Evaluation of potential complication of interstitial lung disease with abemaciclib and palbociclib treatments

Background: Various cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have demonstrated promising anti-tumor effects. The Japanese Ministry of Health, Labour and Welfare has issued a warning about interstitial lung diseases as an adverse effect of CDK4/6 inhibitors. However, a large-scale evaluation of potential complications has not been conducted to date, and the occurrence of these adverse effects is unclear. Aim: The aim of this study was to evaluate the clinical incidence of interstitial lung disease caused by two CDK4/6 inhibitors, abemaciclib and palbociclib, and assess the relationship between each drug and interstitial lung disease. Methods and results: We evaluated the relationship between the CDK4/6 inhibitors (abemaciclib and palbociclib) and interstitial lung disease in clinical practice using data from the Japanese Adverse Drug Event Report (JADER) database and FDA Adverse Event Reporting System (FAERS) to detect adverse event signals with reported odds ratios (RORs). Furthermore, we performed an adverse event-time analysis for each drug using data from the JADER database to examine the time of onset of the adverse events. The analysis of the reports in the JADER database showed that the lower limit of the 95% confidence interval (CI) of ROR for abemaciclib was >1 regardless of age, and a signal was detected. Interstitial lung disease associated with abemaciclib and palbociclib use has been reported, with an average onset period from treatment initiation [median (25th-75th quartile)] of 65.1 [56.0 days (25.3-98.3 days)] and 53.1 days [38.0 days (10.8-76.0 days)], respectively. The analysis of the reports in the FAERS showed that the lower limit of the 95% CI of the ROR for the two drugs was >1, and a signal was detected. Conclusion: Treatment with abemaciclib and palbociclib is associated with a potential complication of interstitial lung disease, regardless of age

ILD CAUSED BY ANTIFIBROTIC AGENTS

Interstitial lung disease (ILD), as an adverse effect of certain drugs, leads to inflammation and damage in the walls of the alveoli, making it difficult for the alveoli to take up oxygen. Interstitial pneumonia with no identifiable cause is called idiopathic interstitial pneumonia (IIP), and, among the major IIPs, idiopathic pulmonary fibrosis (IPF) is diagnosed in about half of patients. Current treatment options are limited, among which the antifibrotic drugs nintedanib (Ofev) and pirfenidone (Pirespa) are the first-line drugs. In this study, we investigated the incidence of ILD possibly caused by antifibrotic agents using data from the Japanese Adverse Drug Event Report (JADER) database, a database of spontaneous adverse event reports published by the Pharmaceuticals and Medical Devices Agency (PMDA), and the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), published by the FDA. We used the FAERS and JADER to detect the signals of adverse events on the basis of reporting odds ratios. The relationship between indications and adverse events was clarified by separating indications and adverse events using the spontaneous adverse event reporting database with novel drug involvement. Regarding the involvement of nintedanib and pirfenidone in the development of ILD, JADER and FAERS showed signals for both nintedanib and pirfenidone as suspect drugs, and no signals for nintedanib or pirfenidone as concomitant drug interactions were detected. We highlight this because there are only a few effective drugs for IPF, and effective and safe drug therapies should be implemented by taking into consideration drug-induced ILD

Evaluation of Potential Complications of Interstitial Lung Disease Associated With Antiandrogens Using Data From Databases Reporting Spontaneous Adverse Effects

From 2002 to 2018, the number of patients with prostate cancer significantly increased from 679,023 to 1276,106 worldwide. Total prostatectomy (including robot-assisted prostatectomy), radiation therapy, and pharmacological treatment are commonly used to treat prostate cancer. The Chief of the Pharmaceutical Safety Division, that is, the Federation of Pharmaceutical Manufacturers’ Associations of Japan (FPMAJ), recently called for the revision of package inserts for ethical drugs. However, the pathogenesis of interstitial lung disease (ILD), a serious drug-induced adverse effect, remains unclear. Moreover, there have been no large-scale evaluations of potential complications associated with currently used antiandrogens, which are commonly employed to treat prostate cancer. Hence, ILD, as an adverse event, remains poorly understood. Therefore, we conducted a survey of reports in the Japanese Adverse Drug Event Report (JADER) database to investigate the potential association between the reporting of ILD and antiandrogen drug use in clinical practice. The occurrence of ILD was investigated by evaluating the relationship between antiandrogen drug use and ILD. Adverse event signals were detected with reporting odds ratios (RORs), using data from the JADER and FDA Adverse Event Reporting System (FAERS) databases, for the analysis of post-marketing adverse event reports. The JADER was used to examine the time profile of adverse event occurrence for each drug, whereas the FAERS was used to screen cases of unknown adverse events and analyze their trends of occurrence. The analysis of data from both databases revealed the 95% confidence interval lower limits of ROR for bicalutamide and flutamide to be > 1, and adverse event signals were detected following the use of either drug. While caution should be exercised for drugs that are new to the market, we conclude that drugs with similar therapeutic effects that have been in use for a long period should also be re-examined for potential adverse events

Investigation of drugs for the prevention of doxorubicin-induced cardiac events using big data analysis

Aim: Doxorubicin, an anthracycline anti-tumour agent, is an essential chemotherapeutic drug; however, the adverse events associated with doxorubicin usage, including cardiotoxicity, prevent patients from continuing treatment. Here, we used databases to explore existing approved drugs with potential preventative effects against doxorubicin-induced cardiac events and examined their efficacy and mechanisms. Methods: The Gene Expression Omnibus (GEO), Library of Integrated Network-based Cellular Signatures (LINCS), and Food and Drug Administration Adverse Events Reporting System (FAERS) databases were used to extract candidate prophylactic drugs. Mouse models of doxorubicin-induced cardiac events were generated by intraperitoneal administration of 20 mg/kg of doxorubicin on Day 1 and oral administration of prophylactic candidate drugs for 6 consecutive days beginning the day before doxorubicin administration. On Day 6, mouse hearts were extracted and examined for mRNA expression of apoptosis-related genes. Results: GEO analysis showed that doxorubicin administration upregulated 490 genes and downregulated 862 genes, and LINCS data identified sirolimus, verapamil, minoxidil, prednisolone, guanabenz, and mosapride as drugs capable of counteracting these genetic alterations. Examination of the effects of these drugs on cardiac toxicity using FAERS identified sirolimus and mosapride as new prophylactic drug candidates. In model mice, mosapride and sirolimus suppressed the Bax/Bcl-2 mRNA ratio, which is elevated in doxorubicin-induced cardiotoxicity. These drugs also suppressed the expression of inflammatory cytokines Il1b and Il6 and markers associated with myocardial fibrosis, including Lgal3 and Timp1. Conclusion: These findings suggest that doxorubicin-induced cardiac events are suppressed by the administration of mosapride and sirolimus

Evaluation of the potential complication of interstitial lung disease associated with antifibrotic drugs using data from databases reporting spontaneous adverse effects

Abstract Interstitial lung disease (ILD), as an adverse effect of certain drugs, leads to inflammation and damage in the walls of the alveoli, making it difficult for the alveoli to take up oxygen. Interstitial pneumonia with no identifiable cause is called idiopathic interstitial pneumonia (IIP), and, among the major IIPs, idiopathic pulmonary fibrosis (IPF) is diagnosed in about half of patients. Current treatment options are limited, among which the antifibrotic drugs nintedanib (Ofev) and pirfenidone (Pirespa) are the first‐line drugs. In this study, we investigated the incidence of ILD possibly caused by antifibrotic agents using data from the Japanese Adverse Drug Event Report (JADER) database, a database of spontaneous adverse event reports published by the Pharmaceuticals and Medical Devices Agency (PMDA), and the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), published by the FDA. We used the FAERS and JADER to detect the signals of adverse events on the basis of reporting odds ratios. The relationship between indications and adverse events was clarified by separating indications and adverse events using the spontaneous adverse event reporting database with novel drug involvement. Regarding the involvement of nintedanib and pirfenidone in the development of ILD, JADER and FAERS showed signals for both nintedanib and pirfenidone as suspect drugs, and no signals for nintedanib or pirfenidone as concomitant drug interactions were detected. We highlight this because there are only a few effective drugs for IPF, and effective and safe drug therapies should be implemented by taking into consideration drug‐induced ILD

Utility of simple suspension method compared to loss of drug using crushing method on tube administration

【目的】従来の薬剤経管投与法である粉砕法は薬効の減少につながる薬剤量の損失が指摘されている。そこで粉砕法による薬剤量損失に対する簡易懸濁法の有用性について検討した。 【方法】頻繁に粉砕指示がなされる5種類の薬剤を用いて粉砕・分包による薬物含量減少、薬剤調製時の懸濁性および実際の経管投与を想定した薬物含量について2つの方法を比較した。 【結果】薬剤を粉砕・分包するとそれぞれの薬物含量は減少した。またワーファリン®錠を粉砕して水に溶解すると完全には懸濁せず、小さな塊が生じたが、簡易懸濁法では均一に懸濁した。ワーファリン®錠の経管投与を想定した実験において粉砕法では薬物含量が大幅に減少したが、簡易懸濁法では、ほとんど損失が認められなかった。【結論】簡易懸濁法は粉砕法に比べて薬剤損失の面で有用性が高いことが示唆され、ワーファリン®錠のように安定性が悪い薬剤では特に適正な薬物投与に貢献出来ると考えられる。Objective: In the past, a conventional crushing method was used for the administration of tablets or capsules by tube in patients with dysphagia. However, this method has several problems, such as a loss of the drug amount and tube clogging. Recently, tube administration by a simple suspension method was developed to solve these problems in the conventional crushing method. Methods: In the present study, we investigated to what extent the dosage amount is lost using the simple suspension method compared to crushing method, employing 5 drugs which are frequently administered by tube in Okayama University Hospital. Results: Drug weights of the 5 agents decreased by 70 ～ 90% in the grinding and packaging processes because of drug adhesion to the mortar, packaging machine, and drug package paper. The suspension of all drugs using the simple suspension method was uniform, while only the suspension of Warfarin® ground using the crushing method was shown to be showed inhomogeneous, which is expected to lead to a loss of drug. The drug content on assuming clinical a setting after tube passage was compared between the two methods. The recovery of warfarin®, characterized as unstable using the crushing method, was nearly 50%, but loss was prevented by 80% with the use of bags of medicine. For the simple suspension method, the recovery of warfarin® was almost 100%. Conclusion: The results of this study suggest that the simple suspension method is particularly effective for the tube administration of drugs characterized as unstable