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Blood, 15 April 2007, Vol. 109, No. 8, pp. 3609-3610.
CORRESPONDENCE Imatinib increases the intracellular concentration of nilotinib, which may explain the observed synergy between these drugsTo the editor:Weisberg et al1 recently demonstrated additive or synergistic effects when nilotinib was combined with imatinib in BCR-ABL+ leukemic cell lines. The authors speculated that this synergy might be due to interactions with drug transporters. Recent studies in our laboratory using 14C-labeled imatinib and nilotinib in an assay measuring intracellular uptake and retention (IUR)2 have assessed the effect of adding unlabeled nilotinib to the 14C-labeled imatinib IUR, and conversely, unlabeled imatinib to 14C-labeled nilotinib IUR. All combination studies were performed at the clinically achievable drug concentrations of 1 and 2 µM. To date, we have performed assays in 5 newly diagnosed patients with CML, and 2 cell lines. The results of triplicate analyses are shown in Table 1.
While there is variation in the degree of response between patients, these data demonstrate a significant increase in the IUR of 1 µM 14C-labeled nilotinib when either 1 or 2 µM imatinib is added. An increase, though not statistically significant, was also noted in 4 of 5 patients when imatinib was added to 2 µM 14C-labeled nilotinib. In contrast, the addition of nilotinib to 14C-labeled imatinib resulted in a decrease in IUR in most patients, though this decrease failed to reach statistical significance. The results in cell lines were similar to results in primary cells. These data suggest the benefit of combined therapy is most likely mediated through an increase in the intracellular concentration of nilotinib, but not imatinib. Recent experiments in our laboratory assessing the effect of temperature (37°C vs 4°C) on nilotinib uptake and retention in an ABCB1-expressing cell line suggest that nilotinib is transported by ABCB1. Therefore, imatinib inhibition of ABCB1-mediated efflux may be the cause for the increased IUR for nilotinib that is observed when both drugs are combined. An interaction with other efflux proteins, such as ABCG2, is also possible, especially given recent findings suggesting imatinib is an inhibitor but probably not a substrate of this transporter.3,4 Our findings raise the possibility that in combination regimens, imatinib may exacerbate nilotinib side effects by increasing cellular concentrations of nilotinib in other tissues. While this is a consideration, significant increases in intracellular nilotinib were limited to low drug doses, suggesting additive effect/synergy may be most evident at low doses. This finding is consistent with the findings of Weisberg et al.1 In summary, we show that the synergistic/additive effects reported may be mediated through an increase in the intracellular concentration of nilotinib. While other factors may also contribute to synergy, the magnitude of the increase in intracellular nilotinib induced by concomitant administration of imatinib would probably be sufficient to account for the additive and synergistic effects observed by Weisberg et al. Authorship Correspondence: Deborah L. White, Division of Hematology, IMVS & Hanson Institute, Frome Road, Adelaide, Australia; e-mail: deb.white{at}imvs.sa.gov.au Conflict-of-interest disclosure: S.R.Q. and P.W.M. are both employees of Navartis Pharmaceuticals. D.L.W. and T.P.H. have received honoraria from Novartis Pharmaceuticals. T.P.H. has received research funds from Novartis Pharmaceuticals.
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| Copyright © 2007 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
