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

Abstract

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.

Incident pulmonary arterial hypertension associated with Bosutinib

“…A postulated mechanism for TKI-induced PAH is offtarget inhibition of Src, a family of kinases involved in modulating pulmonary vascular tone and remodelling. 11,13 A significant correlation between pharmacovigilance signals and affinity for Src kinases has been found. 11 Dasatinib and Bosutinib are potent inhibitors of Src.…”

“…11,13 A significant correlation between pharmacovigilance signals and affinity for Src kinases has been found. 11 Dasatinib and Bosutinib are potent inhibitors of Src. PAH has also been reported with Ponatinib, 14 a third-generation TKI which also inhibits Src.…”

Novel techniques for advancing our understanding of pulmonary arterial hypertension

“…It is in this background that CORNET et al [3] thoughtfully sought a novel approach to further our understanding of the pathophysiology of PAH. Nine incident cases of PAH were noted in the French Pulmonary Hypertension registry between 2006 and 2010 in patients receiving dasatinib, a potent second-generation protein kinase inhibitor (PKI), used for the treatment of chronic myelogenous leukaemia.…”

“…In their report published in this issue of the European Respiratory Journal, CORNET et al [3] used the World Health Organization's pharmacovigilance database, Vigibase, to identify 22 PKIs associated with at least one case of PAH. Pharmacovigilance is the practice of extracting adverse drug events (ADEs) from spontaneous reporting systems to identify previously unestablished post-market ADEs.…”

“…The paper by CORNET et al [3] demonstrates that novel research methods and resources can be used to further our understanding of the pathophysiology of PAH. Armed with new, sophisticated tools, the future of PAH diagnosis, treatment and prognosis lies with a more precise understanding of individual disease phenotypes that will direct preventative strategies, individualise treatments, and improve prognostication.…”