PT  - JOURNAL ARTICLE
AU  - L. Cornet
AU  - C. Khouri
AU  - M. Roustit
AU  - C. Guignabert
AU  - M. C. Chaumais
AU  - M. Humbert
AU  - B. Revol
AU  - F. Despas
AU  - D. Montani
AU  - J. L. Cracowski
TI  - Pulmonary Arterial Hypertension associated with Protein Kinase Inhibitors: A pharmacovigilance-pharmacodynamic study
AID  - 10.1183/13993003.02472-2018
DP  - 2019 Jan 01
TA  - European Respiratory Journal
PG  - 1802472
4099  - http://erj.ersjournals.com/content/early/2019/02/20/13993003.02472-2018.short
4100  - http://erj.ersjournals.com/content/early/2019/02/20/13993003.02472-2018.full
AB  - The pathophysiology of pulmonary arterial hypertension (PAH) induced by protein kinase inhibitors (PKI) remains unclear. To gain knowledge into this rare and severe pathology we performed a study combining a pharmacovigilance approach and the pharmacodynamics properties of PKI.A disproportionality analysis on the WHO pharmacovigilance database 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 PKI. 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 and p=0.00027), c-yes (r=0.82 and p=0.00015), Lck (r=0.81 and p=0.00046), Lyn (r=0.80 and p=0.00036), all belonging to the SRC protein kinase family; and TEC (r=0.85 and p=0.00006). Kinases of the BMP signalling pathway also seem to play a role in the pathophysiology of PKI-induced PAH. Interestingly, dasatinib affinity profile seems different from that of other PKIs in the cluster analysis.The study highlights potential role of SRC protein kinases family and TEC in PAH induced by PKI. This approach combining pharmacovigilance and pharmacodynamics data allowed us to generate some hypothesis about the pathophysiology of the disease, however the results have to be confirmed by further studies.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. CORNET has nothing to disclose.Conflict of interest: Dr. khouri has nothing to disclose.Conflict of interest: Dr. Roustit reports grants from United Therapeutics, outside the submitted work.Conflict of interest: Dr. Guignabert has nothing to disclose.Conflict of interest: Dr. Chaumais reports non-financial support from Bayer, personal fees from actelion, outside the submitted work.Conflict of interest: Dr. Humbert reports personal fees from Actelion, personal fees from Bayer, personal fees from GSK, personal fees from Merck, personal fees from United Therapeutics, during the conduct of the study.Conflict of interest: Dr. REVOL has nothing to disclose.Conflict of interest: Dr. Despas has nothing to disclose.Conflict of interest: Dr. MONTANI reports grants and personal fees from Actelion, grants and personal fees from Bayer, personal fees from BMS,personal fees from GSK, personal fees from MSD, personal fees from Pfizer, outside the submitted work.Conflict of interest: Dr. Cracowski reports grants from Bioprojet, grants from Topadur, outside the submitted work.