Pulmonary arterial hypertension associated with protein kinase inhibitors: a pharmacovigilance-pharmacodynamic study.

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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Copyright ©ERS 2019.

Déclaration de conflit d'intérêts

Conflict of interest: L. Cornet has nothing to disclose. Conflict of interest: C. Khouri has nothing to disclose. Conflict of interest: M. Roustit reports grants from United Therapeutics outside the submitted work. Conflict of interest: C. Guignabert has nothing to disclose. Conflict of interest: M-C. Chaumais reports nonfinancial support from Bayer and personal fees from Actelion, outside the submitted work. Conflict of interest: M. Humbert reports personal fees from Actelion, Bayer, GSK, Merck and United Therapeutics, during the conduct of the study. Conflict of interest: B. Revol has nothing to disclose. Conflict of interest: F. Despas has nothing to disclose. Conflict of interest: D. Montani reports grants and personal fees from Actelion and Bayer, and personal fees from BMS, GSK, MSD and Pfizer, outside the submitted work. Conflict of interest: J-L. Cracowski reports grants from Bioprojet and Topadur, outside the submitted work.