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

Abstract

Purpose: Imatinib is currently used for the treatment of chronic myeloid leukemia (CML) patients. 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 (MannWhitney 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.

Treatment of Philadelphia chromosome‐positive acute lymphoblastic leukaemia with imatinib combined with a paediatric‐based protocol

“…However, we cannot exclude an additional influence of imatinib. As a potent CYP3A4 inhibitor, imatinib could theoretically increase the exposure to vincristine and dexamethasone, both of which are metabolized by the enzyme (Duckett & Cameron, 2010;Green et al, 2010;Nebot et al, 2010).…”

Measurement of imatinib uptake by flow cytometry

“…A defined number (5 3 10 6 ) of K562 cells were incubated for 1 h with different concentrations of IM (1,5,10,15,20,25,50, and 100 lM) at 378C in a saturated humidified atmosphere of 5% CO 2 . After 1 h, we stopped IM uptake by immediate dilution of the cell suspension with cold medium; the cell suspension was then washed twice and kept at cold temperature (tubes on ice, cold centrifugation).…”

“…Some studies using cell-line models have identified other events leading to IM resistance, such as BCR-ABL gene amplification (5), high expression of efflux transporter of the drug (6,7), clonal evolution with acquisition of additional chromosomal abnormalities, or persistence of quiescent stem cells (8 Another obvious resistance mechanism concerns IM pharmacokinetics, because it is essential that sufficient concentrations of the drug reach the cell target to be fully effective. IM bioavailability is subject to considerable interindividual variability, due in part to digestive absorption, plasma protein binding (9), interaction with others drugs, and CYP3 A4 activity (10). A residual plasma threshold value (1,002 ng/ ml) with a predictive value for achieving complete cytogenetic response (CCyR) and major molecular response has been identified (11).…”

Association between imatinib transporters and metabolizing enzymes genotype and response in newly diagnosed chronic myeloid leukemia patients receiving imatinib therapy

“…To date, there have been no studies addressing the functional implications of this specific polymorphism in vivo; however, in vitro experiments have suggested that the variant allele may be associated with higher CYP3A4 expression. 39,40 Pharmacokinetic and pharmacodynamic assessments in the phase I study of imatinib in CML proposed that variability in CYP3A4 activity might, at least in part, account for the observed interpatient variability in drug exposure and that co-administration of drugs inducing CYP3A4 could increase imatinib metabolism and lead to low/ineffective imatinib plasma levels. 41 One would thus expect lower response rates to be associated with the rs270574 variant -which actually contrasts with our findings.…”