Role of pharmacogenetics in personalised imatinib dosing

Imatinib is the original tyrosine kinase inhibitor specifically designed and clinically used for the molecularly targeted treatment of chronic myeloid leukaemia (CML). It remains one of the most widely used first-line treatments for CML, and is now also indicated in multiple other BCR-ABL-, c-KIT- and PDGFR-driven cancers. Imatinib is orally administered, predominantly hepatically cleared with a low hepatic extraction ratio, is 95% bound to plasma proteins, and has an intracellular site of action. In the CML setting, treatment outcomes correlate with plasma imatinib concentrations, which show large interpatient variability. Treatment outcomes also correlate with markers of drug transporter variability considered to influence imatinib distribution into CML cells. Personalised imatinib dosing is therefore expected to improve treatment outcomes compared to a “one-dose-fits-all” approach, with a potential additional role for pharmacogenetics. Imatinib is metabolised by CYPs 2C8 and 3A4 in vitro. CYP2C8 genotype significantly affects imatinib metabolism, and consequently imatinib systemic exposure in CML patients. Conversely, there is no consistent evidence that CYP3A4 or CYP3A5 inhibitors, inducers or genetics alter imatinib metabolism and pharmacokinetics clinically. Imatinib is also a substrate for uptake and efflux transporters expressed in the liver and/or CML cells, although exactly which transporters is an area of open debate. The clear majority of studies indicate no significant effect of transporter genotypes on plasma imatinib concentrations or clearance, and any positive findings to date have not been replicated. Various measures of CML treatment outcome have been correlated with transporter genotype, and from this implied an effect of transporter genetics on imatinib distribution into CML cells. However, due to study design limitations it is unclear if these observations are due to genetic effects on imatinib clearance, intracellular distribution, or possibly neither. Other potentially novel genetic factors influencing imatinib disposition, such as xenobiotic-responsive receptor gene polymorphisms, remain to be thoroughly investigated. In summary, studies to date indicate a potential genetic influence on imatinib disposition, however evidence is still lacking to support a pharmacogenomic approach to personalised imatinib dosing. Whether pharmacogenomic information might be complementary to potential therapeutic drug monitoring or target concentration intervention for imatinib is an ongoing question. Improved study designs are required to gain greater mechanistic understanding of the factors governing variable imatinib intracellular distribution and its relationship to response, and move toward improved tools for personalised imatinib dosing.