PLOS Digit Health. 2025 Jun 26;4(6):e0000892. doi: 10.1371/journal.pdig.0000892. eCollection 2025 Jun.

ABSTRACT

The Medical Informatics Initiative Germany (MII) aims to facilitate the interoperability and exchange of electronic health record data from all German university hospitals. The MII use case "POLyphamacy, drug interActions and Risks" (POLAR_MI) was designed to retrospectively detect medication-related risks in adult inpatients. As part of POLAR_MI, we aimed to build predictive models for specific adverse events. Here, using the two adverse events gastrointestinal bleeding and drug-related hypoglycaemia as examples, we present our initial investigation to determine whether these adverse events and their associations with potential risk factors can be detected. We applied a two-step distributed analysis approach to electronic health record data from 2018 to 2021. This approach consisted of a local statistical data analysis at ten participating centres, followed by a mixed-effects meta-analysis. For each adverse event, two multivariable logistic regression models were constructed: (1) including only demographics, diagnoses and medications, and (2) extended by laboratory values. As numerically stable estimations of both models were not possible at each centre, we constructed different centre subgroups for meta-analyses. We received prevalence estimates of around 1.2% for GI bleeding and around 3.0% for drug-related hypoglycaemia. Although unavailability of laboratory values was a common reason hindering model estimation, multivariable regression models were obtained for both adverse events from several centres. Regarding our original intention to build predictive models, the median area under the receiver operating characteristic curve was above 0.70 for all multivariable regression models, indicating feasibility. In conclusion, plausible estimates for prevalence and regression modelling odds ratios were received when using a distributed analysis approach on inpatient treatment data from diverse German university hospitals. Our results suggest that the development of predictive models in a distributed setting is possible if the research question is adapted to the infrastructure and the available data.

PMID:40569944 | DOI:10.1371/journal.pdig.0000892

CEN Case Rep. 2025 Jun 26. doi: 10.1007/s13730-025-01012-2. Online ahead of print.

ABSTRACT

Drug-induced kidney injury is a major cause of acute tubulointerstitial nephritis (AIN). The standard treatment for AIN is discontinuation of the causative agent; however, if discontinuation alone is insufficient, glucocorticoid therapy may be effective. A 51-year-old woman was admitted to our hospital with acute kidney injury, presenting with an estimated glomerular filtration rate (eGFR) of 6.3 mL/min/1.73m2. She was diagnosed with AIN after a renal biopsy. Drug-induced lymphocyte stimulation tests were performed on the herbal medicine she had been taking for 5 months, Saikokaryukotsuboreito (comprising Bupleurum root, Pinellia tuber, Scutellaria root, and Ginseng as key ingredients). The test results were positive for all four components. The patient discontinued the causative agent, and her renal function improved with oral glucocorticoid therapy (prednisolone 30 mg/day). After 6 months of treatment, her renal function stabilized, with only minor residual tubular acidosis. This case of AIN induced by Saikokaryukotsuboreito, which responded to glucocorticoid therapy, highlights the potential for recovery with appropriate treatment.

PMID:40569518 | DOI:10.1007/s13730-025-01012-2

Front Pharmacol. 2025 Jun 11;16:1605458. doi: 10.3389/fphar.2025.1605458. eCollection 2025.

ABSTRACT

BACKGROUND: Carboplatin is a renally excreted antineoplastic drug associated with myelotoxic effects. Doses are calculated according to the Calvert formula. The change from Cockcroft-Gault (CG) to the race-free Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) may have an impact on doses. The aim of the study was to evaluate the difference in carboplatin doses based on estimated glomerular filtration rate (eGFR) calculated using the two different equations (i.e., CG and CKD-EPI) applied to a real-world dataset of carboplatin administrations.

MATERIALS AND METHODS: Retrospective study simulating the effect of switching to CKD-EPI on doses calculated using CG. Real-world data were collected on all carboplatin doses administered in a general hospital oncology day-care unit during 2023. Doses originally calculated using CG estimates were recalculated using CKD-EPI results. A Bland-Altman analysis was performed to assess the discrepancies between the two equations. Correlations with anthropometric data were examined.

RESULT: A total of 487 cycles were administered to 126 patients with a mean age of 58.3 years (SD 12.6), 60.3% were female. There was a significant mean difference (p < 0.001) with a moderate effect (Cohen's d = 0.474) between clearance calculated with CG and eGFR calculated with CKD-EPI. CKD-EPI calculated doses had a mean 52 mg higher (limits of agreement -107 + 211). Percentage differences between CKD-EPI and CG doses ranged from +70.9% (CG = 405 mg, CKD-EPI = 692 mg) to -24.3% (CG = 684 mg, CKD-EPI = 518 mg). Differences were strongly correlated with body mass index (BMI) (p < 0.001, R = 0.681).

CONCLUSION: Clinically relevant differences were found between carboplatin doses calculated with CG and CKD-EPI. These differences were more relevant in male patients with low BMI.

PMID:40567373 | PMC:PMC12187738 | DOI:10.3389/fphar.2025.1605458

Gut Liver. 2025 Jun 26. doi: 10.5009/gnl250019. Online ahead of print.

ABSTRACT

BACKGROUND/AIMS: To compare the efficacy and safety of fexuprazan and lansoprazole for preventing peptic ulcers (PUs) induced by nonsteroidal anti-inflammatory drugs (NSAIDs).

METHODS: This multicenter, double-blind, randomized, active-controlled study was conducted across 32 hospitals in South Korea. Patients with musculoskeletal disease requiring long-term treatment with celecoxib, naproxen, or meloxicam were randomized to receive either fexuprazan 20 mg/day (n=212) or lansoprazole 15 mg/day (n=211) for 24 weeks. The primary endpoint was the occurrence of PUs, which were confirmed via esophagogastroduodenoscopy (EGD), with a non-inferiority margin of 8.3%. Only ulcers that developed during the treatment period were examined in the analysis. The occurrence of gastroduodenal bleeding was also monitored via EGD, and symptoms were assessed by using the Patient Assessment of Upper Gastrointestinal Disorders Symptom Severity Index (PAGI-SYM). Adverse events were recorded during the study.

RESULTS: The incidence rate of EGD-confirmed PUs at week 24 was 1.16% in the fexuprazan group and 2.76% in the lansoprazole group, with a between-group difference of -1.64% (95% confidence interval, -4.52% to 1.25%), demonstrating non-inferiority. No patients presented with gastroduodenal bleeding. No significant between-group differences were found in the PAGI-SYM scores (leastsquare mean difference in the total score at week 24, -0.42; 95% confidence interval, -2.48 to 1.64; p=0.69). There were low rates of adverse drug reactions in the fexuprazan and lansoprazole groups (8.57% vs 4.78%, respectively p=0.12).

CONCLUSIONS: Given its non-inferiority to lansoprazole and similar safety profile, fexuprazan is a promising alternative for the prevention of NSAID-induced PUs (ClinicalTrials.gov identifier NCT04784910).

PMID:40567214 | DOI:10.5009/gnl250019

Pharmacoepidemiol Drug Saf. 2025 Jul;34(7):e70182. doi: 10.1002/pds.70182.

ABSTRACT

PURPOSE: Good documentation of adverse events related to medicines is essential for the assessment of safety signals. Information on the clinical quality of primary pregnancy safety data sources is lacking. The objective of this study was to assess the differences in clinical quality of various sources of primary pregnancy pharmacovigilance (PV) data.

METHODS: Fifty reports of exposures to medicines during pregnancy were collected from: spontaneous and literature reports from EudraVigilance, European Network of Teratology Information Services (ENTIS), the Dutch Pregnancy Drug Register, enhanced PV programmes (EPV), and patient support programmes (PSP). Reports were standardized and anonymized, after which their clinical quality was assessed. Mean scores per source were compared using ANOVA (analysis of variance test).

RESULTS: Mean clinical quality scores were 89.0% (SD 10.1%) for the Dutch Pregnancy Drug Register, 77.1% (SD 13.3%) for TIS, 64.7% (SD 20.5%) for EPVs, 49.5% (SD 16.2%) for PSPs, 40.9% (SD 21.6%) for spontaneous reports, and 38.6% (SD 18.0%) for literature reports. All were statistically significantly different (p ≤ 0.05) except for spontaneous versus literature reports (mean difference 2.2%, p = 0.99) and spontaneous reports versus reports from PSPs (-8.6%, p = 0.14).

CONCLUSIONS: For data sources specifically designed for pregnancy data collection, the clinical quality of information generally outweighed sources designed to capture general safety information. EPV methods showed better scores for clinical quality compared to spontaneous reporting data for pregnancy PV.

PMID:40566817 | DOI:10.1002/pds.70182

J Pharmacokinet Pharmacodyn. 2025 Jun 25;52(4):37. doi: 10.1007/s10928-025-09985-4.

ABSTRACT

The questions and answers (Q&A) document for ICH E14/S7B provides the following advancements for QTc assessment: concentration-QTc modeling (C-QTc) as the primary analysis, accepting alternative approaches (Q&A 5.1 and 6.1) to thorough QT (TQT) studies, and incorporating an integrated nonclinical risk assessment as supporting evidence. Based on QT study reports reviewed by the FDA between 2016 and 2024, changes to the E14 guideline have resulted in a 34% decrease in the proportion of TQT studies, while the use of C-QTc analysis as the primary analysis has significantly increased. Studies using C-QTc instead of by-time analysis as the primary analysis reduced median sample sizes by 67%, 42%, and 35% for parallel, nested crossover, and crossover studies, respectively. The white paper C-QTc model was used for 60% of drugs that prolonged the QTc interval. From 2020 to 2024, reviews incorporating an integrated nonclinical risk assessment have also increased. The advancements in QTc assessments have streamlined QTc assessment and made clinical trials less resource-intensive. As the advancements continue to evolve the drug safety evaluation is likely to become even more adaptive and enable more precise and targeted QTc assessment.

PMID:40560402 | DOI:10.1007/s10928-025-09985-4

Gen Dent. 2025 Jul-Aug;73(4):10-14.

ABSTRACT

This case report describes the emergence of oral immune-related adverse events following the administration of pembrolizumab, an immune checkpoint inhibitor (ICI), for cutaneous melanoma. The affected patient developed drug-induced oral lichenoid hypersensitivity reactions, oral candidiasis, and angular cheilitis that were successfully managed with topical dexamethasone and nystatin rinses and systemic fluconazole. Patients undergoing prolonged ICI therapy should be informed about the potential for oral complications and the need for close monitoring by oral healthcare providers. Proper management of ICI-related oral sequelae is essential to preserve dental and soft tissue health and prevent potential delays or premature discontinuation of oncologic treatment resulting from oral manifestations.

PMID:40560079

Hematol Rep. 2025 May 30;17(3):29. doi: 10.3390/hematolrep17030029.

ABSTRACT

Background and Clinical Significance: Intermediate- to high-risk Myelodysplastic Syndrome (MDS), according to the Revised International Prognostic Scoring System (IPSS-M), confers a high risk of progression into acute myeloid leukemia. Treatment with hypomethylating agents, including azacitidine and decitabine, represents the current standard of care. In eligible patients, hypomethylating agents are used as a bridge for allogeneic stem cell transplantation, currently the only curative approach in these malignancies. The most common side effects of hypomethylating agents are myelosuppression, cutaneous injection site reactions (when azacitidine is given subcutaneously), and gastrointestinal symptoms. Uncommon, disabling, and long-lasting side effects represent a threat to effective treatment in this group of patients. Case Presentation: We describe the case of a 49-year-old male patient with IPSS-M intermediate-risk MDS, intended to receive first-line treatment with azacitidine followed by allogeneic stem cell transplantation. The first, late-onset azacitidine reaction was observed 48 h after the first exposure, with cutaneous and respiratory toxicity, followed by the late-onset recurrence of symptoms after azacitidine withdrawal and decitabine introduction. Conclusions: This case highlights atypical, disabling, and long-lasting drug reactions to two hypomethylating agents, with the persistence of hypersensitivity manifestations months after medication withdrawal.

PMID:40558807 | DOI:10.3390/hematolrep17030029

BioTech (Basel). 2025 May 24;14(2):39. doi: 10.3390/biotech14020039.

ABSTRACT

As part of the substantial public discourse surrounding the distribution and use of mifepristone, which is used with misoprostol to facilitate drug-induced abortions, claims comparing the safety of this regimen to that of common pharmaceuticals have emerged and proliferated. Offered in forums ranging from social media to the Supreme Court, these claims have so gained public acceptance that they are now echoed without scrutiny and, at times, reference. Yet the simplistic slogan that "mifepristone is safer than Tylenol", though easily disseminated, defies both an intuitive understanding of how we evaluate drug safety and our norms and regulations for doing so. Indeed, if such an assertion was attributable to the manufacturer, it would precipitate a reprimand by the FDA given the lack of specific, controlled, and head-to-head evidence rightly required for its support. To the extent that these claims persist, however, including among the outputs of medical societies, abortion centers, clinical researchers, and government officials, and to the extent that they aim to inform both individual and public decision-making, it is critical that the evidence offered for their support be thoroughly explored. Such examination reveals these claims to be wholly unfounded, offering deficient and disingenuous representations of safety for any of the drugs compared.

PMID:40558388 | DOI:10.3390/biotech14020039

Antibiotics (Basel). 2025 May 27;14(6):548. doi: 10.3390/antibiotics14060548.

ABSTRACT

Background: Fosfomycin is used as a combination partner for the treatment of severe non-urinary tract infections. Individualized dosing of fosfomycin based on therapeutic drug monitoring (TDM) has the potential to reduce drug-related adverse events (AEs). Methods: This retrospective study used routine data from patients receiving intravenous fosfomycin therapy. Plasma concentrations of fosfomycin were categorized into three different ranges: <64 mg/L, 64-128 mg/L, and >128 mg/L. Subsequently, the influence of acute kidney injury (AKI) on reaching the specific plasma concentration ranges and the occurrence of AEs was analyzed. Results: The study included 143 patients (median age 73 years, 66.4% male) with fosfomycin plasma measurements. Beta-lactam antibiotics were most frequently used in combination (62.2%), followed by tetracyclines (12.2%), cotrimoxazole (8.1%), and other agents (17.5%). Fosfomycin concentrations were >128 mg/L in 45% (36/80) of patients with normal renal function, 70.4% (38/54) of patients with AKI stages I to III, and 77.8% (7/9) of patients with renal replacement therapy. AEs occurred in 54% (77/143), mainly hypernatremia (42.6%), hypokalemia (39.9%), and gastrointestinal symptoms (19.6%), with the median fosfomycin plasma concentration being significantly higher in patients with AEs (158 mg/L vs. 131 mg/L, p = 0.01). Multivariate logistic regression analysis revealed that patients aged ≥70 years (OR 3.70, 95% CI 1.24-11.5; p = 0.02) and patients with fosfomycin plasma concentrations > 128 mg/L (OR 3.30, 95% CI 1.09-10.4; p = 0.04) had a higher risk of AEs. Conclusions: There was a significant association between high plasma exposure and the occurrence of AEs. In particular, the impact of acute renal insufficiency on fosfomycin plasma concentrations should be considered. Individualized fosfomycin dosing based on TDM and the intensive monitoring of renal function contribute to reducing drug-related side effects.

PMID:40558138 | DOI:10.3390/antibiotics14060548

Pak J Biol Sci. 2025 Feb;28(3):162-168. doi: 10.3923/pjbs.2025.162.168.

ABSTRACT

&lt;b&gt;Background and Objective:&lt;/b&gt; A common folate antagonist used to treat neoplastic conditions is methotrexate (MTX); the drug's biotransformation in the liver results in active metabolites that increase hepatotoxicity. Olive leaf extract is one type of antioxidant that may shield our bodies from the damaging effects of free radicals. The current study aimed to assess olive extract's hepato-protective potential against MTX-induced liver injury in rats. &lt;b&gt;Materials and Methods:&lt;/b&gt; Twenty-four male rats were divided into three groups of eight. The control group received no treatment, the methotrexate (MTX) group was administered a single 20 mg/kg dose of MTX intraperitoneally and the third group received olive leaf extract (1 mL/100 g body weight) daily for one month after the same MTX injection. Serum globulin levels were measured and histological, histochemical and immunohistochemical investigations were performed. Statistical analysis was conducted using ANOVA with p<0.05 considered significant. &lt;b&gt;Results:&lt;/b&gt; With a highly significant decrease in mean total proteins and albumin levels and an insignificant decrease in globulin values, the second group showed a highly significant increase in mean total bilirubin and hepatic enzyme levels. Additionally, compared to the control group, this one showed worsened microscopic alterations. In addition to noticeably better microscopical results than the second group, the third group also showed reversed biochemical results. &lt;b&gt;Conclusion:&lt;/b&gt; This research found that administering olive extract to individuals receiving methotrexate is important for managing and shielding them from the drug's serious hepatotoxic side effects.

PMID:40556102 | DOI:10.3923/pjbs.2025.162.168

Sci Rep. 2025 Jun 24;15(1):20272. doi: 10.1038/s41598-025-05680-z.

ABSTRACT

Lorazepam is extensively used to treat anxiety disorders and anxiety associated with depression. This study evaluates the safety of lorazepam based on real-world data from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). Data were collected from January 2004 to June 2024. After standardizing the data, we quantified signals using four algorithms, including the Reporting Odds Ratio (ROR), the Proportional Reporting Ratio (PRR), the Bayesian Confidence Propagation Neural Network (BCPNN), and the Multi-Item Gamma Poisson Shrinker (MGPS) to quantize the signal by Bayesian analysis and disproportionation analysis. AE signals were predominantly involved psychiatric disorders, nervous system disorders, injury, poisoning and procedural complications, and cardiac disorders. Notably, new potential AE signals of clinical value were identified in this study, including tachycardia, rhabdomyolysis, neologism, phagophobia, pancreatic fibrosis, and pneumonia. Sex-stratified analysis showed that the risk of poisoning was more pronounced in females and the AEs of sedation were more pronounced in males. Age-stratified analysis demonstrated variations in AEs across different age groups.The findings of this study were consistent with clinical trials, and identified several new potential AE signals. In addition, there are gender and age differences in some AEs. These findings provide valuable insights into lorazepam in clinical practice.

PMID:40555731 | DOI:10.1038/s41598-025-05680-z

Hum Vaccin Immunother. 2025 Dec;21(1):2518646. doi: 10.1080/21645515.2025.2518646. Epub 2025 Jun 24.

ABSTRACT

A clear consensus on the factors contributing to adverse reactions following the mRNA COVID-19 vaccine has yet to be reached. Therefore, the present study investigated adverse reactions following the first three doses of the BNT162b2 mRNA COVID-19 vaccine and examined associated factors, including previous experience of adverse reactions. Two prospective cohort studies were integrated for this study, and 218 participants (79% female; median age 46.5 years) who had completed all three doses of BNT162b2 were included in the final analyses. Data were collected through self-administered electronic questionnaires. Local and systemic adverse reactions following vaccinations were classified with severity grading. Modified Poisson regression models were used to examine the association of adverse reactions. Local reactions were reported by 91-96% of participants, with moderate or severe local reactions in 27-43%. Systemic reactions were reported by 56-88% of participants, with moderate or severe systemic reactions in 19-56%. Participants with a history of moderate or severe local reactions were more likely to subsequently have moderate or severe local reactions (relative risk: 2.32 [95% confidence interval: 1.52-3.55] for the second dose, 1.89 [1.33-2.69] for the third dose), but not systemic reactions. Participants with a history of moderate or severe systemic reactions were more likely to subsequently have moderate or severe systemic reactions (1.31 [0.99-1.72] for the second dose, 2.18 [1.56-3.06] for the third dose), but not local reactions. These results may contribute to a more detailed understanding of mRNA COVID-19 vaccines and provide information for future vaccine development.

PMID:40555671 | DOI:10.1080/21645515.2025.2518646

Gut. 2025 Jun 24:gutjnl-2025-335577. doi: 10.1136/gutjnl-2025-335577. Online ahead of print.

ABSTRACT

BACKGROUND: Despite inadequate supply and potential contamination risk, human plasma has remained the only source for human serum albumin (pHSA) intravenous administration since the 1940s.

OBJECTIVE: We sought to establish the safety and efficacy of OsrHSA, a recombinant HSA from bioengineered Oryza sativa (rice).

DESIGN: In this multicentre, randomised, double-blind and positive-controlled study, patients with decompensated liver cirrhosis and serum albumin ≤30 g/L were recruited from 22 centres in China. The patients were randomly assigned to OsrHSA or pHSA (4:1) to once-daily intravenous injection (10 g or 20 g) until their serum albumin level reached 35 g/L, for a maximum of 2 weeks, with 2 weeks of follow-up. The primary outcome was the proportion of patients to reach a serum albumin level of 35 g/L (non-inferiority margin <-0.20). Outcomes were evaluated in patients who received the study drug and had at least one post-baseline serum albumin value (full analysis set, FAS). Safety was evaluated in all patients who received the study drug.

RESULTS: Between 22 March 2021 and 2 June 2022, 220 patients received OsrHSA (n=175) or pHSA (n=45). 216 patients were included in the FAS (OsrHSA, n=171; pHSA, n=45). Primary outcome of OsrHSA (130/171, 76%) was non-inferior to pHSA (34/45, 75.6%) (difference=0.5%; lower limit of 97.5% CI=-0.119). There was no significant difference between all secondary outcomes of OsrHSA and pHSA. There were no drug-related serious adverse events.

CONCLUSIONS: Rice-derived HSA is non-inferior to plasma-derived HSA in efficacy and safety. This finding should be confirmed in phase 3 trial.

TRIAL REGISTRATION NUMBER: NCT04835480.

PMID:40555465 | DOI:10.1136/gutjnl-2025-335577

Biomater Adv. 2025 Jun 19;177:214393. doi: 10.1016/j.bioadv.2025.214393. Online ahead of print.

ABSTRACT

Current drug carriers, while effective in mitigating therapeutic side effects, frequently elicit non-drug-related adverse reactions, including hepatorenal toxicity, oxidative stress and allergic responses. To address these issues and enhance drug efficacy, we propose a "drug-carrying-drug" strategy that integrates photodynamic therapy (PDT) with chemotherapy for potential tumor eradication. Traditional photosensitizers often confront a paradoxical dilemma between aggregation-induced photodynamic deactivation and dispersion-mediated premature photobleaching. To overcome these limitations, we developed PPCNM, a multifunctional micellar carrier. PPCNM is constructed by PEGylating pyropheophorbide-α (PPA), a porphyrin-based photosensitizer, and conjugating it with the tumor-targeting pentapeptide CREKA. Before entering tumor cells, PPCNM remains aggregated to prevent photobleaching. Upon internalization, it disassembles to activate PDT and stably delivers doxorubicin (DOX). DOX@PPCNM not only mitigates photobleaching and phototoxicity caused by premature PDT activation but also alleviates adverse effects associated with chemotherapeutic monotherapy. The fibrin- specific CREKA peptide, which targets tumor vasculature, improves the precise delivery of photosensitizers and chemotherapeutics to tumor tissues. Overall, this study presents a promising strategy for developing a dual-drug targeted delivery system combining PDT with other therapies.

PMID:40555158 | DOI:10.1016/j.bioadv.2025.214393

J Clin Oncol. 2025 Jun 24:JCO2402744. doi: 10.1200/JCO-24-02744. Online ahead of print.

ABSTRACT

PURPOSE: Patritumab deruxtecan (HER3-DXd; MK-1022) is an investigational HER3-directed antibody-drug conjugate composed of a human immunoglobulin G1 monoclonal antibody to HER3 (patritumab) covalently linked via a stable tetrapeptide-based cleavable linker to a topoisomerase I inhibitor payload that has shown durable antitumor activity in previously treated patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC). We extend these observations to patients with advanced NSCLC with other/no identified driver genomic alterations.

METHODS: Patients with advanced squamous or nonsquamous NSCLC without a common EGFR-activating mutation whose disease had progressed on previous therapies including platinum-based chemotherapy, immune checkpoint inhibitors, and targeted therapy (for patients with known actionable genomic alterations) received HER3-DXd 5.6 mg/kg intravenously once every 3 weeks. The primary end point was confirmed objective response rate (cORR).

RESULTS: Forty-seven patients were treated with HER3-DXd (median treatment duration, 4.2 [range, 0.7-19.8] months). The cORR was 27.7% (95% CI, 15.6% to 42.6%), and the median duration of response was 8.1 (95% CI, 4.2 to not evaluable) months. The median progression-free survival was 5.5 (95% CI, 4.0 to 11.2) months, and the median overall survival was 15.2 (95% CI, 10.8 to 17.7) months. Similar efficacy was observed in patients with NSCLC harboring identified driver genomic alterations and in those without such genomic features. The rate of study drug discontinuation associated with treatment-emergent adverse events (TEAEs) was 12.8%. Study drug-related grade ≥3 TEAEs occurred in 51.1% of patients and were serious in 12.8% (none were associated with death). Adjudicated treatment-related interstitial lung disease occurred in five patients (10.6%; all grade 1 or 2).

CONCLUSION: The previously reported efficacy and safety of HER3-DXd in heavily pretreated patients with EGFR-mutated NSCLC are also observed in those with other NSCLC subtypes and warrant further clinical evaluation.

PMID:40554742 | DOI:10.1200/JCO-24-02744

Front Immunol. 2025 Jun 9;16:1529637. doi: 10.3389/fimmu.2025.1529637. eCollection 2025.

ABSTRACT

BACKGROUND: The growing use of immune checkpoint inhibitors (ICIs) in the neoadjuvant treatment of colorectal cancer (CRC) has highlighted immune-related adverse events (irAEs) as a major concern. This study aimed to investigate the characteristics of irAEs.

METHODS: This study was a retrospective, multicenter, registry-based investigation conducted in China, including 148 patients who developed irAEs after neoadjuvant immunotherapy between September 2020 and March 2024. The study analyzed the types, severity, risk factors and management strategies of irAEs. Data were collected on patient demographics, tumor assessments, neoadjuvant therapy regimens, and irAEs. Statistical analyses were conducted to identify the characteristics of irAEs and to assess their impact on surgical outcomes.

RESULTS: Among the 148 patients, a total of 203 irAEs were documented, primarily affecting the skin, endocrine system, and liver. Most irAEs (95.6%) were mild-to-moderate in severity and were effectively managed with symptomatic treatment. Hepatotoxicity was the most frequent irAE, notably associated with the combination of radiotherapy and the CAPOX chemotherapy regimen. The severity of irAEs did not affect surgical complexity or postoperative complications.

CONCLUSION: Neoadjuvant immunotherapy combined with chemoradiotherapy demonstrates a favorable safety profile, with most irAEs being manageable. The findings support the clinical feasibility of combined regimens in CRC treatment, emphasizing the need for individualized management and extended follow-up for late-onset or chronic irAEs.

PMID:40552298 | PMC:PMC12183158 | DOI:10.3389/fimmu.2025.1529637

Blood Neoplasia. 2024 Sep 18;1(4):100043. doi: 10.1016/j.bneo.2024.100043. eCollection 2024 Dec.

ABSTRACT

This phase 1b trial aimed to determine the safety, tolerability, and preliminary efficacy of mezagitamab, a subcutaneously administered anti-CD38 monoclonal antibody, in patients with relapsed/refractory multiple myeloma (RRMM). Eligible patients had received ≥3 prior lines of treatment, including an immunomodulatory drug (IMiD), a proteasome inhibitor (PI), and a steroid, or ≥2 prior lines in which 1 included a PI + IMiD, and were refractory or intolerant to ≥1 IMiD and ≥1 PI. Fifty patients were enrolled: 44 received mezagitamab monotherapy (dose-escalating cohorts at 45-1200 mg) and 6 received mezagitamab 300 mg in combination with pomalidomide plus dexamethasone. Patients received mezagitamab weekly for 8 doses, every other week for 8 doses, and monthly thereafter. No dose-limiting toxicities were reported with single-agent mezagitamab, and the recommended phase 2 dose was determined as 600 mg. The most common drug-related treatment-emergent adverse events (TEAEs) were fatigue in the monotherapy cohort (9/44 patients) and neutropenia in the combination cohort (4/6 patients); neutropenia was the only drug-related grade ≥3 TEAE to occur in >1 patient. No infusion reactions occurred, and 4 injection-site reactions were reported. Three patients discontinued treatment due to TEAEs. Among the 22 patients receiving 600 mg mezagitamab, the overall response rate was 47%, and the median duration of response was 22.1 months. Mezagitamab outcomes were comparable to those reported with other anti-CD38 therapies in patients with advanced RRMM. Further development of mezagitamab in myeloma is not planned, but studies are underway in autoimmune conditions. This trial was registered at www.ClinicalTrials.gov as #NCT03439280.

PMID:40552138 | PMC:PMC12182851 | DOI:10.1016/j.bneo.2024.100043

J Headache Pain. 2025 Jun 23;26(1):147. doi: 10.1186/s10194-025-02091-3.

ABSTRACT

BACKGROUND: Gepants have demonstrated notable benefits in migraine therapy, yet their safety profiles are not thoroughly investigated. This study comprehensively analyzed the adverse event (AE) risk signals of the currently approved gepants using the U.S. Food and Drug Administration Adverse Event Reporting System database, aiming to gain better understanding of their post-marketing safety features and potential risks.

METHODS: All data of the gepants (rimegepant, atogepant, ubrogepant, and zavegepant) from January 1st 2020 to December 31st 2024 were retrieved from the database. Descriptive analysis was conducted to characterize the features of gepant-associated AEs. Disproportionality analysis and subsequent sensitivity analysis were employed to evaluate the risk signals of the gepants utilizing the algorithms of reporting odds ratio (ROR), proportional reporting ratio (PRR), and information component (IC).

RESULTS: A total of 7766 reports of rimegepant, 3672 reports of atogepant, 1958 reports of ubrogepant, and 463 reports of zavegepant were identified after data processing. Most AEs were occurred within 30 days after gepant administration. The integration of disproportionality analysis and sensitivity analysis indicated that "feeling abnormal" was the most reported AE of rimegepant (n = 185, 6.81%, ROR025 = 6.46, IC025 = 2.59, PRR = 7.24, χ2 = 998.58), while "constipation" was the most common AE of atogepant (n = 288, 16.09%, ROR025 = 19.99, IC025 = 4.10, PRR = 20.72, χ2 = 5418.12). The most prevalent AE of ubrogepant was "fatigue" (n = 60, 7.19%, ROR025 = 1.88, IC025 = 0.84, PRR = 2.38, χ2 = 48.82), whereas "dysgeusia" was the most frequently observed AE of zavegepant (n = 150, 45.18%, ROR025 = 212.07, IC025 = 6.10, PRR = 181.96, χ2 = 26,975.74). Comparative analysis of AEs revealed that two AEs were shared among all gepants and zavegepant had the largest collection of unique AEs (n = 15).

CONCLUSIONS: The present pharmacovigilance study systematically revealed the significant risk signals of gepants. The common AEs and unique AEs of the four gepants were also identified and explored. Our results would provide valuable reference for the safe use of gepants, guiding personalized drug selection in clinical practice.

PMID:40551098 | DOI:10.1186/s10194-025-02091-3

BMJ Open. 2025 Jun 23;15(6):e094409. doi: 10.1136/bmjopen-2024-094409.

ABSTRACT

OBJECTIVE: Amoxicillin-clavulanate is commonly used to prevent infections following snakebites despite the lack of clinical evidence. We aimed to demonstrate that clinically directed initiation of amoxicillin-clavulanate would be non-inferior to routine use in this setting.

DESIGN: Open-label, randomised, non-inferiority trial with blinded adjudication of endpoints.

SETTING: Emergency department of a teaching hospital in southern India.

PARTICIPANTS: Adults with local swelling following snakebites within 24 hours of bite.

INTERVENTIONS: In the routine use strategy, intravenous followed by oral amoxicillin-clavulanate was administered for at least 5 days. In the clinically directed strategy, the antibiotic was only initiated for clinical failures.

PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcomes were protocol-defined clinical failure and total antibiotic consumption. Non-inferiority margin was prespecified as 10%. Secondary outcomes were the length of hospital stay, total antivenom consumption, new-onset organ failure, bleeding requiring transfusion, death/need for surgical intervention and drug-related adverse events.

RESULTS: The trial was prematurely stopped due to the COVID-19 situation after randomising 66 patients-34 to clinically directed initiation and 32 to routine use arms. Russell's viper was the most common (21 (32%)) biting snake species identified; 52 (79%) patients had evidence of haemotoxic envenomation at baseline, and 24 (36%) patients developed AKI. There were 10 clinical failures-six in the clinically directed initiation arm and four in the routine use arm. The difference in clinical failure between the two arms was 5.2% (-12.0%-21.7%; p=0.291); the upper bound of the CI exceeded the prespecified non-inferiority margin. Total antibiotic consumption, expressed in DDDs, was significantly lower in the clinically directed initiation arm (0 (0-1) vs 5.31 (4.67-6.17); p<0.001). Three serious adverse events resulting in two deaths (one in each arm) were observed.

CONCLUSIONS: We could not demonstrate the non-inferiority of clinically directed initiation compared with routine use of amoxicillin-clavulanate among patients with local swelling caused by haemotoxic snakebites. However, the frequency of clinical failures was similar, and antibiotic consumption was substantially lower with the clinically directed initiation strategy.

TRIAL REGISTRATION NUMBER: ClinicalTrials.gov; NCT02570347.

PMID:40550712 | DOI:10.1136/bmjopen-2024-094409