Pharmacokinetics and Disposition

European Journal of Clinical Pharmacology

, Volume 66, Issue 4, pp 383-386

CYP3A activity influences imatinib response in patients with chronic myeloid leukemia: a pilot study on in vivo CYP3A activity

  • Henrik GréenAffiliated withDivision of Drug Research/Clinical Pharmacology, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University
  • , Karin SkoglundAffiliated withDivision of Drug Research/Clinical Pharmacology, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University Email author 
  • , Franz RommelAffiliated withDepartment of Hematology, Linköping University Hospital
  • , Rajaa A. MirghaniAffiliated withDivision of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska University Hospital-Huddinge, Karolinska InstituteDivision of Pharmacology, Faculty of Medicine, King Fahad Medical City
  • , Kourosh LotfiAffiliated withDivision of Drug Research/Clinical Pharmacology, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping UniversityDepartment of Hematology, Linköping University Hospital

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Abstract

Purpose

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.

Methods

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.

Results

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).

Conclusions

These results indicate a clinical significance of the CYP3A activity and its metabolic products in CML patients treated with imatinib.

Keywords

Chronic myeloid leukemia Imatinib CYP3A4 CYP3A5 CGP74588 Complete molecular response