Title

 

Authors

S. Montagnani*, M. Tuccori***, C. Scollo*, S. Mantarro*, G. Giustarini*, C. Blandizzi^*,**

*Interdepartmental Centre for Research in Clinical Pharmacology and Experimental Therapeutics, University of Pisa, Italy 
**Division of Pharmacology, Department of Internal Medicine, University of Pisa 
***Unit of Pharmacology, University Hospital of Pisa 

 

Abstract

Tyrosin kinase inhibitors (TKIs) comprise a class of anti-cancer agents, which have gained wide diffusion in the treatment of several tumours. These drugs have been developed to inhibit specific targets in tumour cells, thus limiting their toxicities toward healthy organs and tissues. Most toxicities observed with the use of TKIs, such as skin rashes, appear to be linked to their mechanism of action. Other potential adverse reactions to TKIs, including psychiatric disorders, remain to be investigated. The present study was aimed at describing the clinical characteristics of psychiatric adverse events associated with TKIs and assessing whether these events may represent possible “alarm signals” by disproportional analysis of an Italian database of spontaneous adverse drug reaction (ADR) reporting. This analysis was performed on spontaneous ADR reports recorded in VigiSegn (January 1988–January 2011), a database that includes reports from the Italian Drug Agency (AIFA) and Interregional Group of Pharmacovigilance (GIF). Associations between TKI agents and psychiatric disorders were assessed by means of ADR proportional reporting ratio (PRR), as a measure of disproportionality. Cases were defined as reports including at least one ADR codified with the WHOART preferred term included into the system organ class “psychiatric disorders”. Index reports included ADR linked with erlotinib, sunitinib, sorafenib, nilotinib, dasatinib, lapatinib or imatinib. All ADR reports not involving index drugs were used as controls. The database contains an overall number of 116,142 reports and 2087 reports of TKI-associated ADR: 660 for erlotinib, 549 for sunitinib, 543 for sorafenib, 49 for nilotinib, 43 for lapatinib, 235 for imatinib and 168 for dasatinib. According to the selection criteria, 22 adverse psychiatric events associated with TKIs were selected (17 patients, 11 males and 6 females; median age: 69.4 years (range: 51-80 years). The indications for treatment were: 3 lung cancer, 8 liver cancer, 5 renal cancer and 1 chronic myeloid leukaemia). The distribution of adverse reactions was as follows: 5 for erlotinib (1 hallucination, 2 confusion, 1 loss of memory, 1 mental disorder); 5 for sunitinib (2 confusion, 1 agitation, 1 depression, 1 disorientation); 11 for sorafenib (3 confusion, 2 agitation, 3 depression, 2 insomnia, 1 bradyphrenia); 1 for nilotinib (confusion). The time to event onset since first drug administration ranged from 1 week to 40 weeks. Complete recovery was achieved in 5 cases (time to recovery since drug discontinuation: 4 weeks), improvement in 4 cases, recovery with sequelae in 3 cases. One case resulted in death. The outcome was not available in 4 cases. Eight cases were classified as serious.PRR for psychiatric ADR associated with TKIs was 0.6 [95%CI: 0.3-2.1]. Overall, several case reports of psychiatric disorders have been reported for TKIs to the Italian database. The estimation of PRR does not suggest a significant risk of psychiatric disorder reporting for TKIs. However, these results should be interpreted with caution. Indeed, psychiatric disorders are commonly reported for several drugs, thus resulting in a dilution of reports. This circumstance might have altered the possibility for disproportional analysis to identify a possible alarm signal for psychiatric events associated with TKIs. Moreover, it is important consider that psychiatric disorders are a relevant issue in cancer patients, and this fact may represent an important confounding for the identification of drug-related psychiatric disorders in these patients. Further monitoring on the incidence and risk factors of psychiatric events in patients treated with TKIs is needed.

References

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