Date: 07 Jan 2010
CYP3A activity influences imatinib response in patients with chronic myeloid leukemia: a pilot study on in vivo CYP3A activity
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Imatinib is currently used for the treatment of chronic myeloid leukemia (CML). The main metabolite CGP74588 has similar potency to that of imatinib and is a product of CYP3A4 and CYP3A5 metabolism. However, the clinical significance of the metabolism on therapeutic response and pharmacokinetics is still unclear. We designed this study to investigate the role of the CYP3A activity in the response to imatinib therapy.
Fourteen CML patients were phenotyped for in vivo CYP3A activity using quinine as a probe drug. The plasma concentration ratio of quinine and its CYP3A metabolite was used for assessing CYP3A activity. The patients were divided into complete molecular responders with undetectable levels of BCR-ABL transcripts after 12 months of therapy and into partial molecular responders who had failed to achieve a complete molecular response.
Patients that achieved complete molecular response showed significantly (Mann-Whitney U-test, p = 0.013) higher in vivo CYP3A activity (median quinine metabolic ratio = 10.1) than patients achieving partial molecular response (median = 15.9).
These results indicate a clinical significance of the CYP3A activity and its metabolic products in CML patients treated with imatinib.
Henrik Gréen and Karin Skoglund contributed equally to this work.
Cohen MH, Williams G, Johnson JR, Duan J, Gobburu J, Rahman A et al (2002) Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia. Clin Cancer Res 8:935–942PubMed
Hasford J, Pfirrmann M, Hehlmann R, Allan NC, Baccarani M, Kluin-Nelemans JC et al (1998) A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group. J Natl Cancer Inst 90:850–858CrossRefPubMed
Gambacorti-Passerini C, Zucchetti M, Russo D, Frapolli R, Verga M, Bungaro S et al (2003) Alpha1 acid glycoprotein binds to imatinib (STI571) and substantially alters its pharmacokinetics in chronic myeloid leukemia patients. Clin Cancer Res 9:625–632PubMed
Roy L, Guilhot J, Krahnke T, Guerci-Bresler A, Druker BJ, Larson RA et al (2006) Survival advantage from imatinib compared with the combination interferon-alpha plus cytarabine in chronic-phase chronic myelogenous leukemia: historical comparison between two phase 3 trials. Blood 108:1478–1484CrossRefPubMed
Quintas-Cardama A, Kantarjian H, Jones D, Shan J, Borthakur G, Thomas D et al (2009) Delayed achievement of cytogenetic and molecular response is associated with increased risk of progression among patients with chronic myeloid leukemia in early chronic phase receiving high-dose or standard-dose imatinib therapy. Blood 113:6315–6321CrossRefPubMed
- CYP3A activity influences imatinib response in patients with chronic myeloid leukemia: a pilot study on in vivo CYP3A activity
European Journal of Clinical Pharmacology
Volume 66, Issue 4 , pp 383-386
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- Chronic myeloid leukemia
- Complete molecular response
- Industry Sectors
- Author Affiliations
- 1. Division of Drug Research/Clinical Pharmacology, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, 581 85, Linköping, Sweden
- 2. Department of Hematology, Linköping University Hospital, Linköping, Sweden
- 3. Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska University Hospital-Huddinge, Karolinska Institute, Stockholm, Sweden
- 4. Division of Pharmacology, Faculty of Medicine, King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia