scholarly journals Correlation analysis of target selectivity and side effects of FDA-approved kinase inhibitors

2021 ◽  
Author(s):  
Omer Bayazeid ◽  
Taufiq Rahman
Keyword(s):  
Side Effects ◽  
Correlation Analysis ◽  
Kinase Inhibitors ◽  
Adverse Event Reporting System ◽  
Adverse Event Reporting ◽  
Maximum Serum ◽  
Structural Activity Relationship ◽  
Maximum Serum Concentration ◽  
Relationship Of

Kinase inhibitors (KIs) represent a popular class of therapeutic agents and chemical probes but most of them tend to be polypharmacological. Receptor and non-receptor Tyrosine KIs can target more than 100 kinases simultaneously compare to other KIs. We here analyze the molecular targets of 41 U.S. Food and Drug Administration (FDA)-approved KIs. We chose 18 drugs (Tyrosine KIs) and sought out to evaluate their selectivity profile and engagement with a number of targets in vivo at clinically relevant doses . We also wanted to see whether there prevails any correlation between the target engagement profile and the reported side effects for specific KIs chosen as test cases. To explore all clinical targets of the 18 KIs, we considered the free (unbound) maximum serum concentration (Cmax) of each KI and only chose targets for which the cognate affinities lie within the reported free Cmax values, thereby allowing plausible interaction in clinical doses. We retrieved the side effects of those KIs that is reported in the FDA adverse event reporting system. We illustrate how correlation analysis of target−side effect can give a new insight into the off target of KIs and their effect on increasing the toxicity of KIs. These analyses could aid our understanding of the structural-activity relationship of KIs.

Comparison of Adverse Drug Reactions for Patients Treated with Tyrosine Kinase Inhibitors: Data Mining of the Public Version of the FDA Adverse Event Reporting System (AERS)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1698-1698
Author(s):  
Tetsuya Tanimoto ◽  
Yasuo Oshima ◽  
Koichiro Yuji ◽  
Masahiro Kami
Keyword(s):  
Data Mining ◽  
Adverse Event ◽  
Odds Ratio ◽  
Kinase Inhibitors ◽  
Reporting System ◽  
Adverse Event Reporting System ◽  
Adverse Event Reporting ◽  
Drug Reactions ◽  
Suspected Drug ◽  
Event Reporting

Abstract Abstract 1698 Backgrounds: The consecutive approvals of tyrosine kinase inhibitors (TKIs) have been changing the landscape of treatment strategy for patients with chronic myeloid leukemia (CML). Currently, three TKIs are available worldwide, including imatinib (Glivec/Gleevec; Novartis Pharmaceuticals, East hanover, NJ), nilotinib (Tasigna; Novartis Pharmaceuticals) and dasatinib (Sprycel; Bristol-Myers Squibb, Princeton, NJ). Although second generation TKIs (nilotinib and dasatinib) have shown their efficacy and safety in recent clinical trials, additional data are needed for better understanding and differences in their safety profiles may be helpful when choosing a TKI. We compared the adverse drug reactions (ADRs) for patients treated with three TKIs using spontaneous adverse event reporting after approval to investigate the characteristics of safety profiles. Method: To compare adverse events characteristics among three TKIs, the case/noncase adverse events reports associated with TKIs use were retrieved from the U.S. Food and Drug Administration Adverse Event Reporting System (AERS) between 2004 and 2010. We calculated the reporting odds ratio (ROR), which is known as one of data mining algorithms for signal detection techniques of ADRs, characterized by providing a fast and cost-efficient way of detecting possible ADR signals. All events in the AERS have been coded for data entry in accordance with the standardized terminology, known as Preferred Terms, in the Medical Dictionary for Regulatory Activities. The ROR is similar to the idea of odds ratio, calculating the odds of exposure of the suspected drug in patients who had events divided by the odds of exposure of the suspected drug in those without events. The ROR -1.96 standard error greater than 1 with at least 4 ADR reports was used as a signal criterion in this study. Results: We identified 18,979 ADRs for imatinib, 5,388 ADRs for nilotinib, and 2,482 ADRs for dasatinib. The number of ADRs flagged by our signal criterion was 91 for imatinib, 82 for nilotinib, and 109 for dasatinib. Top 10 lists of ADRs with higher ROR are shown in Table for each TKI. The safety profiles were almost different among TKIs. ADRs related to skin and hepatic function were noted for imatinib, whereas ADRs related to cardiac events were prominent for nilotinib, and ADRs related to lymphocytosis, edema and effusion were noticeable for dasatinib. The different dosing requirements of dasatinib and nilotinib may be an additional factor of ADRs. Conclusions: ADRs reported in the AERS for each TKI were relatively consistent with known characteristics of ADRs reported in previous clinical trials. Our information would be supportive data for choosing a TKI for CML patients based on comorbidities and drug safety profiles. The choice of therapy in a given patient with CML may depend on age, past history and comorbidities as well as disease risk score and mutational analysis. Disclosures: Oshima: Sanofi Aventis: Employment.

Manifestations of cardiovascular toxicity associated with the approved tyrosine kinase inhibitors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14152-14152
Author(s):  
S. L. Verbois ◽  
H. Saber ◽  
K. A. Benson ◽  
D. E. Morse ◽  
R. Justice
Keyword(s):  
Cardiac Function ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Vascular Inflammation ◽  
Adverse Event Reporting System ◽  
Clinical Signs ◽  
Adverse Event Reporting ◽  
Specific Pattern ◽  
Patient Reports

14152 Background: Since 2001, 5 tyrosine kinase inhibitors (TKi’s; imatinib, erlotinib, sorafenib, sunitinib and dasatinib) have been approved for hematologic and solid tumor indications including, CML, ALL, GIST, RCC, pancreatic and NSCLC. While individual agents are designed to inhibit the TK activity of specific targets, “cross-talk” with non-target TKs (e.g., ABL, EGFR, VEGFRs, KIT, KDR, CSF1R, PDGFRs, RET, the SRC family, EPHA2, RAF, and FLT3) is extensive. The relationship between inhibition of individual kinases and the toxicity profile of each drug is unclear. Methods: Following from the observation of cardiovascular (CV) toxicity in clinical settings (pre- and post- marketing) and from the original non-clinical toxicologic evaluations, a new “class-related” review of non-clinical toxicological findings was conducted. To compare the non-clinical and clinical CV findings, the Adverse Event Reporting System (AERS) was searched for all events, excluding those of non-CV nature and those unlikely to be drug-related (e.g. hemorrhagic events were excluded from the initial analyses). Individual patient reports were not reviewed in full, therefore definitive attribution of disease related events can not be made. Results: While variable in expression, the non-clinical signs of toxicity included cardiac and vascular inflammation, cardiac degeneration and hypertrophy, decreased cardiac function (e.g. LVEF decreases), alterations in blood pressure, and QT prolongation. Clinical reports for the TKi’s have included hypo- and hypertension, conduction abnormalities and arrhythmias, cardiac hypertrophy and changes in cardiac function (LVEF and CHF). Conclusions: It is not possible at this time to relate the CV toxicities associated with the TKi’s to a specific pattern of TK inhibition. CV toxicity has been observed both clinically and non-clinically and warrants further investigation. No significant financial relationships to disclose.

scholarly journals Novel Microcrystal Formulations of Sorafenib Facilitate a Long-Acting Antitumor Effect and Relieve Treatment Side Effects as Observed With Fundus Microcirculation Imaging

2021 ◽  
Vol 11 ◽  
Author(s):  
Junxiao Wang ◽  
Rui Liu ◽  
Yun Zhao ◽  
Zhenhu Ma ◽  
Zejie Sang ◽  
...  
Keyword(s):  
Side Effects ◽  
Antitumor Effect ◽  
Kinase Inhibitors ◽  
Advanced Hepatocellular Carcinoma ◽  
Related Factors ◽  
Treatment Side Effects ◽  
Tumor Tissues ◽  
Long Acting ◽  
Medical Burden

The tyrosine kinase inhibitors (TKIs), including sorafenib, remain one first-line antitumor treatment strategy for advanced hepatocellular carcinoma (HCC). However, many problems exist with the current orally administered TKIs, creating a heavy medical burden and causing severe side effects. In this work, we prepared a novel microcrystalline formulation of sorafenib that not only achieved sustainable release and long action in HCC tumors but also relieved side effects, as demonstrated by fundus microcirculation imaging. The larger the size of the microcrystalline formulation of sorafenib particle, the slower the release rates of sorafenib from the tumor tissues. The microcrystalline formulation of sorafenib with the largest particle size was named as Sor-MS. One intratumor injection (once administration) of Sor-MS, but not Sor-Sol (the solution formulation of sorafenib as a control), could slow the release of sorafenib in HCC tumor tissues and in turn inhibited the in vivo proliferation of HCC or the expression of EMT/pro-survival–related factors in a long-acting manner. Moreover, compared with oral administration, one intratumor injection of Sor-MS not only facilitated a long-acting antitumor effect but also relieved side effects of sorafenib, avoiding damage to the capillary network of the eye fundus, as evidenced by fundus microcirculation imaging. Therefore, preparing sorafenib as a novel microcrystal formulation could facilitate a long-acting antitumor effect and relieve drug-related side effects.

scholarly journals Cardiac adverse events associated with chloroquine and hydroxychloroquine exposure in 20 years of drug safety surveillance reports

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Isaac V. Cohen ◽  
Tigran Makunts ◽  
Talar Moumedjian ◽  
Masara A. Issa ◽  
Ruben Abagyan
Keyword(s):  
Adverse Event ◽  
Side Effects ◽  
Lupus Erythematosus ◽  
Adverse Event Reporting System ◽  
The United States ◽  
Adverse Event Reporting ◽  
World Health ◽  
Cardiac Complications ◽  
Cardiac Side Effects ◽  
Therapeutic Decision Making

Abstract Chloroquine (CQ) and hydroxychloroquine (HCQ) are on the World Health Organization’s List of Essential Medications for treating non-resistant malaria, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). In addition, both drugs are currently used off-label in hospitals worldwide and in numerous clinical trials for the treatment of SARS-CoV-2 infection. However, CQ and HCQ use has been associated with cardiac side effects, which is of concern due to the higher risk of COVID-19 complications in patients with heart related disorders, and increased mortality associated with COVID-19 cardiac complications. In this study we analyzed over thirteen million adverse event reports form the United States Food and Drug Administration Adverse Event Reporting System to confirm and quantify the association of cardiac side effects of CQ and HCQ. Additionally, we identified several confounding factors, including male sex, NSAID coadministration, advanced age, and prior diagnoses contributing to drug related cardiotoxicity. These findings may help guide therapeutic decision making and ethical trial design for COVID-19 treatment.

scholarly journals Relationship between mirtazapine dose and incidence of adrenergic side effects: An exploratory analysis

2019 ◽  
Vol 9 (1) ◽  
pp. 41-47 ◽  
Author(s):  
Michael Shuman ◽  
Athena Chukwu ◽  
Nathan Van Veldhuizen ◽  
Steven A. Miller
Keyword(s):  
Adverse Event ◽  
Side Effects ◽  
Neuropsychiatric Symptoms ◽  
Adverse Event Reporting System ◽  
Final Analysis ◽  
Adverse Event Reporting ◽  
The Us ◽  
Increasing Risk ◽  
Higher Doses ◽  
Specific Adverse Event

Abstract Introduction Mirtazapine is an antidepressant with US Food and Drug Administration approval for management of major depressive disorder. Low doses of mirtazapine are often used for management of insomnia, with higher doses expected to provide more noradrenergic effect, and thus a higher degree of activation. If so, use of higher doses at bedtime may not be advisable and may worsen certain neuropsychiatric symptoms. No studies have been performed to evaluate these outcomes. Methods This study consisted of a retrospective review of data submitted to the US Food and Drug Administration's Adverse Event Reporting System from January 1, 1995, to August 1, 2015. Cases that were deemed by study authors to represent activation of the noradrenergic system, and for which other confounders could not be identified, were included in the final analysis. The frequency of each specific adverse event was evaluated based on dose and compared to recent prescribing rates to determine if likelihood of a side effect increased with higher dose. Results The study identified 308 incidences of anxiety, agitation, delusion, hallucination, hypertension, insomnia, nightmare, or tachycardia. After controlling for frequency of prescribing at a given dose, there was a statistically significant increase in rates of tachycardia which correlated with dose. However, after correction for multiple comparisons, results were no longer significant. Discussion This study failed to support the hypothesis that mirtazapine is more activating at higher doses and appears to support the safety of increasing dose without increasing risk of noradrenergic side effects. Prospective studies will be necessary to confirm these findings.

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