Therapeutic Drug Monitoring of Imatinib and Impact on Clinical Decision Making.

Abstract

OBJECTIVES: Imatinib (IM) has demonstrated durable clinical efficacy in the majority of chronic myeloid leukemia (CML) patients. Optimal response may be influenced by multiple innate and external factors, some of which may be controlled by monitoring plasma concentrations of the drug. This abstract reports 6 cases where analyzing plasma IM trough concentrations (Cmin) in patients treated with three commonly used IM doses (400, 600, and 800 mg daily) influenced clinical decision making.METHODS: IM trough blood samples were collected at a time before that day's IM dosing. Plasma concentrations of IM were determined by a validated LC/MS/MS method.RESULTS: In large population studies of CML patients enrolled in Phase I, II, and III clinical trials, the mean Cmin levels of IM at 400 mg qd, 600 mg qd, and 400 mg bid doses were: 981 (±543, 55%, n=394), 1572 (±1032, 66%, n=14), and 3479 (±1264, 36%, n=14) ng/mL, respectively. Large inter-patient variability was shown at all three doses. Of the 6 cases detailed in the table below, 4 (ID 1, 3, 4, and 5) had dose reduction due to tolerability concerns with subsequent improvement of symptoms following dose adjustment. One patient (ID 2) had a dose increase because of a poor qRT-PCR response. Another (ID 6) had a dose increase due to low plasma IM exposure resulting from drug-drug interaction with phenytoin, a known inducer of CYP3A4 (the major metabolizing isozyme for IM). After dose adjustment, all six patients showed good clinical response to IM treatment. The new mean Cmin value in these patients was 2000 (±471) ng/mL, representing a 24% coefficient of variability.CONCLUSIONS: Although the data is limited, IM drug monitoring proved useful in managing tolerability, lack of efficacy, adherence or potential drug interactions that modulate imatinib drug concentrations. More prospective studies are needed to demonstrate the value of IM drug monitoring in routine clinical practice.Patient IDAge, SexCML StageIM Daily Dose1st Cmin (ng/mL)Reason for Dose ChangeNew Dosing RegimenNew Cmin (ng/mL)154, fCP200 mg bid, Jan 033048, Sep 05transfusion-dependent, anemia, Sep 05300 mg, Oct 052130, Jan 0629, fCP300 mg, Jan 05not doneqRT-PCR 0.016, Jan 06400 mg, Jan 062341, Jul 06313, fCP300 mg bid, May 05; 700 mg, Aug 05; 600 mg, Sep 051966, Feb 06nausea, fatigue, arthralgias, myalgia, ongoing400 mg, Mar 061222, May 06467, fCP400 mg, Feb 05not donemyelosuppression, Mar 05200 mg, Mar 051928, May 06553, fCP400 mg, Apr 03; 600 mg, May 03; 800 mg, Jul 04not doneinflammatory pulmonary reaction with shortness of breath; dose held, Mar 05400 mg, Oct 052378, May 06673, mCP350 mg, on phenytoin, Apr 9935, Jun 99stopped phenytoin, Jul 99500 mg, Jul 99not done; qRT-PCR negative, Jul 06CP, chronic phase1