Cheminformatics-aided pharmacovigilance: application to Stevens-Johnson Syndrome

Abstract

Objective Quantitative Structure-Activity Relationship (QSAR) models can predict adverse drug reactions (ADRs), and thus provide early warnings of potential hazards. Timely identification of potential safety concerns could protect patients and aid early diagnosis of ADRs among the exposed. Our objective was to determine whether global spontaneous reporting patterns might allow chemical substructures associated with Stevens-Johnson Syndrome (SJS) to be identified and utilized for ADR prediction by QSAR models.Materials and Methods Using a reference set of 364 drugs having positive or negative reporting correlations with SJS in the VigiBase global repository of individual case safety reports (Uppsala Monitoring Center, Uppsala, Sweden), chemical descriptors were computed from drug molecular structures. Random Forest and Support Vector Machines methods were used to develop QSAR models, which were validated by external 5-fold cross validation. Models were employed for virtual screening of DrugBank to predict SJS actives and inactives, which were corroborated using knowledge bases like VigiBase, ChemoText, and MicroMedex (Truven Health Analytics Inc, Ann Arbor, Michigan).Results We developed QSAR models that could accurately predict if drugs were associated with SJS (area under the curve of 75%–81%). Our 10 most active and inactive predictions were substantiated by SJS reports (or lack thereof) in the literature.Discussion Interpretation of QSAR models in terms of significant chemical descriptors suggested novel SJS structural alerts.Conclusions We have demonstrated that QSAR models can accurately identify SJS active and inactive drugs. Requiring chemical structures only, QSAR models provide effective computational means to flag potentially harmful drugs for subsequent targeted surveillance and pharmacoepidemiologic investigations.

Methods for Identifying Culprit Drugs in Cutaneous Drug Eruptions: A Scoping Review

“…As well, allergies to drug intermediates or drug-carrier protein conjugates may result in false negatives because the techniques often test the parent drug and not the intermediate or metabolite that may actually be the culprit such as with acrolein, the metabolite of cyclophosphamide, which is a serious ADR. 32,33 These investigations may be useful alternatives to the riskier current gold standard, which is re-exposure to the culprit drug (i.e. confirmatory/provocation testing).…”

Chemistry-Wide Association Studies (CWAS): A Novel Framework for Identifying and Interpreting Structure–Activity Relationships

“…For the purposes of this study, we employed a dataset studied in our recent work. 23 Briefly, the original SJS dataset originally consisted of 436 drugs extracted from VigiBase, the largest database of adverse drug reactions reports maintained by the World Health Organization Uppsala Monitoring Centre. 24 After curation (see Data Curation Section), 365 compounds (194 active and 170 inactive) remained.…”

Therapeutic Causes of Stevens - Johnson Syndrome - A Mini Review

“…Growing digitalization of health care data enables detection of adverse drug reactions ADR using electronic health records, biomedical literature, drug labels, bioassays and quantitative, structure-activity relationship (QSAR) models [9][10][11][12][13]. Therefore, QSAR models could identify SJS active and inactive drugs Open Access Journal of Toxicology when chemical structures are used [14]. But warning signals require significant number of reports on SJS [15] signifying that pharmacovigilance.…”