Abstract 5473: The contribution of P-glycoprotein to clinical pharmacokinetic interactions between lenalidomide and temsirolimus

Abstract

Abstract Purpose: To evaluate the source of an apparent clinical pharmacokinetic interaction between lenalidomide (an Immunomodulatory Drug, IMiD) and temsirolimus (mTOR inhibitor). Background: The combination of lenalidomide with temsirolimus demonstrated a synergistic effect in in vitro models of Multiple Myeloma (MM), thus providing rationale for this combination in patients with relapsed MM. However pharmacokinetic interactions between these two agents have not been reported. In the current study, clinical pharmacokinetic interactions of lenalidomide with temsirolimus and the underlying mechanisms were investigated. Methods: A phase I clinical trial was completed for patients with relapsed multiple myeloma with oral lenalidomide (15-25 mg) days 1-21 of a 28 day cycle and weekly × 4 intravenous temsirolimus (15-20 mg). Pharmacokinetic data for both agents were obtained and potential drug-drug interactions were further evaluated using in vitro transport and uptake studies. An apparent clinical interaction was observed between lenalidomide and temsirolimus as demonstrated by statistically significant changes in clearance, maximum concentrations (Cmax), and area under the concentration-time curves (AUCs) for constant doses of lenalidomide with increased doses of temsirolimus. Similar and significant changes for temsirolimus pharmacokinetics at a fixed dose were also observed when lenalidomide doses were increased. In vitro studies indicated a higher basolateral-to-apical (BL-to-AP) flux compared to AP-to-BL flux for lenalidomide in MDCKII monolayers, suggesting an apically directed active transport of lenalidomide. Further evaluation of intracellular lenalidomide uptake showed an approximately 2-fold higher accumulation of lenalidomide in HL-60 than in P-glycoprotein (P-gp, ABCB1, MDR-1)-overexpressing HL-60/VCR cells (38.4 ± 13.2 vs. 19.2 ± 9.6 pmol/mg protein, respectively, P=0.005). Co-incubation with temsirolimus, a known P-gp substrate and inhibitor, resulted in increased lenalidomide accumulation (37.2 ± 6.0 vs. 19.2 ± 9.6 pmol/mg protein, respectively, P=0.002) in HL-60/VCR cells, which was equivalent to that in HL-60 cells. Clinical significance of this pharmacokinetic interaction in terms of either toxicity or response has also been evaluated. Conclusions: These results suggest that lenalidomide is a P-gp substrate, explaining the pharmacokinetic interaction between lenalidomide and temsirolimus. Quantifying the interaction of lenalidomide with other P-gp substrates, e.g. dexamethasone, is warranted to optimize dose administration of IMiD-based therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5473. doi:10.1158/1538-7445.AM2011-5473