Abstract 4203: Plasma and tumor pharmacokinetics (PK) of carboplatin in Genetically Engineered Mouse Models of melanoma (GEMMs), murine melanoma, and in patients with cutaneous melanoma

Abstract

Background: It is currently unclear what preclinical tumor model most accurately reflects the tumor disposition and antitumor response of an anticancer agent in patients with solid tumors. GEMMs of melanoma and other solid tumors may better predict drug distribution and antitumor response compared with flank tumor models by allowing for the development of tumor in situ which may more faithfully recapitulate human cancer. We compared the plasma and tumor disposition of carboplatin in a GEMM and murine models of melanoma and in patients with cutaneous melanoma. Methods: Carboplatin was administered at 50mg/kg IV x 1 via a tail vein to a GEMM of melanoma [tyrosinase-H-RasG12V Ink4a/Arf−/− (TRIA)] and mice bearing B16 murine melanoma. Plasma total and ultrafiltrate conc were obtained (n = 3 mice per time point) from 0 to 6 h after administration. Microdialysis studies evaluating carboplatin in tumor extracellular fluid (ECF) were performed (n = 6 mice) from 0 to 4 h after administration. Six patients with cutaneous metastatic melanoma were administered carboplatin at 400mg/m2 IV over 20 minutes. Plasma total and tumor ECF, collected by microdialysis, were obtained from 0 to 6 h after administration. Platinum (Pt) conc were measured by ICP-MS, FAAS and FAAS in the GEMM, B16 and patient studies, respectively. Areas under the plasma conc versus time curves from 0 to infinity (AUC) of standard and allometrically scaled data were calculated. Results: Results are in the table: UnitsHumanGEMMB16Standard / Unscaled Plasma Total Pt AUCµg/mL·h26.028.540.5Plasma Ultrafiltrate Pt AUCµg/mL·h—25.427.9Tumor ECF Pt AUCµg/mL·h15.38.61.9Allometrically Scaled Plasma Total Pt AUC(µg/mL)/(mg/kg)]·(h/kg)0.841.372.15Tumor ECF Pt AUC(µg/mL)/(mg/kg)]·(h/kg)0.490.410.10Ratio of Plasma Total pt AUC to Tumor ECF pt AUC 0.580.300.05 Conclusion: The tumor PK of carboplatin in GEMM models of melanoma more closely resembles the tumor disposition in patients with melanoma as compared with flank tumor models. GEMMs show promise in becoming an improved prediction model for drug PK and response in patient tumors. Studies are being conducted to determine the basis for differences in tumor drug delivery between GEMMs and transplanted tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4203.