Impact of Imatinib Levels in CML

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Emerging Evidence of a Relationship Between

Imatinib Plasma Levels and Response

" Imatinib mesylate has demonstrated significant clinical efficacy in the

treatment of Philadelphia-positive chronic myeloid leukemia (CML) and

KIT-positive gastrointestinal tumors (GIST). However, suboptimal responses have

been reported in some patients.It has been suggested that a key factor

contributing to suboptimal response in some patients may be subtherapeutic

imatinib plasma concentrations. The pharmacokinetic (PK) profile of imatinib

demonstrates significant interpatient variability, which may stem from

differences in:

a.. Drug absorption

b.. Degree of protein bindingThe impact of various cellular influx and efflux

mechanisms

c.. Cytochrome P450 enzyme activity (either intrinsic or due to drug-drug

interactions)

d.. Adherence

" Evidence supporting this hypothesis has recently emerged from analyses of

imatinib plasma concentrations conducted in chronic myeloid and

gastrointenstinal stromal tumor patients.

The Impact of Imatinib Levels in CML

" Larson et al compared imatinib trough plasma levels to response to therapy in

351 chronic-phase (CP) CML patients from the landmark IRIS trial who were

treated with the standard daily dose of 400 mg of imatinib and for whom

steady-state PK data were available. The investigators found a significant

correlation between achieving a complete crytogenic response (CCyR) during the

5-year follow-up period and a higher imatinib plasma concentration.

Specifically, patients who achieved a CCyR had a mean imatinib trough level of

1009 + 544 ng/mL; in contrast, patients who did not achieve a CCyR had a mean

trough level of 812 + 409 ng/mL (P = 0.01, Figure). Patients with high imatinib

plasma concentrations were also significantly more likely to achieve a major

molecular response (MMR) (P = 0.02). The investigators concluded that

maintaining imatinib plasma trough levels above 1000 ng/mL is an independent

prognostic factor that may be important for achieving CCyR and MMR. " More at

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