Abstract 5446: The activity and pharmacokinetics of capecitabine in a mouse model (K8484) of pancreatic adenocarcinoma

Abstract

Abstract The pharmacokinetics (PK) of the oral fluoropyrimidine capecitabine were investigated in a mouse model of pancreatic cancer. Allografts of a cell line (K8484) derived from a pancreatic adenocarcinoma which occurred in a KrasG12D; p53R172H; Pdx1-Cre (KPC) mouse (S. Hingorani, et al., Cancer Cell 2005) were grown subcutaneously in left and right flanks of syngeneic immunocompetent recipient mice. Mice were dosed with either a single dose or 5 daily doses of capecitabine at 755 mg/kg (2.1 mmol/kg/day) with tumour volumes of approximately 250 mm3. Plasma and tissue homogenates were analysed using an LC-MS/MS assay developed to simultaneously detect capecitabine and its 3 metabolites DFCR, DFUR and 5-FU (S.M.Guichard, et al., J. Chrom. B. 2005). Forty minutes after a single dose the mean plasma concentrations (n=3) were 28 +/- 20 mg/ml capecitabine, 78 +/- 48 mg/ml DFCR, 41 +/- 17 mg/ml DFUR and 0.19 +/- 0.07 mg/ml (1.5 µM) 5-FU, with concentrations of all analytes falling at 2 and 4 hours. In the tumour tissue, mean concentrations at 40 mins were capecitabine: 37 +/- 19 ng/mg tissue, DFCR: 56 +/- 12 ng/mg; DFUR: 20 +/- 8 ng/mg and 5-FU: 3.3 +/- 0.7 ng/mg. At 2 and 4 hours the tumour 5-FU concentrations were 3.0 +/- 1.1 and 1.4 +/- 0.6 ng/mg respectively. In the liver, DFCR concentrations were higher than in the tumour from the same mice but DFUR concentrations were lower and 5-FU was below the limit of quantification (<0.4 ng/mg) in most, consistent with the reported distribution of carboxylesterases, cytidine deaminase and thymidine phosphorylase in tissues (M. Miwa, et al., Eur. J. Cancer 1998). In animals dosed for 5 days, there was no evidence of accumulation of capecitabine or its metabolites in tumour tissue when compared to the single dose. The concentration of tumour 5-FU, ranging from 1.4 to 3.3 ng/mg, is estimated to be equivalent to 11 to 25 µM, more than 10-fold higher than the plasma concentration. The IC50 for 5-FU in K8484 cells, grown in vitro, was 1.4 +/- 0.8 µM suggesting that oral dosing with capecitabine delivers a therapeutically effective dose to the allograft. This was then confirmed in an efficacy study, treating tumour-bearing mice with oral capecitabine for 5 days per week for 3 weeks, which resulted in significant inhibition of tumour growth rate compared to the vehicle treated group, with mean tumour doubling time of 7.5 +/- 3.0 days for capecitabine compared to 3.5 +/- 0.5 days for the vehicle treated group (P < 0.001). Despite identical germline Kras and p53 genotypes, the KPC PDA and KPC allograft tumour types have previously shown differences in gemcitabine sensitivity in vivo, predicted to be due to differences in drug delivery (K. Olive, et al., Science 2009). Therefore, capecitabine PK and efficacy are now being investigated in the autochthonous tumours arising in the KPC model. 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 5446. doi:10.1158/1538-7445.AM2011-5446