Therapeutic Drug Monitoring of Imatinib for Chronic Myeloid Leukemia Patients

Imatinib mesylate (Glivec®; Novartis, Basel, Switzerland), a protein kinase inhibitor of the BCR–ABL fusion protein, has demonstrated significant clinical efficacy in the treatment of Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML). Imatinib mesylate (hereinafter shortly referred to as imatinib) produces durable responses and prolonged survival; therefore, it has become the standard of care for this disease (Goldman 2007; O'Brien, et al. 2003a). Notwithstanding the positive effects of imatinib, nearly 20% of the patients who take imatinib fail to achieve a complete cytogenetic response (CCyR); others may develop intolerable side effects or drug resistance overtime. Factors that might be associated with suboptimal responses and failure to treatment include (i) biological factors, such as the baseline presence or later emergence of BCR–ABL mutations or other genetic variants (Gorre, et al. 2001; Radich, et al. 2006), or organic cation transporter-1 (OCT1)-mediated drug influx (White, et al. 2010); (ii) clinical features, such as the disease status of the patients or the Sokal risk score at baseline (Crossman and O'Brien 2004); (iii) pharmacokinetic (PK) factors, such as PK-related interindividual variation affecting imatinib metabolism and drug–drug interactions (Cortes, et al. 2009; Peng, et al. 2004b); and (iv) the patient’s compliance with therapy (Marin, et al. 2010). In this chapter, we review the factors that affect imatinib pharmacokinetics, including the daily dose of imatinib, polymorphisms of imatinib-associated drug transporters, and the currently available methods for quantitative determination of imatinib. Moreover, we discuss the clinical significance of therapeutic drug monitoring (TDM) of imatinib.