Therapeutic drug monitoring for imatinib: Current status and Indian experience

Abstract

Imatinib is the current gold standard for treatment of chronic myeloid leukemia (CML). Recent pharmacokinetic studies have shown considerable variability in trough concentrations of imatinib due to variations in its metabolism, poor compliance, or drug-drug interactions and highlighted its impact on clinical response. A trough level close to 1000 ng/mL, appears to be correlated with better cytogenetic and molecular responses. Therapeutic Drug Monitoring (TDM) for imatinib may provide useful added information on efficacy, safety and compliance than clinical assessment alone and help in clinical decision making. It may be particularly helpful in patients with suboptimal response to treatment or treatment failure, severe or rare adverse events, possible drug interactions, or suspected nonadherence. Further prospective studies are needed to confirm relationship between imatinib plasma concentrations with response, and to define effective plasma concentrations in different patient populations.

Keywords

Blood-level testing - chronic myeloid leukemia - imatinib - pharmacodynamics - pharmacokinetics - tyrosine kinase inhibitors

Publication History

Article published online:
19 July 2021

• References

• 1 Goldman JM, Melo JV. Chronic myeloid leukemia - Advances in biology and new approaches to treatment. N Engl J Med 2003;349:1451-64.
• 2 Baccarani M, Saglio G, Goldman J, Hochhaus A, Simonsson B, Appelbaum F, et al. Evolving concepts in the management of chronic myeloid leukemia: Recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2006;108:1809-20.
• 3 National comprehensive cancer network guidelines version 2.2009. URL: http://www.nccn.org/professionals/physician-gls/pdf/cml.pdf.
• 4 Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 2001;293:876-80.
• 5 Radich JP, Dai H, Mao M, Oehler V, Schelter J, Druker B, et al. Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc Natl Acad Sci U S A 2006;103:2794-9.
• 6 Larson RA, Druker BJ, Guilhot F, O′Brien SG, Riviere GJ, Krahnke T, et al. Imatinib pharmacokinetics and its correlation with response and safety in chronic-phase chronic myeloid leukemia: A subanalysis of the IRIS study. Blood 2008;111:4022-8.
• 7 Picard S, Titier K, Etienne G, Teilhet E, Ducint D, Bernard MA, et al. Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood 2007;109:3496-9.
• 8 Guilhot F, Hughes TP, Cortes J, Druker BJ, Baccarani M, Gathmann I, et al. Plasma exposure of imatinib and its correlation with clinical response in the Tyrosine Kinase Inhibitor Optimization and Selectivity Trial. Haematologica. 2012 ; 97:731-8.
• 9 Takahashi N, Wakita H, Miura M, Scott SA, Nishii K, Masuko M, et al. Correlation between imatinib pharmacokinetics and clinical response in Japanese patients with chronic-phase chronic myeloid leukemia. Clin Pharmacol Ther 2010;88:809-13.
• 10 Forrest DL, Trainor S, Brinkman RR, Barnett MJ, Hogge DE, Nevill TJ, et al. Cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia are correlated with Sokal risk scores and duration of therapy but not trough imatinib plasma levels. Leuk Res 2009;33:271-5.
• 11 Mahon FX, Molimard M. Correlation between trough imatinib plasma concentration and clinical response in chronic myeloid leukemia. Leuk Res 2009;33:1147-8.
• 12 Widmer N, Decosterd LA, Leyvraz S, Duchosal MA, Rosselet A, Debiec-Rychter M, et al. Relationship of imatinib-free plasma levels and target genotype with efficacy and tolerability. Br J Cancer 2008;98:1633-40.
• 13 Peng B, Hayes M, Resta D, Racine-Poon A, Druker BJ, Talpaz M, et al. Pharmacokinetics and pharmacodynamics of imatinib in a phase I trial with chronic myeloid leukemia patients. J Clin Oncol 2004;22:935-42.
• 14 Peng B, Lloyd P, Schran H. Clinical pharmacokinetics of imatinib. Clin Pharmacokinet 2005;44:879-94.
• 15 Osterberg L, Blaschke T. Adherence to medication. N Engl J Med 2005;353:487-97.
• 16 Cortes JE, Egorin MJ, Guilhot F, Molimard M, Mahon FX. Pharmacokinetic/pharmacodynamic correlation and blood-level testing in imatinib therapy for chronic myeloid leukemia. Leukemia 2009;23:1537-44.
• 17 Cohen MH, Williams G, Johnson JR, Duan J, Gobburu J, Rahman A, et al. Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia. Clin Cancer Res 2002;8:935-42.
• 18 Wilkinson GR. Cytochrome P4503A (CYP3A) metabolism: Prediction of in vivo activity in humans. J Pharmacokinet Biopharm 1996;24:475-90.
• 19 Beumer JH, Natale JJ, Lagattuta TF, Raptis A, Egorin MJ. Disposition of imatinib and its metabolite CGP74588 in a patient with chronic myelogenous leukemia and short-bowel syndrome. Pharmacotherapy 2006;26:903-7.
• 20 Gambacorti-Passerini C, Zucchetti M, Russo D, Frapolli R, Verga M, Bungaro S, et al. Alpha1 acid glycoprotein binds to imatinib (STI571) and substantially alters its pharmacokinetics in chronic myeloid leukemia patients. Clin Cancer Res 2003;9:625-32.
• 21 Bakhtiar R, Lohne J, Ramos L, Khemani L, Hayes M, Tse F. High-throughput quantification of the anti-leukemia drug STI571 (Gleevec) and its main metabolite (CGP 74588) in human plasma using liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2002;768:325-40.
• 22 Titier K, Picard S, Ducint D, Teilhet E, Moore N, Berthaud P, et al. Quantification of imatinib in human plasma by high-performance liquid chromatography-tandem mass spectrometry. Ther Drug Monit 2005;27:634-40.
• 23 Hegedus T, Orfi L, Seprodi A, Váradi A, Sarkadi B, Kéri G. Interaction of tyrosine kinase inhibitors with the human multidrug transporter proteins, MDR1 and MRP1. Biochim Biophys Acta 2002;1587:318-25.
• 24 Hamada A, Miyano H, Watanabe H, Saito H. Interaction of imatinib mesilate with human P-glycoprotein. J Pharmacol Exp Ther 2003;307:824-8.
• 25 Burger H, van Tol H, Boersma AW, Brok M, Wiemer EA, Stoter G, et al. Imatinib mesylate (STI571) is a substrate for the breast cancer resistance protein (BCRP)/ABCG2 drug pump. Blood 2004;104:2940-2.
• 26 White DL, Saunders VA, Dang P, Engler J, Venables A, Zrim S, et al. Most CML patients who have a suboptimal response to imatinib have low OCT-1 activity: Higher doses of imatinib may overcome the negative impact of low OCT-1 activity. Blood 2007;110:4064-72.
• 27 Kantarjian HM, Larson RA, Guilhot F, O′Brien SG, Mone M, Rudoltz M, et al. Efficacy of imatinib dose escalation in patients with chronic myeloid leukemia in chronic phase. Cancer 2009;115:51-60.
• 28 Blasdel C, Egorin MJ, Lagattuta TF, Druker BJ, Deininger MW. Therapeutic drug monitoring in CML patients on imatinib. Blood 2007;110:1699-701.
• 29 Mahon FX. Pharmacologic monitoring and determinants of intracytoplasmic drug levels. Best Pract Res Clin Haematol 2009;22:381-6.
• 30 Singh N, Kumar L, Meena R, Velpandian T. Drug monitoring of imatinib levels in patients undergoing therapy for chronic myeloid leukaemia: Comparing plasma levels of responders and non-responders. Eur J Clin Pharmacol 2009;65:545-9.
• 31 Buclin T. Imatinib concentration monitoring evaluation: the clinical usefulness of ′′routine′′ versus ′′rescue′′ therapeutic drug monitoring (TDM) interventions in chronic myeloid leukaemia (CML) patients. International Standard Randomised Controlled Trial Number Register Web site. Available from: http://www.controlled-trials.com/ISRCTN31181395. [cited 2013 August 28]