Therapeutic drug monitoring of imatinib

In this issue of the Revista Brasileira de Hematologia e Hemoterapia, Martins et al. (1) are publishing an interesting review, a meta-analysis, of the clinical and analytical aspects of therapeutic drug monitoring of imatinib in chronic myeloid leukemia (CML). Imatinib, the archetype for tyrosine kinase inhibitor therapeutics, is an excellent example of intelligent drug development accompanied by growing therapeutic drug monitoring (TDM). It is the current standard of care in the treatment of CML as it induces durable responses and prolonged survival. Martins et al. should have mentioned that imatinib is also recommended in the treatment of gastrointestinal stromal tumors (GISTs) for its exceptional activity in inhibiting the constitutively active conformation of the KIT and PDGFRA genes found in the majority of patients with this disease. Plasma imatinib levels were frequently unrelated to the daily administered dose of imatinib. It is well established that imatinib, similar to many other drugs, produces significant interindividual pharmacokinetic variability and as a consequence, plasma exposure to the drug from a given dosing regimen can vary widely among patients. The causes of such variability may be related to several factors including – environmental factors and diseases (food, liver function, abnormal clearance volume, protein contents, etc.) (4) – drug interactions (cytochrome inducers or inhibitors) – genetic polymorphisms (mainly CYP3A5, but also CYP2D6, CYP2C9 or CYP2C19, influx or efflux transport proteins, such as OCT1, OCTN2, OATP1A2, OATP1B3, and ABCB1 or ABCG2, respectively) (5) – lack of compliance In both diseases, a good and statistically significant pharmacokinetic-pharmacodynamic relationship has been reported by several studies with better outcomes when plasma imatinib levels are kept above a defined cutoff point. The most frequent pharmacodynamic biomarkers used to assess treatment efficacy are complete cytogenetic response (CCR), complete molecular response (CMR) and major molecular response (MMR). A general consensus has been reached that suggests that 1000 ng/mL is the minimal plasma concentration of imatinib. The definition of the upper therapeutic concentration is less clear as the drug does not appear to cause severe side effects and long-term effects have not been ascertained yet. Some authors have suggested an interest for imatinib free fraction determination, corresponding to the active fraction reaching target cells. Patient selection and frequency of analyses should be better determined. But questions remain such as should plasma drug determination be performed early after the onset of treatment in order to prevent therapeutic failure and the occurrence of side effects, or …