Drug clustering to anticipate new aspects of drug safety profile: Application to gabapentinoids and other voltage-gated calcium channel ligand drugs

Abstract

Aims: Gabapentin and pregabalin bind to α2-δ subunit of voltage-gated calcium channels (Ca_v ). Other drugs targeting Ca_v include cardiovascular calcium channel blockers (CCBs) and anticonvulsants (levetiracetam, ethosuximide and zonisamide). In addition to pharmacodynamics, the safety profile of gabapentinoids seems to overlap with the one of cardiovascular CCBs (oedema) and Ca_v -blocking anticonvulsants (suicide and ataxia). The objective of this study was to cluster the safety profile of different Ca_v -ligand drugs by focusing on whether gabapentinoids present a distinct adverse drug reaction (ADR) signature from cardiovascular CCBs and anticonvulsants.

Methods: We extracted all ADRs with at least one significant disproportionate reporting (reporting odds ratio) related to gabapentinoids, CCBs or anticonvulsants in VigiBase. After principal component analysis preprocessing, a hierarchical ascendent classification was performed to cluster gabapentinoids and other Ca_v -ligand drugs that share a similar ADR signature. The robustness of the results was determined through four sensitivity analyses, varying on the dataset or the clustering method.

Results: A total of 16 drugs and 65 ADRs were included. Gabapentinoids were in Cluster #1, which included eight other drugs (isradipine, nicardipine, lacidipine, lercanidipine, ethosuximide, levetiracetam, zonisamide and nimodipine). Cluster #2 contained two drugs (diltiazem and verapamil) and Cluster #3 contained four drugs (amlodipine, felodipine, nifedipine and nitrendipine). The clustering results were consistent in all sensitivity analyses.

Conclusions: The safety profile of gabapentinoids overlaps with those of some dihydropyridine CCBs and Ca_v -blocking anticonvulsants. These results could be used to anticipate some unidentified ADRs of gabapentinoids from information accumulated with older drugs and sharing a common molecular target and ADR signature.

Keywords: anticonvulsants; calcium channel blockers; clustering; gabapentinoids; pharmacovigilance.