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Association of temozolomide with progressive multifocal leukoencephalopathy: a disproportionality analysis integrated
Vipin Bhati1, Anoop Kumar1, Viney Lather2
1Department of Pharmacology, Delhi Pharmaceutical Sciences and Research University, New Delhi, India.
Background:
Temozolomide (TMZ) is an alkylating agent approved for the management of glioblastoma. The TMZ is not known for progressive multifocal leukoencephalopathy (PML). The main objective of the current study is to find out the association of TMZ with PML using disproportionality analysis of FDA Adverse Event Reporting System (FAERS) data integrated with network pharmacological approaches.
Research Design And Methods:
OpenVigil tool was used to query the FAERS database. The disproportionality measures were calculated. The network has been constructed using Cytoscape. Finally, the possible binding interactions were studied using Glide, Schrödinger Inc.
Results:
A total number of 3502 cases of PML were reported in the FAERS database. Out of these, 10 cases were found with TMZ. The subgroup analysis results have shown a greater number of cases in females. The network has indicated the involvement of human mitogen-activated protein kinase, 3-phosphoinositide-dependent protein kinase 1 protein, human mTOR complex protein, phosphatidylinositol 4,5-bisphosphate 3-kinase protein, and glycogen synthase kinase-3 beta protein. The docking results have indicated good interactions of TMZ with active site of glycogen synthase kinase-3 beta and mitogen-activated protein kinase 1 as compared to other identified targets.
Conclusion:
The PML is identified as novel signal with temozolomide.
Insights
Progressive multifocal leukoencephalopathy (PML) is a novel safety signal associated with temozolomide (TMZ), an alkylating agent used for glioblastoma. This study analyzed FAERS data and network pharmacology to investigate the TMZ-PML association.
Area of Science:
- Pharmacology
- Oncology
- Neuroscience
Background:
- Temozolomide (TMZ) is a standard alkylating agent for glioblastoma treatment.
- Progressive multifocal leukoencephalopathy (PML) is a rare, serious demyelinating disease.
- A potential association between TMZ and PML has not been previously established.
Purpose of the Study:
- To investigate the association between temozolomide (TMZ) and progressive multifocal leukoencephalopathy (PML).
- To identify potential pharmacological mechanisms linking TMZ and PML.
Main Methods:
- Disproportionality analysis of FDA Adverse Event Reporting System (FAERS) data.
- Network pharmacological analysis using Cytoscape.
- Molecular docking studies using Glide (Schrödinger Inc.).
Main Results:
- A total of 3502 PML cases were reported in FAERS, with 10 cases involving TMZ.
- Subgroup analysis indicated a higher incidence in females.
- Network analysis implicated several key proteins, including MAPK, PDK1, mTOR, PI3K, and GSK-3β.
- Docking studies revealed favorable interactions between TMZ and GSK-3β and MAPK1.
Conclusions:
- Progressive multifocal leukoencephalopathy (PML) is identified as a novel safety signal associated with temozolomide (TMZ).
- The findings suggest potential molecular pathways underlying the TMZ-PML association.
