamphetamine in the past month. Changes in anxiety and depression symptom scores were associated with change in route of administration from non-injecting to injecting [adjusted coefficient (adj. coeff.) = 1.44, 95% confidence intervals (CI) = 0.39, 2.48, adj. coeff. = 1.49, 95% CI = 0.39, 2.58], change in severity of dependence for methamphetamine (adj. coeff. = 0.29, 95% CI = 0.21, 0.37, adj. coeff. = 0.34, 95% CI = 0.26, 0.42), starting treatment for drugs other than methamphetamine (adj. coeff. = -2.21, 95% CI = -3.70, -0.73, adj. coeff. = -2.09, 95% CI = -3.60, -0.58) and other covariates. Among regular methamphetamine users in Australia, changes in anxiety or depression scores are associated with changes in route of administration, dependence severity and starting treatment for other drugs, but do not appear to be associated with frequency of methamphetamine use.

The HDAC6 inhibitor AVS100 (SS208) induces a pro-inflammatory tumor microenvironment and potentiates immunotherapy.

Histone deacetylase 6 (HDAC6) inhibition is associated with an increased pro-inflammatory tumor microenvironment and antitumoral immune responses. Here, we show that the HDAC6 inhibitor AVS100 (SS208) had an antitumoral effect in SM1 melanoma and CT26 colon cancer models and increased the efficacy of anti-programmed cell death protein 1 treatment, leading to complete remission in melanoma and increased response in colon cancer. AVS100 treatment increased pro-inflammatory tumor-infiltrating macrophages and CD8 effector T cells with an inflammatory and T cell effector gene signature. Acquired T cell immunity and long-term protection were evidenced as increased immunodominant T cell clones after AVS100 treatment. Last, AVS100 showed no mutagenicity, toxicity, or adverse effects in preclinical good laboratory practice studies, part of the package that has led to US Food and Drug Administration clearance of an investigational new drug application for initiating clinical trials. This would be a first-in-human combination therapy of pembrolizumab with HDAC6 inhibition for locally advanced or metastatic solid tumors.

Key influencers of mass drug administration implementation and scale-up: a social network analysis of soil-transmitted helminth intervention platforms in Benin, India, and Malawi

IntroductionLarge community-based public health programs, like mass drug administration (MDA), require coordination across many stakeholders. We used social network analysis (SNA) to systematically identify the network of stakeholders who influence delivery of school-based and community-wide MDA for soil-transmitted helminths (STH) in Benin, India, and Malawi and determine how network dynamics may impact implementation and scale-up across these delivery platforms.MethodsThis study was embedded within the implementation science research of the DeWorm3 Project, a hybrid clinical trial in Benin, India, &amp;amp; Malawi testing the feasibility of STH transmission interruption via community-wide MDA. Sites developed lists of stakeholders engaged in both MDA programs and indicated stakeholders’ attitudes towards the intervention and influence over intervention delivery. We developed digital sociograms for both MDA networks by site, comparing baseline vs. endline. We descriptively compared changes over time in stakeholder attitudes and influence and key SNA measures, including centrality, centralization, and density.ResultsAcross sites, we identified an expansive network of stakeholders involved in delivery of school-based (N= 139, 63, 58 vs. N=139, 162, 63) and community-wide MDA programs (N=52, 137, 54 vs. N=54, 136, 60) at baseline vs. endline in Benin, India, and Malawi, respectively. At both timepoints, a majority (&amp;gt;70%) of stakeholders held positive attitudes towards both programs. For both programs, stakeholders with the highest degree centrality scores (i.e., the most connected individuals) were those responsible for implementation such as community drug distributors or school teachers, while those with the highest betweenness centrality scores (i.e. those who controlled resource or information flow across networks) were responsible for policy-making &amp;amp; program leadership (e.g., NTD Program Managers). Low density scores indicated networks had poor overall connectedness due to minimal connectivity across administrative levels, while low centralization scores reflected stable networks where no single individual exhibited high control over resource flow.ConclusionDuring stages of innovation, redesign, or scale-up, analyzing the network of policymakers and implementers provides an opportunity to optimize effectiveness and efficiency of public health programs. Study findings provide useful insight for NTD policymakers and implementers in STH-endemic countries aiming to successfully interrupt STH transmission by transitioning from school-based to community-wide MDA.

Performance evaluation of the Specific Reveal system for rapid antibiotic susceptibility testing from positive blood cultures containing Gram-negative pathogens.

Rapid antimicrobial drug administration is crucial for the efficient treatment of sepsis or septic shock, but empirical therapy is limited by the increasing prevalence of multidrug-resistant bacteria. Thus, rapid and reliable antimicrobial susceptibility testing (AST) is needed to start appropriate antimicrobial drug administration as quickly as possible. In the present study, we evaluated the performance of the Reveal rapid AST system. From February to April 2021, 102 positive blood culture bottles (BCBs) from hospitalized patients with bacteremia caused by Gram-negative bacteria were included in the study. All isolates were tested by the Reveal system directly from the positive BCBs in comparison to the DxM MicroScan WalkAway. Essential agreement (EA) and category agreement (CA) were high with 98.5% and 97.1%, respectively. We also determined the susceptibility of 10 highly resistant CDC & FDA AR strains in duplicate. Here, EA was 99.6% and CA 97.9%. The average time to result by Reveal was 5.4 h ± 1.2 h compared to an average of 16 h by DxM MicroScan WalkAway for clinical strains and 3.8 h ± 1.2 h for more resistant CDC & FDA AR strains. Susceptibility determination with the Reveal rapid AST system directly from positive BCBs is for the frequently represented bug-drug combinations a reliable and accurate approach, meeting the European ISO guideline for the performance of AST systems. Moreover, AST directly from blood cultures performed with the Reveal system saves time when compared to the conventional AST, as no subculturing is needed and time to result is very short.

Hepatitis associated with immune checkpoint inhibitors-based combinations of other therapies: A real-world pharmacovigilance analysis based on the FDA adverse event reporting system (FAERS) database.

The combination regimen with immune checkpoint inhibitors (ICIs) and other therapies has been widely applied for patients with non-small-cell lung cancer (NSCLC). To date, no literature has systematically addressed the risk of hepatitis associated with the combination therapy. We conducted this pharmacovigilance analysis using the Food and Drug Administration Adverse Event Reporting System (FAERS). A total of 587,016 NSCLC reports were extracted from FAERS database spanning from the first quarter of 2013 to the second quarter of 2023. After filtering duplicate reports, logistic regression model was used to detect safety signals, and multivariable logistic regression model was used to confirm the interaction between ICI and other drugs. Of the 81,512 patients with NSCLC, 2785 cases developed hepatitis. Multivariable logistic regression analyses revealed that the adjusted ROR of ICI combined with targeted therapy (TT) was the highest 1.64 (95% CI, 1.32-2.02; P < 0.0001) among all therapies, while that of TT and ICI treatment were 1.07 (95% CI, 0.98-1.17; P = 0.1097) and 1.12 (95% CI, 1.03-1.22; P = 0.0111), respectively. The adjusted ROR for the interaction effect was 1.64 (95% CI, 1.32-2.02; P < 0.0001). Furthermore, the adjusted ROR of ICI combined with KRAS-targeted drugs was the highest 3.03 (95% CI, 1.49-5.93; P = 0.0016) among all targeted drugs, with an adjusted ROR of 3.03 (95% CI, 1.49-5.93; P = 0.0016), indicating a meaningful interaction of these two kinds of drugs. We confirmed that combination treatment of ICI and TT is associated with the amplified risk of hepatitis, which is partly due to the interaction between ICI and TT, and the KRAS-targeted drugs may harbor the highest potential for hepatitis induction among TT drugs when combined with ICI. Besides, the combination treatment of ICI- and KRAS-targeted drugs also increases the incidence of colitis, pulmonary embolism and dehydration.

Pharmacokinetics of Antiretroviral Drugs in Older People Living with HIV, Part II: Drugs Licensed Before 2005.

Advances in antiretroviral therapy led to an increase in life expectancy among people living with human immunodeficiency virus (HIV). As aging is characterized by several physiological changes that can influence pharmacokinetics (PK), this systematic review aims to describe the impact of aging on the PK of antiretrovirals (ARV) approved by the Food and Drug Administration (FDA) before 2005. Searches were performed in BVS, EMBASE, and PubMed databases for publications until June 2024. Peer-reviewed published studies were included if they met the following criteria: adults (≥ 18 years) living with HIV; reporting at least one PK parameter or plasma concentration of any ARV approved by the US FDA before 2005 and still used in the clinic: lamivudine (3TC), emtricitabine (FTC), tenofovir disoproxil fumarate (TDF), abacavir (ABC), zidovudine (ZDV), efavirenz (EFV), nevirapine (NVP), atazanavir (ATV), lopinavir (LPV), ritonavir (RTV), tipranavir (TPV), and fosamprenavir (FPV); PK parameters stratified per age group as young (aged 18-49 years) or older (age ≥ 50 years) adults; and manuscripts published in English, Portuguese, or Spanish. All studies were evaluated for risk of bias. The review protocol was registered in the PROSPERO database (registration no. CRD42023463092). Among 106 studies included, only 22 evaluated the PK of participants aged 50 years or older and only 5 studies compared the PK between young and older adults for ATV, RTV, EFV, and 3TC. Our analysis revealed an increase in minimal concentration (Cmin) values for LPV, RTV, and ATV in older adults. While increased values of the area under the curve (AUC) and maximum concentration (Cmax) were observed in older adults using ATV, 3TC, and FTC, no differences in PK were apparent between young and older adults for ABC and EFV, with no estimation possible for ZDV. Exposure to 3TC, TDF, FTC, ATV, LPV, and RTV increases with age, while exposure to ABC and EFV appears to be unaffected. Despite the large quantity of data on PK in young adults, there is still a gap in knowledge about the effects of aging on the PK of these ARVs.

Treatment discontinuation in adults with atypical hemolytic uremic syndrome (aHUS): a qualitative study of international experts' perspectives with associated cost-consequence analysis.

Atypical hemolytic uremic syndrome (aHUS) is a rare, life-threatening thrombotic microangiopathy (TMA) related to congenital mutations impeding control of the alternative pathway of complement. Following approval of the complement C5 inhibitor eculizumab by the European Medicines Agency and the US Food and Drug Administration, initial guidelines suggested lifelong therapy. Yet, growing evidence indicates that discontinuation of eculizumab, or its long-acting form ravulizumab, is possible for many patients. This mixed-methods study sought to explore international experts' perspectives and experiences related to treatment duration in adult patients with aHUS, while also estimating the financial and potential health consequences of early discontinuation. Between January and December 2023, we conducted 10 qualitative interviews with experts in the treatment of aHUS, based upon which we constructed a quantitative decision tree, designed to estimate time on treatment and treatment- and disease-related adverse events. Thematic analysis of the interview data identified four main themes: (1) Concerns and prior experience; (2) High-risk vs. low-risk groups; (3) Patient preference and adherence; and (4) Funding for monitoring and re-treatment. Although most interviewees were in favour of considering treatment discontinuation for many patients (citing the high cost, burden, and potential side effects of lifelong treatment as key reasons), a prior negative experience of discontinuation seemed to make others more reluctant to stop. Deciding which patients required lifelong treatment and which not involved consideration of a wide range of factors, including patient- and system-related factors. Cost-consequence analysis demonstrated the financial savings associated with early treatment discontinuation at the expense of increased risk of recurrent TMA events. Close monitoring for these events had the potential to minimise any long-term injury, primarily renal, with an estimated one event per 100 patient years. For patients at high risk of TMA and with poor adherence to monitoring, rates of renal injury rose to three events per 100 patient years. aHUS treatment protocols are changing globally in response to new clinical evidence. Against this backdrop, our mixed-methods study provides compelling evidence on the complexity of factors influencing treatment discontinuation decisions in aHUS, as well as the financial and health consequences of early discontinuation.