Non-Steroidal Anti-Inflammatory Drugs and Imatinib; Drug Interactions That May Impact Efficacy,

The human organic cation transporter-1 (OCT-1) is the primary active influx protein for imatinib (IM) into target BCR-ABL-positive cells. The functional activity of the OCT-1 protein (OCT-1 activity; OA) is predictive of molecular response and event-free survival in de-novo chronic phase chronic myeloid leukemia (CP-CML) patients. Due to the common use of non-steroidal anti-inflammatory drugs (NSAIDs) among CML patients on IM to treat musculoskeletal pain, it is of particular interest to investigate the impact of NSAIDs on OCT-1 mediated IM uptake.

12 NSAIDs were firstly examined for their impact on OA using the intracellular uptake and retention (IUR) assay and [14-C]-IM. The degree of in vitro kinase inhibition achieved was assessed using p-Crkl in the IC50^imatinib assay. Viable cell numbers were determined by trypan blue exclusion method after 72 hours incubation with the co-administration of NSAIDs and IM. NSAIDs concentration was adjusted to median blood levels on standard doses.

The majority of NSAIDs (10 of 12) selected did not induce any significant change in OA in CML cell lines. Compared to control cells, increased OA were observed when K562 or KU812 cells were treated with diclofenac (10μM), and this resulted in a concomitant decrease in the IC50^imatinib. In keeping with this, after 72 hours co-incubation with IM, diclofenac resulted in a significantly lower viable cell number compared with IM alone. In contrast, ibuprofen (130μM) led to a significant decrease in OA, resulting in an increased IC50^imatinib and thus reduced the inhibition of IM on cell growth number (Table 1).

The effects of diclofenac and ibuprofen on IM efficacy were then further investigated using primary samples. In keeping with the results observed in cell lines, diclofenac resulted in significant increases in OA, which translated to a significant decrease in IC50^imatinib. Ibuprofen induced significant decreases in OA in all patients and healthy donors (Table 1).

These finding provide strong evidence for interactions between some NSAIDs and IM which may substantially impact the response of CML patients to IM. While drugs such as diclofenac are likely to have a positive influence on IM efficacy, the findings observed with ibuprofen suggest caution when administrating NSAIDs to CML patients on IM treatment.

Hughes:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ARIAD: Honoraria, Membership on an entity's Board of Directors or advisory committees. Osborn:Novartis: Research Funding. White:Novartis Pharmaceuticals: Research Funding; BMS: Research Funding.