Expert Opin Drug Saf. 2025 Feb 25. doi: 10.1080/14740338.2025.2472918. Online ahead of print.

ABSTRACT

BACKGROUND: To evaluate the incidence and risk of drug-induced interstitial lung disease (DIILD) associated with anti-neoplastic drugs among patients with cancer in Korea. Research design and methods: This nested case-control study included 457,685 patients diagnosed with cancer and treated with anti-neoplastic drugs from a retrospective nationwide population-based cohort between 2017 and 2021. The incidence rate of DIILD and the risks of DIILD by anti-neoplastic drug categories were analyzed.

RESULTS: Among 270,595 patients, 2,634 developed ILD, resulting in an incidence rate of 4.12 per 1,000 person-years (95% confidence interval (CI): 3.97-4.28). DIILD was more prevalent in men, older patients, and those with a history of pulmonary disease or lung cancer. In a multivariable conditional logistic regression analysis, immune checkpoint inhibitors (odds ratio (OR): 2.37; 95%CI: 1.48-3.78), mammalian target of rapamycin inhibitors (OR: 9.79; 95%CI: 5.20-18.45), antibody-drug conjugates (OR: 7.99; 95%CI: 3.24-19.74), cyclin-dependent kinase 4/6 inhibitors (OR: 2.28; 95%CI: 1.26-4.12), and any combination of different drug categories (OR: 1.93; 95%CI: 1.21-3.09) were associated with an increased risk of DIILD.

CONCLUSION: Our findings suggest that the risk of incident DIILD depends on the category of anti-neoplastic drugs. Patients with identified risk factors and treated with these drugs should be monitored closely.

PMID:40007198 | DOI:10.1080/14740338.2025.2472918

Vaccines (Basel). 2025 Feb 7;13(2):161. doi: 10.3390/vaccines13020161.

ABSTRACT

Background: Despite adverse events following immunization (AEFI) being well described in vaccine trials, there is a need to produce more real-world data on events supposedly attributed to vaccination against COVID-19. This study aims to estimate the prevalence of AEFI in the first dose of COVID-19 vaccines in the state of Brazil and to verify whether such events differ among the types of vaccines offered in this country. Methods: A population-based study using linked administrative data on vaccine registry and adverse events following immunization in 2021 and 2022. The study included 10,169,378 individuals aged 18 or over who lived in Bahia and received the first dose of COVID-19 vaccines. We calculated AEFI prevalence and verified differences among vaccines by logistic regression to estimate crude and adjusted by sex and age group prevalence ratio (PR). Results: The prevalence of AEFI was 74.3 per 100,000 doses applied, with a higher rate of nonserious events, mainly following the ChAdOx1-S. More than two-thirds of these adverse effects occurred in women, and almost half were between 30 and 49 years old. The individuals who received ChAdOx1-S had a 125% higher prevalence than those who received CoronaVac. Those who received BNT162b2 and Ad26.COV2.S had a 71% and 58%, respectively, lower prevalence of AEFI than those who received CoronaVac. Conclusions: The use of vaccines against COVID-19 has proven to be positive and effective in combating SARS-CoV-2, significantly reducing morbidity and mortality from the disease. We cannot deny the presence of adverse events in the context of vaccination. However, the vaccines have proven to be safe and reliable. The results of this study offer relevant data that can contribute to the qualification of AEFI pharmacovigilance in Brazil and worldwide.

PMID:40006708 | DOI:10.3390/vaccines13020161

Pharmaceuticals (Basel). 2025 Jan 29;18(2):180. doi: 10.3390/ph18020180.

ABSTRACT

The emergence of antibody-drug conjugates (ADCs) has transformed the treatment landscape of a variety of cancers. ADCs typically consist of three main components: monoclonal antibody, chemical linker, and cytotoxic payload. These integrated therapeutic modalities harness the benefits of each component to provide a therapeutic response that cannot be achieved by conventional chemotherapy. Antibodies play roles in determining tumor specificity through target-mediated uptake, prolonging the circulation half-life of cytotoxic payloads, and providing additional mechanisms of action inherent to the original antibody, thus significantly contributing to the overall performance of ADCs. However, ADCs have unique safety concerns, such as drug-induced adverse events related to the target-mediated uptake of the ADC in normal tissues (so-called "on-target, off-tumor toxicity") and platform toxicity, which are partially derived from limited tumor uptake of antibodies. Identifying suitable target antigens thus impacts the clinical success of ADCs and requires careful consideration, given the multifaceted aspects of this unique treatment modality. This review briefly summarizes the representative roles that antibodies play in determining the efficacy and safety of ADCs. Key considerations for selecting suitable cell surface target antigens for ADC therapy are also highlighted.

PMID:40005994 | DOI:10.3390/ph18020180

Pathogens. 2025 Feb 15;14(2):195. doi: 10.3390/pathogens14020195.

ABSTRACT

Adverse events following immunizations (AEFIs) with recombinant zoster vaccine (RZV) are underexplored in fragile populations. This study aims to assess incidence, duration, and characteristics of AEFIs, focusing on the impact of sex, age, and prior Herpes Zoster (HZ) infection in a frail population, including solid organ transplant recipients. We conducted an observational study on patients receiving RZV, and AEFIs were classified as local or systemic and analyzed for incidence, duration, and patterns across groups. We showed that females had a higher incidence of AEFIs (p = 0.02), both local and systemic symptoms, such as swelling +/- redness at the site of injection and fatigue, after the first and second doses. Younger adults experienced more systemic reactions, while older adults reported more local events (e.g., redness and swelling, p = 0.01). Moreover, patients with previous HZ infection exhibited a higher incidence of AEFIs after the second dose (68% vs. 38%, p = 0.001). In conclusion, sex, age, and clinical history significantly influenced AEFI incidence and manifestations. Therefore, it is important to personalize vaccination strategies in frail populations, by tailored administration and monitoring plans, especially in females and individuals with prior HZ infection, to improve vaccine safety and patient outcomes.

PMID:40005570 | DOI:10.3390/pathogens14020195

J Chem Inf Model. 2025 Mar 10;65(5):2256-2267. doi: 10.1021/acs.jcim.4c01320. Epub 2025 Feb 25.

ABSTRACT

Drug safety is affected by multiple molecular properties and safety assessment is critical for clinical application. Evaluating a drug candidate's therapeutic potential is facilitated by machine learning models trained on extensive compound bioactivity data sets, presenting a promising approach to drug safety assessment. Here, we introduce SynthMol, a deep learning framework that integrates pre-trained 3D structural features, graph attention networks, and molecular fingerprints to achieve high accuracy in molecular property prediction. Evaluation of SynthMol on 22 data sets, including MoleculeNet, MolData and published drug safety data, showed that it could provide higher prediction accuracy than state-of-the-art model in most tasks. SynthMol achieved an ROC-AUC value of 0.944 in the BBBP data set, 2.61% higher than the next best model, and an ROC-AUC of 0.906 on the hERG data set, a 2.38% improvement. Validation of SynthMol in real-world applications with experimentally determined hERG toxicity and CYP inhibition data supported its capacity to distinguish functional changes for drug development. The implementation code and data are available at https://github.com/ThomasSu1/SynthMol.

PMID:40000610 | DOI:10.1021/acs.jcim.4c01320

Transplant Proc. 2025 Feb 24:S0041-1345(25)00083-1. doi: 10.1016/j.transproceed.2025.02.008. Online ahead of print.

ABSTRACT

Cytomegalovirus (CMV) is one of the most common opportunistic infections affecting solid organ transplant recipients (SOTRs). In this article, we presented the case of a 39-year-old patient with end-stage renal disease after kidney transplantation with refractory CMV infection, who was successfully treated with maribavir for the first time in Poland. The use of maribavir resulted in a significant reduction of CMV viremia in ganciclovir/valganciclovir-resistant CMV infection and resolution of CMV disease symptoms in the absence of drug-related adverse events.

PMID:40000309 | DOI:10.1016/j.transproceed.2025.02.008

PLoS One. 2025 Feb 25;20(2):e0314970. doi: 10.1371/journal.pone.0314970. eCollection 2025.

ABSTRACT

Assessing the potential for oseltamivir-induced liver damage is essential to ensure its safe administration. The aim of this study was to examine the association between hepatotoxicity and oseltamivir use and to describe the features of oseltamivir-induced hepatotoxicity. Data were obtained from the Adverse Event Reporting System of the US Food and Drug Administration (FAERS). Disproportionality and proportionality analyses were performed to evaluate the safety profile of oseltamivir-related hepatotoxicity and the occurrence of hepatotoxicity-related adverse events across sex and age groups. The FAERS recorded 20,340,254 adverse event reports between 2004 and 2023, of which 16,960,996 reports were included in the analysis. We identified 14 types of oseltamivir-related adverse events that were hepatotoxic and showed positive signals. The most frequently reported adverse event was abnormal hepatic function (n = 54), and the most severe adverse event was fulminant hepatitis. Compared with that for male individuals, the reporting odds ratio (ROR) was 0.5 for female individuals; and for male individuals, the ROR, compared with that for female individuals, was 4.19. The median time to hepatotoxic adverse events, excluding mixed liver injury, was < 5 days. Oseltamivir can cause liver toxicity, which is influenced by sex and age. Liver function tests and monitoring for signs of liver disease are crucial when using oseltamivir.

PMID:39999160 | DOI:10.1371/journal.pone.0314970

PLoS One. 2025 Feb 25;20(2):e0318597. doi: 10.1371/journal.pone.0318597. eCollection 2025.

ABSTRACT

Serious Adverse Drug Reactions (ADRs) can cause a longer stay, which can result in fatal outcomes. Understanding the prognostic factors for the serious ADRs play a vital role in developing appropriate serious ADR prevention strategies. This study aimed to analyze nationwide database in Thailand to identify predisposing factors associated with the serious ADRs, explore drug exposure, distribution of serious ADRs, types of ADRs, and classify the determinants of serious ADR due to anti-infective in Thailand. The national database of anti-infective-induced ADRs from January 2012 to December 2021 in Thailand's 77 provinces, Thai Vigibase at the Health Product Vigilance Center (HPVC), was considered. After pre-processing, frequencies and percentages were used to investigate the distribution of ADR seriousness. To determine the significance of the independent variables on the seriousness of anti-infective-induced ADRs, logistic regression and the Classification and Regression Tree (CART) model were performed. A p-value < 0.05 was considered statistically significant. A total of 82,333 ADR cases, of which 20,692 were serious ADRs (25.13%). Serious ADRs is statistically associated with region, gender, ethnicity, age, type of patient, history of drug allergy, chronic disease and dose frequency (p-value < 0.001). The most commonly reported serious ADRs were in the South region of Thailand (OR = 1.92, 95% CI = 1.88-1.97), followed by the North region (OR = 1.68, 95% CI = 1.64-1.71) of Thailand. Gender and history of drug allergy were also statistically associated with the seriousness of ADRs (p-value = 0.001). Reported ADRs revealed that patients were males (OR = 1.11, 95% CI = 1.11-1.13) and those with a prior history of drug allergy (OR = 1.22, 95% CI = 1.20-1.24) were more likely to experience serious ADRs. The risk of having an ADR reported as serious was significantly higher in patients aged 60 and over (OR = 1.42, 95% CI = 1.39-1.46) and patients aged 40-59 years (OR = 1.34, 95% CI = 1.31-1.37) compared to patients aged 0-19 years. IPD patients most commonly associated with serious ADRs. The results of this study will enable healthcare professionals to use caution when prescribing to those groups. Furthermore, developing a reporting system to reduce serious ADR evidence, such as software with electronic prescribing databases or applications that enable efficient detection of ADRs in high-risk groups, was critical in order to closely monitor and improve patient safety.

PMID:39999099 | DOI:10.1371/journal.pone.0318597

Adv Respir Med. 2025 Feb 6;93(1):3. doi: 10.3390/arm93010003.

ABSTRACT

BACKGROUND: Asthma significantly impacts global health, necessitating effective management strategies. A combination of inhaled corticosteroids (ICSs) and long-acting β2-agonists (LABA) is recommended for patients with inadequately controlled asthma.

METHOD: This prospective, open-label, multicenter study (PROMISING-SHIFT) study evaluated the safety and efficacy of once-daily Indacaterol/Mometasone (IND/MF) dry powder inhaler (DPI) in Indian asthma patients (≥12 years), inadequately controlled with prior therapies. Patients received IND/MF DPI in three strengths (150/80 mcg, 150/160 mcg, 150/320 mcg) over 12 weeks.

RESULTS: The study included a total of 174 participants, and 27 adverse events (AEs) in 25 patients (14.37%) were reported, primarily mild to moderate, with no serious adverse events (SAEs). Drug-related treatment-emergent adverse events (TEAEs) were observed in 11 patients. Significant improvements were noted in the mean trough FEV1 and FVC, increasing from baseline to week 4 and week 12 (p < 0.001). The mean ACQ-5 score significantly decreased from 3.0 ± 0.73 baseline to 2.50 ± 0.53 (16.67%) at week 4 and further to 1.73 ± 0.35 at week 12, along with reduced exacerbations (p < 0.001). The need for rescue medication declined from 13.79% to 8.62%, and 96.55% of patients reported treatment satisfaction by study completion.

CONCLUSION: Once-daily IND/MF DPI demonstrated a favorable safety profile with marked improvements in lung function, asthma control, and patient satisfaction, making it a promising option for long-term asthma management in Indian patients.

PMID:39996620 | DOI:10.3390/arm93010003

Pharmacol Res Perspect. 2025 Apr;13(2):e70080. doi: 10.1002/prp2.70080.

ABSTRACT

Concern over the side effects of anti-obesity medications, particularly if severe, has grown as their use has increased. Thus, the objective was to use trends in the reporting of suspected adverse events associated with anti-obesity medications that have been approved for sale in the European Union to attempt to uncover discrepancies in the safety of these medications. The study was designed as secondary research, based on data about the number of adverse drug reactions (both serious and non-serious) reported to the EudraVigilance database. Trends of the annual reporting rates for the six anti-obesity drugs were analyzed by the Joinpoint Trend Analysis Software that divides the trendline into an optimum number of segments connected by "joinpoints" and tests the significance of the trend within each segment. The trends of serious adverse drug events showed clear differences among the anti-obesity drugs: while all drugs had significant increasing trends during a few initial years after their appearance on the market, only the annual number of reports for semaglutide continued to grow ever since (annual change + 67.1%, p = 0.000). On the contrary, a continuous increase in the reporting rate of non-serious adverse drug events was observed only for liraglutide (annual change + 33.8%, p = 0.000) while for the other anti-obesity drugs, including semaglutide, the trends after the initial period were either negative or did not increase significantly. In conclusion, among the anti-obesity drugs currently approved, only semaglutide shows a continuously increasing trend in the annual reporting of serious adverse events, suggesting a need for further investigation of safety signals.

PMID:39995024 | DOI:10.1002/prp2.70080

Hum Vaccin Immunother. 2025 Dec;21(1):2463194. doi: 10.1080/21645515.2025.2463194. Epub 2025 Feb 24.

ABSTRACT

Invasive meningococcal disease is an uncommon but serious disease predominantly affecting children. This phase 2b study evaluated MenABCWY in 6-month-old infants followed by MenB-fHbp and MenABCWY in 2-month-old infants, the latter being the target age and intervention. Participants were randomized to MenABCWY, 60 µg or 120 µg MenB-fHbp+MenACWY-TT, or 4CMenB+MenACWY-TT, administered as 2 primary and 1 booster dose. The primary safety objective was to describe the safety profile of MenABCWY in participants enrolled at 2 months. Primary immunogenicity objectives were the percentage of participants achieving seroprotective serum bactericidal antibody using human complement titers. Overall, 314 and 12 participants were randomized to sentinel cohort and open-label expanded-enrollment stages, respectively. Based on 2 reports of fever requiring invasive investigations and accompanied by cerebrospinal fluid pleocytosis and 1 report arising from a previous study, the Sponsor terminated the study. Local reactions and systemic events after primary vaccination were generally mild to moderate, and tended to be higher with MenABCWY versus 4CMenB+MenACWY-TT. Immunogenicity data suggest that 1 month after vaccination 2, MenABCWY responses for MenA/C/W/Y were robust and comparable with 4CMenB+MenACWY-TT in 2-month-old participants. Immune responses for MenB test strains were higher with MenABCWY versus 4CMenB+MenACWY-TT and generally similar with 60 µg and 120 µg MenB-fHbp+MenACWY-TT or MenABCWY. Based on the limited results, the consistency of MenB immune responses with 60 µg and 120 µg MenB-fHbp suggests doses < 60 µg could be investigated to assess whether a more acceptable safety profile in conjunction with beneficial immune responses is possible in 2-month-old infants.

PMID:39993937 | DOI:10.1080/21645515.2025.2463194

Drug Discov Ther. 2025 Feb 23. doi: 10.5582/ddt.2024.01071. Online ahead of print.

ABSTRACT

Numerous medications have been associated with an increased risk of vaginal hemorrhage in women. In this study, we analyzed data from the FDA Adverse Event Reporting System (FAERS), focusing on reports of drug-induced vaginal bleeding in women. Risk signals were assessed using disproportionality analyses, specifically the reporting odds ratio (ROR) and the proportional reporting ratio (PRR), to identify significant associations between drugs and adverse events. We found that anticoagulants, hormonal drugs, psychotropic drugs, hypoglycemic agents, antineoplastic agents, anti-inflammatory drugs, immunological agents, and some drugs for osteoporosis were significantly associated with the risk of vaginal hemorrhage. Hormonal drugs, anticoagulants, and particularly antifungal agents were attributed to a notably high proportion of vaginal hemorrhage cases, necessitating further investigation into the underlying mechanisms. Therefore, precise clinical management of medications and optimization of treatment regimens are necessary to reduce the risk of vaginal hemorrhage and improve safety.

PMID:39993768 | DOI:10.5582/ddt.2024.01071

Medicine (Baltimore). 2025 Feb 21;104(8):e41482. doi: 10.1097/MD.0000000000041482.

ABSTRACT

BACKGROUND: The phase 3 randomized, active-controlled GS-US-380-1844 (NCT02603120) study evaluated switching to the single-tablet regimen bictegravir, emtricitabine, and tenofovir alafenamide (B/F/TAF) from dolutegravir (DTG), abacavir (ABC), and lamivudine (3TC) among people with HIV-1. Previously, results from the 48-week double-blind phase showed that switching to B/F/TAF was noninferior to remaining on DTG/ABC/3TC and that B/F/TAF was well tolerated. Here, we show the long-term safety and efficacy of switching to B/F/TAF from DTG/ABC/3TC among people with HIV-1.

METHODS: Participants were virologically suppressed people with HIV-1 (HIV-1 RNA <50 copies/mL for ≥ 3 months prior to screening) receiving DTG/ABC/3TC at baseline. Participants were randomized 1:1 to switch to B/F/TAF or remain on DTG/ABC/3TC. Following 48 weeks of treatment with B/F/TAF or DTG/ABC/3TC in the double-blind phase, participants had the option to enter an open-label extension phase, during which they received B/F/TAF. Virologic, immunologic, and safety outcomes during treatment with B/F/TAF through the open-label extension up to 168 weeks, including preexisting and treatment-emergent resistance, were analyzed.

RESULTS: Among 547 participants in the all-B/F/TAF analysis set, virologic suppression (HIV-1 RNA < 50 copies/mL) was maintained in 99% to 100% of participants up to 168 weeks into B/F/TAF treatment, including in those with preexisting resistance; no treatment-emergent resistance was detected. CD4 cell counts remained stable during B/F/TAF treatment, with median (interquartile range) changes from baseline of -17 (-120, 65) cells/µL at week 48 and -9 (-100, 108) cells/µL at week 96. Safety and tolerability findings were consistent with previously reported findings up to week 48; most drug-related adverse events were grade 1 or 2 in severity; no new safety signals were identified.

CONCLUSION: Switching to B/F/TAF from DTG/ABC/3TC was associated with continued high rates of virologic suppression up to week 168, with no treatment-emergent resistance. B/F/TAF was well tolerated throughout the study period.

PMID:39993074 | DOI:10.1097/MD.0000000000041482

Exp Ther Med. 2025 Feb 5;29(4):66. doi: 10.3892/etm.2025.12815. eCollection 2025 Apr.

ABSTRACT

Intracranial tuberculoma represents one of the most severe complications of central nervous system tuberculosis (TB), with an incidence that is relatively low. In cases of intracranial tuberculoma, patients may develop drug toxicity and/or immune reconstitution inflammatory syndrome (IRIS) while receiving anti-TB treatment. The current study presented the case of a seven-year-old female patient with intracranial tuberculoma who developed drug-induced hepatotoxicity and IRIS during the course of treatment. During the follow-up of the patient, anti-TB drug-induced hepatitis developed, which led to the discontinuation of the drug twice. In the seventh month of treatment, cranial MRI showed the progression of tuberculoma lesions. The possibility of IRIS or treatment failure was considered and the treatment was restarted with steroids and non-hepatotoxic anti-TB drugs. With steroid and anti-TB treatment, the lesions regressed almost completely and the neurological deficit regressed. Patients receiving treatment should be followed up closely due to the possible side effects of anti-TB drugs, especially IRIS, which develops as an immune restructuring response during the recovery of the immune system.

PMID:39991721 | PMC:PMC11843197 | DOI:10.3892/etm.2025.12815

Clin Epidemiol. 2025 Feb 17;17:87-104. doi: 10.2147/CLEP.S494215. eCollection 2025.

ABSTRACT

PURPOSE: This study aims to investigate the potential association between non-selective RET kinase inhibitors and thyroid dysfunction (TD) by conducting a pharmacovigilance analysis using data from the US FDA Adverse Event Reporting System (FAERS).

METHODS: Data for non-selective RET MKIs were obtained from the FAERS database, spanning the first quarter of 2015 to the fourth quarter of 2023. Disproportionality analysis was used to quantify the AE signals associated with non-selective RET MKIs and to identify TD AEs. Subgroup analyses and multivariate logistic regressions were used to assess the factors influencing the occurrence of TD AEs. Time-to-onset (TTO) analysis and the Weibull Shape Parameter (WSP) test were also performed.

RESULTS: Descriptive analysis revealed an increasing trend in TD adverse events linked to non-selective RET MKIs, with a notable proportion of serious reactions reported. Disproportionality analysis using ROR, PRR, BCPNN, and EBGM algorithms consistently demonstrated a positive association between Sunitinib, Cabozantinib, and Lenvatinib with TD adverse events. Subgroup analyses highlighted differential susceptibility to TD based on age, gender, and weight, with varying patterns observed for each inhibitor. Logistic regression analyses identified factors independently influencing the occurrence of TD adverse events, emphasizing the importance of age, gender, and weight in patient stratification. Time-to-onset analysis indicated early manifestation of TD adverse events following treatment with non-selective RET MKIs, with a decreasing risk over time.

CONCLUSION: The results of our study indicate a correlation between the use of non-selective RET MKIs and the occurrence of TD AEs. This may provide support for the clinical monitoring and risk identification of non-selective RET MKIs. Nevertheless, further clinical studies are required to substantiate the findings of this study.

PMID:39989882 | PMC:PMC11844211 | DOI:10.2147/CLEP.S494215

Comput Biol Med. 2025 Apr;188:109848. doi: 10.1016/j.compbiomed.2025.109848. Epub 2025 Feb 22.

ABSTRACT

Phase I clinical trials are the first-in-human studies that primarily focus on the safety profile of drugs. Traditionally, the primary aim of a phase I clinical trial is to establish the maximum tolerated dose and characterize the toxicity profile of the tested agents. As a secondary aim, some phase I studies also include studies to obtain preliminary efficacy information about the experimental agents. In our research, we consider the optimal design of experiments in extended phase I clinical trials where both efficacy and toxicity are measured and the maximum tolerated dose has been established. We represent the response of both outcomes using a bivariate probit model for correlated responses and propose systematic numerical approaches based on Semidefinite Programming to address the problem. We construct locally optimal experimental designs for the following situations: (i) responses with efficacy and toxicity strongly correlated versus non-correlated, by varying the correlation parameter; (ii) a priori known correlation versus unknown correlation; (iii) unconstrained versus constrained designs, where the constraints represent safety limits, budget constraints and probability bounds; (iv) single versus combined drugs. Additionally, we consider four distinct optimality criteria: D-, A-, E-, and K-optimality. Our methodologies are extensively tested, and we demonstrate the optimality of the designs using equivalence theorems. To enrich our analysis, an equivalence theorem for the K-optimality criterion is derived.

PMID:39987700 | DOI:10.1016/j.compbiomed.2025.109848

Br J Clin Pharmacol. 2025 Feb 23. doi: 10.1002/bcp.70022. Online ahead of print.

ABSTRACT

AIMS: The primary objective of this study was to determine the pharmacokinetics, mass balance and biotransformation of [14C]GT0918 in humans after the drug was administered to healthy Chinese male subjects.

METHODS: The absorption, metabolism, and excretion (AME) of GT0918 was characterized via isotope labelling technology in six healthy Chinese male subjects after receiving a single 200 mg oral dose of [14C]GT0918 (80 μCi), and the phenotype, together with the metabolic mechanism of GT0918, was confirmed in vitro.

RESULTS: The medium Tmax of total radioactivity was 6.00 h (4.00-8.00 h) post-dose, and the mean Cmax was 10.5 μg eq./mL (8.7-12.3 μg eq./mL) in plasma. Drug-related components in the plasma were eliminated slowly, with a mean t1/2 of 67.7 h (54.4-90.7 h), and the radioactivity of the plasma samples from some subjects was above the below the quantization limit (BQL) until 17 days post-dose. After 19 days of dosing, the mean cumulative excreted radioactivity was 82.81% (79.07-86.07%) of the dose, including 29.47% (26.71-32.02%) in urine and 53.34% (52.01-55.62%) in faeces, indicating that the drug-related components of GT0918 were mainly excreted by faeces. Metabolite profiling revealed that the parent drug was detected in plasma, as well as in faeces and not in urine. In plasma, the most abundant metabolite was GT0955, a mono-oxidative metabolite of GT0918; in urine, the primary metabolite was GT0795, a metabolite of oxazole ring-opening followed by N-dealkylation; in faeces, the two main metabolites were M551 and the glucuronidation of GT0955. The majority of the metabolites were formed via an important aldehyde intermediate derived from the oxazole ring-opening, and the intermediate was trapped by methoxyamine hydrochloride in the in-vitro study. CYP3A4 is the main enzyme involved in the metabolism of GT0918.

CONCLUSIONS: Overall, all the dosed subjects completed the study, and GT0918 was found to be safe, with no grade II or above adverse events reported. A total dose of 82.81% was quantified in the urine (29.47%) and faeces (53.34%) of healthy adult male subjects after a single oral administration of 200 mg (80 μCi) GT0918 ([14C]GT0918). The metabolism of GT0918 is catalysed predominantly by CYP3A4, and an uncommon pathway of oxazole ring-opening to an aldehyde intermediate has also been proposed.

PMID:39987943 | DOI:10.1002/bcp.70022

Naunyn Schmiedebergs Arch Pharmacol. 2025 Feb 22. doi: 10.1007/s00210-025-03899-1. Online ahead of print.

ABSTRACT

Studies on the assessment of anticancer efficacy of plant-derived phytochemicals by targeting signaling pathways have drawn a lot of attention recently for human health. Multiple investigations have proposed an involvement of Notch pathway in the processes of cancer angiogenesis and metastasis, and drug resistance. Moreover, overexpression of Notch signaling is associated with increased prostate cancer (PrCa) cell growth and development. A number of chemotherapeutic agents are reported to become resistant over a period of time and have severe side effects. To increase efficacy and lessen drug-induced toxicity, a variety of bioactive compounds have been utilized alone or as adjuncts to traditional chemotherapy. Therefore, in the present study, the potential of AKBA in inhibiting the proliferation of PrCa cells by modulating Notch signaling components and its efficacy in combination with cisplatin was investigated. The results exhibited a substantial reduction in cell survival (IC50 = 25.28 µM at 24 h and 16.50 µM at 48 h) and cellular alterations in AKBA-treated PrCa cells. Additionally, AKBA caused nuclear condensation, increased reactive oxygen species (ROS) generation, mitochondrial membrane depolarization, and caspase activation, ultimately leading to apoptosis in PrCa cells. Moreover, AKBA-elicited apoptosis was evidenced by an augmentation in the Bax to Bcl2 ratio. AKBA was also found to induce G0/G1 arrest which was substantiated by reduced cyclin D1 and CDK4 expression levels concomitantly with increased expression of p21 and p27 genes. Intriguingly, AKBA demonstrated significant downregulation of Notch signaling mediators. Furthermore, the isobolograms of the combination treatment indicated that AKBA has the potential to synergistically enhance the cytotoxic efficacy of cisplatin in DU145 cells, as evidenced by CI < 1 across all tested combinations. Overall, the results of this study suggest strong antiproliferative, apoptotic, and chemo-sensitizing potential of AKBA. Thus, AKBA holds a promising drug candidature warranting further investigation as a probable therapeutic option for both the prevention and treatment of PrCa and other solid tumors.

PMID:39985578 | DOI:10.1007/s00210-025-03899-1

Sci Rep. 2025 Feb 21;15(1):6310. doi: 10.1038/s41598-025-91102-z.

ABSTRACT

Immune related adverse events (irAEs) occur due to the inflammatory side effects of immune check point inhibitors (ICIs) and irAEs have been associated with improved efficacy in advanced non-small lung cancer (NSCLC) patients. Corticosteroids can reduce the efficacy of ICIs due to their immunosuppressive effects. In this study, we aimed to show the effects of the development of irAEs and the use of ≥ 10 mg prednisone and equivalent steroids on treatment response. We analyzed the outcomes of patients with NSCLC treated with ICIs as monotherapy or ICIs in combination with chemotherapy (ChT) at a single academic center based on the presence of irAEs and the use of corticosteroids. A landmark analysis was performed due to the time-dependent nature of irAEs. 90 patients were included in the study. irAEs were seen in a total of 45 (50%) patients. In the landmark analysis, the median overall survival (OS) was 52.1 months in those who developed irAEs and 14.4 months in those who did not (HR 2.71, 95% CI (1.55-4.73), p < 0.001), and the median progression-free survival (PFS) was also higher in the patients with irAEs (25.9 vs. 8.4 months, HR 2.54, 95% CI (1.52-4.25), p < 0.001). The objective response rate (ORR) was significantly higher in patients experiencing irAEs than without irAEs: 60% versus 33.3%, respectively (p = 0.011). The number of patients using steroids was 22 (24%), while 68 patients (76%) were not using steroids. There was no significant difference in mOS: 26.5 versus 28.7 months (HR 1.14, 95% CI (0.63-2.08), p = 0.652) and mPFS: 16.9 versus 13.5 months (HR 0.99, 95% CI (0.57-1.74), p = 0.997) between patients who used steroids and those who did not. ICIs efficacy is higher in patients who developed irAEs. In our analyses, the grade of irAEs or the number of irAEs occurring in the individual had no effect on mOS and mPFS. In our patient group, steroid use was mostly related with irAEs, and we did not detect any negative effects of corticosteroid use on PFS and OS.

PMID:39984593 | DOI:10.1038/s41598-025-91102-z

Pharmacol Res Perspect. 2025 Apr;13(2):e70063. doi: 10.1002/prp2.70063.

ABSTRACT

Interstitial lung disease (ILD) is a clinically relevant adverse event associated with biologic agent use. However, the current incidence of ILD remains unclear as large-scale risk assessments of biologic agents have not been conducted. The aim of this study was to clarify the association between biologic agent use and ILD development in clinical practice by detecting adverse event signals using a spontaneous adverse drug reaction database. The VigiBase database is used for spontaneous adverse event reporting. The analysis focused on nine biologics used to treat psoriasis, rheumatoid arthritis, and Crohn's disease. The safety of each biologic agent was evaluated using the information component signal detection method. There were 32,520,983 reports in VigiBase, of which 68,489 (0.21%) were for ILD. Signals were mainly detected for tumor necrosis factor-α inhibitors when the information component for ILD caused by biologic agents was calculated. Comorbidity analysis in patients who developed ILD and analysis of the time from the start of treatment with each drug to ILD onset showed differences for each biologic agent. ILD is a serious adverse effect of biologic agents, and there are several cases in which a causal relationship with ILD development cannot be ruled out. The occurrence of interstitial ILD should be noted when using biologics, particularly TNF-α inhibitors.

PMID:39984304 | DOI:10.1002/prp2.70063