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 ID . | Age, Sex . | CML Stage . | IM Daily Dose . | 1st Cmin (ng/mL) . | Reason for Dose Change . | New Dosing Regimen . | New Cmin (ng/mL) . |
|---|---|---|---|---|---|---|---|
| CP, chronic phase1 | |||||||
| 1 | 54, f | CP | 200 mg bid, Jan 03 | 3048, Sep 05 | transfusion-dependent, anemia, Sep 05 | 300 mg, Oct 05 | 2130, Jan 06 |
| 2 | 9, f | CP | 300 mg, Jan 05 | not done | qRT-PCR 0.016, Jan 06 | 400 mg, Jan 06 | 2341, Jul 06 |
| 3 | 13, f | CP | 300 mg bid, May 05; 700 mg, Aug 05; 600 mg, Sep 05 | 1966, Feb 06 | nausea, fatigue, arthralgias, myalgia, ongoing | 400 mg, Mar 06 | 1222, May 06 |
| 4 | 67, f | CP | 400 mg, Feb 05 | not done | myelosuppression, Mar 05 | 200 mg, Mar 05 | 1928, May 06 |
| 5 | 53, f | CP | 400 mg, Apr 03; 600 mg, May 03; 800 mg, Jul 04 | not done | inflammatory pulmonary reaction with shortness of breath; dose held, Mar 05 | 400 mg, Oct 05 | 2378, May 06 |
| 6 | 73, m | CP | 350 mg, on phenytoin, Apr 99 | 35, Jun 99 | stopped phenytoin, Jul 99 | 500 mg, Jul 99 | not done; qRT-PCR negative, Jul 06 |
| Patient ID . | Age, Sex . | CML Stage . | IM Daily Dose . | 1st Cmin (ng/mL) . | Reason for Dose Change . | New Dosing Regimen . | New Cmin (ng/mL) . |
|---|---|---|---|---|---|---|---|
| CP, chronic phase1 | |||||||
| 1 | 54, f | CP | 200 mg bid, Jan 03 | 3048, Sep 05 | transfusion-dependent, anemia, Sep 05 | 300 mg, Oct 05 | 2130, Jan 06 |
| 2 | 9, f | CP | 300 mg, Jan 05 | not done | qRT-PCR 0.016, Jan 06 | 400 mg, Jan 06 | 2341, Jul 06 |
| 3 | 13, f | CP | 300 mg bid, May 05; 700 mg, Aug 05; 600 mg, Sep 05 | 1966, Feb 06 | nausea, fatigue, arthralgias, myalgia, ongoing | 400 mg, Mar 06 | 1222, May 06 |
| 4 | 67, f | CP | 400 mg, Feb 05 | not done | myelosuppression, Mar 05 | 200 mg, Mar 05 | 1928, May 06 |
| 5 | 53, f | CP | 400 mg, Apr 03; 600 mg, May 03; 800 mg, Jul 04 | not done | inflammatory pulmonary reaction with shortness of breath; dose held, Mar 05 | 400 mg, Oct 05 | 2378, May 06 |
| 6 | 73, m | CP | 350 mg, on phenytoin, Apr 99 | 35, Jun 99 | stopped phenytoin, Jul 99 | 500 mg, Jul 99 | not done; qRT-PCR negative, Jul 06 |
Disclosures: Wang - Novartis Pharmaceuticals Corporation; Letvak - Novartis Pharmaceuticals Corporation.; Blasdel - 1) Health Ed and Robert Michael Communications - both funded by Novartis; 2) Bristol-Myers Squibb; Druker - Ambit Biosciences, Avalon Pharmaceuticals, Cephalon, Inc., Cylene Pharmaceuticals, Geron Corporation, ICOS Corporation, Kereos, Inc., Portola Pharmaceuticals, SGX Pharmaceuticals, Upstate Biotechnology, Vertex Pharmaceuticals, Breakthrough Therapeutics, Molecular MD; Egorin - I have served as a consultant to Novartis regarding imatinib pharmacokinetics. My laboratory is funded by Novartis to provide assays for imatinib to investigators of clinical trials, preclinical studies, and, on occasion, to physicians who desire measurement of imatinib in plasma (and rarely other biological matrices) of patients under their care.; Druker - 1) Scientific Founder, Molecular MD - equity cannot exceed 5%; 2) Consultant, Breakthrough Therapeutics - equity cannot exceed 5%.; Wang - stock options from Novartis; Letvak - shares in Novartis Pharmaceuticals.; Druker - I am the principal investigator on several Novartis and Bristol-Myers Squibb clinical trials. My institution has contracts with these companies to pay for patient costs, nurse and study coordinator salaries, and institutional overhead. I do not derive salary, nor does my lab receive funds, from these contracts.; Egorin - My laboratory is funded by Novartis to provide assays for imatinib to investigators of clinical trials, preclinical studies, and, on occasion, to physicians who desire measurement of imatinib in plasma (and rarely other biological matrices) of patients under their care.; Blasdel - 1) Lecture honoraria - Novartis; 2) Health Science Center for Continuing Medical Education - supported by education grant from Novartis; Egorin - Lecture honoraria from Novartis.; Blasdel - Past member of Nurse Advisory Board for Bristol-Myers Squibb; Egorin - Novartis Scientific Advisory Board related to imatinib.
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