Title

 

Authors

A. Ariaudo¹, S. De Francia¹, A. D’Avolio², E. Pirro¹, F. Piccione¹, M. Simiele², C. Fava³, G. Saglio³, F. Di Carlo².

¹Clinical Pharmacology of San Luigi Hospital, University of Turin;
²Clinical Pharmacology and Pharmacogenetics of Amedeo di Savoia Hospital, University of Turin;
³Division of Internal Medicine-Haematology of San Luigi Hospital, University of Turin. 

 

Abstract

Imatinib is the gold standard for the treatment of chronic myeloid leukaemia (CML) [1]. Several studies revealed correlation between imatinib trough plasma levels and clinical response, suggesting that measurement of plasma levels can be an useful tool for optimising imatinib therapy [2]. However up to 40% of CML patients show resistance or intolerance to imatinib, leading, as a consequence, a switching therapy to more potent tyrosine kinase inhibitors (TKIs) such as nilotinib and dasatinib. New TKIs, in fact, showed activities both in first and in second line treatment, overcoming imatinib as front-line treatment for CML, even if  literature on the correlation between nilotinib and dasatinib plasma levels and clinical responses is still limited. Measurement of intracellular level of imatinib, furthermore, could become an important strategy to predict the efficacy of treatment in CML patients. Primary aim of our study was to assess the impact of pharmacogenetic (PG) variability on plasmatic pharmacokinetics (PK) of imatinib, nilotinib and dasatinib, and on clinical responses. Drugs plasma troughlevels have been determined by HPLC-UV validated method [3]and clinical response was assessed by evaluation of hemochrome, cytogenetic and molecular results. Candidate genes for PG analysis included MDR1, MRP1, MRP2, SLCO1B1 CYP3A4, CYP3A5, UGT1A1, PXR, CAR. As secondary endpoint we evaluated imatinib, dasatinib and nilotinib intracellular PK and the potential impact of genetic polymorphisms on the TKIs intracellular levels. All patients enrolled in the study signed a consent for the collection of 1 Heparin tube of whole blood for plasma PK analysis and DNA extraction for PG analysis, and 4 EDTA tubes of whole blood for PBMC isolation finalized to intracellular PK analysis. The collection started in January 2010 and will finish within two years.
 
[1] C.L. Sawyers. N. Engl. J. Med. 340, 1330 (1999).

[2] S. Picard et al. Blood.109, 3496 (2007).

[3] E. Pirro, S. De Francia et al. Accepted on JCS (2010).