Safety analysis of pemigatinib leveraging the US Food and Drug administration adverse event reporting system

Background: Cholangiocarcinoma (CCA) is a highly lethal and aggressive epithelial tumor of the hepatobiliary system. A poor prognosis, propensity for relapse, low chance of cure and survival are some of its hallmarks. Pemigatinib, the first targeted treatment for CCA in the United States, has been demonstrated to have a significant response rate and encouraging survival data in early-phase trials. The adverse events (AEs) of pemigatinib must also be determined.Objective: To understand more deeply the safety of pemigatinib in the real world through data-mining of the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS).Methods: Disproportionality analysis was employed in a retrospective pharmacovigilance investigation to identify the AEs linked to pemigatinib use as signals. Data were collected between 1 January 2020 to 30 June 2022. Four data-mining methods (proportional reporting odds ratio; proportional reporting ratio; Bayesian confidence propagation neural networks of information components; empirical Bayes geometric means) were used to calculate disproportionality.Results: A total of 203 cases using pemigatinib as the prime-suspect medication were found in our search, which involved 99 preferred terms (PTs). Thirteen signals of pemigatinib-induced AEs in seven System Organ Classes were detected after confirming the four algorithms simultaneously. Nephrolithiasis was an unexpected significant AE not listed on the drug label found in our data-mining. Comparison of the differences between pemigatinib and platinum drugs in terms of 33 PTs revealed that 13 PTs also met the criteria of the four algorithms. Ten of these PTs were identical to those compared with all other drugs, in which (excluding a reduction in phosphorus in blood) other PT signal values were higher than those of all other drugs tested. However, comparison of the differences between pemigatinib and infigratinib in terms of the 33 PTs revealed no significant signals in each algorithm method.Conclusion: Some significant signals were detected between pemigatinib use and AEs. PTs with apparently strong signals and PTs not mentioned in the label should be taken seriously

Comparison of the safety profiles for pirfenidone and nintedanib: a disproportionality analysis of the US food and drug administration adverse event reporting system

BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease of unknown etiology. Pirfenidone (PFD) and nintedanib (NDN) were both conditionally recommended in the clinical practice guideline published in 2015. Safety and tolerability are related to the risk of treatment discontinuation. Therefore, this study evaluated and compared the adverse events (AEs) of PFD and NDN in a large real-world population by analyzing data from the FDA Adverse Event Reporting System (FAERS) to provide a reference for their rational and safe use.MethodsThe AEs of PFD and NDN were extracted from the FAERS database. The pharmacovigilance online analysis tool OpenVigil 2.1 was used to retrieve data from the FAERS database from the first quarter of 2012 to the second quarter of 2022. The reporting odds ratio (ROR) and proportional reporting ratio were used to detect the risk signals.ResultsThe database included 26,728 and 11,720 reports for PFD and NDN, respectively. The most frequent AEs of PFD and NDN were gastrointestinal disorders. The RORs for these drugs were 5.874 and 5.899, respectively. “Cardiac disorders” was the most statistically significant system order class for NDN with an ROR of 9.382 (95% confidence interval = 8.308–10.594). Furthermore, the numbers of designated medical events of PFD and NDN were 552 and 656, respectively. Notably, liver injury was reported more frequently for NDN (11.096%) than for PFD (6.076%).ConclusionThis study revealed differences in the reporting of AEs between PFD and NDN. The findings provide reference for physicians in clinical practice. Attention should be paid to the risks of cardiac disorders and liver injury associated with NDN

Cost-effectiveness of endovascular thrombectomy with alteplase versus endovascular thrombectomy alone for acute ischemic stroke secondary to large vessel occlusion

Background: Recent randomized trials have suggested that endovascular thrombectomy (EVT) alone may provide similar functional outcomes as the current standard of care, EVT combined with intravenous alteplase treatment, for acute ischemic stroke secondary to large vessel occlusion. We conducted an economic evaluation of these 2 therapeutic options. Methods: We constructed a decision analytic model with a hypothetical cohort of 1000 patients to assess the cost-effectiveness of EVT with intravenous alteplase treatment versus EVT alone for acute ischemic stroke secondary to large vessel occlusion from both the societal and public health care payer perspectives. We used studies and data published in 2009–2021 for model inputs, and acquired cost data for Canada and China, representing high- and middle-income countries, respectively. We calculated incremental cost-effectiveness ratios (ICERs) using a lifetime horizon and accounted for uncertainty using 1-way and probabilistic sensitivity analyses. All costs are reported in 2021 Canadian dollars. Results: In Canada, the difference in quality-adjusted life-years (QALYs) gained between EVT with alteplase and EVT alone was 0.10 from both the societal and health care payer perspectives. The difference in cost was USD2847 from a societal perspective and USD2767 from the payer perspective. In China, the difference in QALYs gained was 0.07 from both perspectives, and the difference in cost was USD1550 from the societal perspective and USD1607 from the payer perspective. One-way sensitivity analyses showed that the distributions of modified Rankin Scale scores at 90 days after stroke were the most influential factor on ICERs. For Canada, compared to EVT alone, the probability that EVT with alteplase would be cost-effective at a willingness-to-pay threshold of USD50 000 per QALY gained was 58.7% from a societal perspective and 58.4% from a payer perspective. The corresponding values for at a willingness-to-pay threshold of USD47 185 (3 times the Chinese gross domestic product per capita in 2021) were 65.2% and 67.4%. Interpretation: For patients with acute ischemic stroke due to large vessel occlusion eligible for immediate treatment with both EVT alone and EVT with intravenous alteplase treatment, it is uncertain whether EVT with alteplase is cost-effective compared to EVT alone in Canada and China

Supplementary Figure 1 Blood Concentrations of Cyclosporine and Sirolimus in Various Regimens.tif

Blood Concentrations of Cyclosporine and Sirolimus in Various Regimens</p

Supplementary Figure 1 Blood Concentrations of Cyclosporine and Sirolimus in Various Regimens

Supplementary Figure 1 Blood Concentrations of Cyclosporine and Sirolimus in Various Regimens</p

'Seminar-CBL-Ideological and Political Education' Innovative Mode in Clinical Pharmacology Teaching

Clinical pharmacology is an important discipline that bridges clinical medicine and pharmacology. In the teaching practice, it is necessary to keep up with educational reform and adopt the seminar teaching method combined with case-based learning (CBL), so as to practically improve the benefits of both 'teaching' and 'learning'. The teaching of ideology and politics in the curriculum is the key to cultivate students' high sense of responsibility and noble medical ethics, and realize the goal of moral education. At present, in the teaching of clinical pharmacology of antineoplastic drugs, there are problems such as students' weak basic knowledge of oncology pharmacology, separation of 'teaching' and 'learning' due to the traditional teaching method, outdated teaching materials, and low motivation of students. Therefore, this paper takes this part of the course teaching as an example to initially explore the role of the innovative model of 'Seminar-CBL-Ideological and Political Education ' in the teaching practice of clinical pharmacology, with the hope of stimulating the students' interest in learning, cultivating students' correct outlook on the world, life, and values, achieving the goals of 'teaching' and 'learning', and providing reference for optimizing clinical pharmacology education

Current Situation of Potentially Inappropriate Medication in Older Cancer Patients and Strategies to Address It

An increasing number of studies have demonstrated that potentially inappropriate medication (PIM) occurs commonly in elderly patients with cancer, with higher prevalence of PIM than general elderly, which may lead to adverse effects on prognosis of the patients. Therefore, it is necessary to conduct a systematic and comprehensive review of previous studies to provide support and reference for future studies. PubMed, CNKI and Wanfang Data were systematically searched to summarize and analyze the screen tools of PIM, prevalence of PIM, main drugs involved, influencing factors and the relationship between PIM and adverse outcomes. The results showed that the prevalence of PIM varied when different PIM screen tools were used in older patients with cancer, and the list of medications commonly used for supportive care that are of concern in older patients provided by the NCCN Guidelines for Older Adult Oncology (2020.v2) demonstrated advantages in providing individualized medication management for elderly patients with cancer. Polypharmacy, age, and comorbidities were significantly associated with the development of PIM. Benzodiazepines and analgesics are commonly used as high-risk drugs in elderly patients with cancer. PIM may be associated with higher mortality rates, drug interaction rates, adverse event rates, emergency and hospital readmission rates in elderly patients with cancer. It is hoped that this article will provide a reference for conducting studies related to PIM in elderly patients with cancer in China and provide support for promoting the safe and rational use of medication in elderly patients with cancer

DataSheet1_Dose- and time-dependent manners of moxifloxacin induced liver injury by targeted metabolomics study.zip

Moxifloxacin is the most widely prescribed antibiotics due to its excellent oral bioavailability and broad-spectrum antibacterial effect. Despite of its popularity, the rare and severe liver injury induced by moxifloxacin is a big concern that cannot be ignored in clinical practice. However, the early warning and related metabolic disturbances of moxifloxacin induced hepatoxicity were rarely reported. In this study, the dose- and time-dependent manners of moxifloxacin induced liver injury were investigated by a targeted metabolomics method. In dose-dependent experiment, three different dosages of moxifloxacin were administered to the rats, including 36 mg kg−1 d−1, 72 mg kg−1 d−1, and 108 mg kg−1 d−1. In time-dependent experiment, moxifloxacin was orally administered to the rats for 3, 7 or 14 consecutive days. Pathological analysis showed that moxifloxacin caused obvious transient hepatotoxicity, with the most serious liver injury occurred in the 7 days continuous administration group. The transient liver injury can be automatically restored over time. Serum levels of liver function related biochemical indicators, including ALT, AST, TBIL, alkaline phosphatase, superoxide dismutase, and malondialdehyde, were also measured for the evaluation of liver injury. However, these indicators can hardly be used for the early warning of hepatotoxicity caused by moxifloxacin due to their limited sensitivity and significant hysteresis. Targeted metabolomics study demonstrated that serum concentrations of fatty acyl carnitines, fatty acids and dehydroepiandrosterone can change dynamically with the severity of moxifloxacin related liver injury. The elevated serum levels of fatty acyl carnitine, fatty acid and dehydroepiandrosterone were promising in predicting the hepatotoxicity induced by moxifloxacin.</p

Metabolomics of Hydrazine-Induced Hepatotoxicity in Rats for Discovering Potential Biomarkers

Metabolic pathway disturbances associated with drug-induced liver injury remain unsatisfactorily characterized. Diagnostic biomarkers for hepatotoxicity have been used to minimize drug-induced liver injury and to increase the clinical safety. A metabolomics strategy using rapid-resolution liquid chromatography/tandem mass spectrometry (RRLC-MS/MS) analyses and multivariate statistics was implemented to identify potential biomarkers for hydrazine-induced hepatotoxicity. The global serum and urine metabolomics of 30 hydrazine-treated rats at 24 or 48 h postdosing and 24 healthy rats were characterized by a metabolomics approach. Multivariate statistical data analyses and receiver operating characteristic (ROC) curves were performed to identify the most significantly altered metabolites. The 16 most significant potential biomarkers were identified to be closely related to hydrazine-induced liver injury. The combination of these biomarkers had an area under the curve (AUC) > 0.85, with 100% specificity and sensitivity, respectively. This high-quality classification group included amino acids and their derivatives, glutathione metabolites, vitamins, fatty acids, intermediates of pyrimidine metabolism, and lipids. Additionally, metabolomics pathway analyses confirmed that phenylalanine, tyrosine, and tryptophan biosynthesis as well as tyrosine metabolism had great interactions with hydrazine-induced liver injury in rats. These discriminating metabolites might be useful in understanding the pathogenesis mechanisms of liver injury and provide good prospects for drug-induced liver injury diagnosis clinically

Targeted metabolomics profiling in pregnancy associated with vitamin D deficiency

Abstract Background Vitamin D deficiency is common in pregnancy, however, its effects has not been fully elucidated. Here, we conducted targeted metabolomics profiling to study the relationship. Methods This study enrolled 111 pregnant women, including sufficient group (n = 9), inadequate group (n = 49) and deficient group (n = 53). Ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS)-based targeted metabonomics were used to characterize metabolite profiles associated with vitamin D deficiency in pregnancy. Results Many metabolites decreased in the inadequate and deficient group, including lipids, amino acids and others. The lipid species included fatty acyls (FA 14:3, FA 26:0; O), glycerolipids (MG 18:2), glycerophospholipids (LPG 20:5, PE-Cer 40:1; O2, PG 29:0), sterol lipids (CE 20:5, ST 28:0; O4, ST 28:1; O4). Decreased amino acids included aromatic amino acids (tryptophan, phenylalanine, tyrosine) and branched-chain amino acids (valine, isoleucine, leucine), proline, methionine, arginine, lysine, alanine, L-kynurenine,5-hydroxy-L-tryptophan, allysine. Conclusions This targeted metabolomics profiling indicated that vitamin D supplementation can significantly affect lipids and amino acids metabolism in pregnancy