| アブストラクト | The pathophysiology of pulmonary arterial hypertension (PAH) induced by protein kinase inhibitors (PKIs) remains unclear. To gain knowledge into this rare and severe pathology we performed a study combining a pharmacovigilance approach and the pharmacodynamic properties of PKIs.A disproportionality analysis on the World Health Organization pharmacovigilance database VigiBase using the reporting odds ratio (ROR) and 95% confidence interval was first performed. Then, we identified the most relevant cellular targets of interest through a systematic literature review and correlated the pharmacovigilance signals with the affinity for the different PKIs. We further performed a hierarchical cluster analysis to assess patterns of binding affinity.A positive disproportionality signal was found for dasatinib, bosutinib, ponatinib, ruxolitinib and nilotinib. Five non-receptor protein kinases significantly correlate with disproportionality signals: c-Src (r=0.79, p=0.00027), c-Yes (r=0.82, p=0.00015), Lck (r=0.81, p=0.00046) and Lyn (r=0.80, p=0.00036), all belonging to the Src protein kinase family, and TEC (r=0.85, p=0.00006). Kinases of the bone morphogenetic protein signalling pathway also seem to play a role in the pathophysiology of PKI-induced PAH. Interestingly, the dasatinib affinity profile seems to be different from that of other PKIs in the cluster analysis.The study highlights the potential role of the Src protein kinase family and TEC in PAH induced by PKIs. This approach combining pharmacovigilance and pharmacodynamics data allowed us to generate some hypotheses about the pathophysiology of the disease; however, the results have to be confirmed by further studies. |
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| 投稿者 | Cornet, Lucie; Khouri, Charles; Roustit, Matthieu; Guignabert, Christophe; Chaumais, Marie-Camille; Humbert, Marc; Revol, Bruno; Despas, Fabien; Montani, David; Cracowski, Jean-Luc |
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| 組織名 | Pharmacovigilance Unit, Grenoble Alpes University Hospital, Grenoble, France.;These two authors contributed equally to this work.;Pharmacovigilance Unit, Grenoble Alpes University Hospital, Grenoble, France;ckhouri@chu-grenoble.fr.;Clinical Pharmacology Dept, INSERM CIC1406, Grenoble Alpes University Hospital,;Grenoble, France.;UMR 1042-HP2, INSERM, Universite Grenoble Alpes, Grenoble, France.;Universite Paris-Sud, Faculte de Medecine, Universite Paris-Saclay, Le;Kremlin-Bicetre, France.;AP-HP, Service de Pneumologie, Hopital Bicetre, Le Kremlin-Bicetre, France.;INSERM UMR_S 999, Hopital Marie-Lannelongue, Le Plessis-Robinson, France.;Universite Paris-Sud, Faculte de Pharmacie Universite Paris-Saclay, Chatenay;Malabry, France.;AP-HP, Service de Pharmacie, Hopital Bicetre, Le Kremlin-Bicetre, France.;Medical and Clinical Pharmacology Unit, CHU Toulouse University Hospital,;Toulouse, France.;INSERM UMR1027, University of Toulouse III Paul-Sabatier, Toulouse, France.;INSERM CIC 1436, Toulouse Clinical Investigation Centre, Toulouse, France. |
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