Abstract #1563: Tolerance and anti-tumoral efficacy of an oral Irinotecan sustained release nanoparticles formulation in HT29 xenograft mice model
Authors: Michele Manon, Jean-Gabriel Judde, Christophe Garreau, Sophie Lebel-Binay, Emilienne Soma
Journal: Cancer Research (2009)

Introduction: Irinotecan (IRN) is a semisynthetic analogue of camptothecin which inhibits the DNA enzyme topoisomerase I. IRN is a prodrug that is converted into its active metabolite, SN-38 by carboxylesterase in the liver, intestinal tract, and some tumors. IRN is currently administrated by intravenous (iv) route mainly for metastatic colorectal cancer treatment. Up to date, the development of oral IRN formulations appears to be limited by the lack of tolerance induced by this route (severe diarrhea). Indeed, oral use of IRN leads to a rapid absorption and a more efficient conversion in the active metabolite SN-38 probably due to first-pass metabolism. Therefore we have designed an oral nanoparticle formulation of IRN which could lead to a better conversion of IRN into SN-38 in the gastrointestinal tract and could reduce the adverse effects. Sustained release nanoparticles (SNR) technology involves an active ingredient, a polymerization medium and a monomer. IRN-SRN is formulated as an oral suspension of IRN-loaded polymeric nanoparticles (1mg/ml) with a size comprised between 200 and 400 nm. To evaluate its tolerance, efficacy and pharmacokinetic profile, the new IRN-SRN oral formulation was tested on a xenograft model of nude mice bearing HT29 human colorectal tumors. The oral formulations of IRN-SRN, given once a day for 5 days, were compared to oral and iv administration of free IRN. Results: First, we evaluated the maximum tolerated dose (MTD) of oral IRN-SRN. Nude mice bearing HT29 tumors were treated with 50, 100, 200 and 300 mg/kg of IRN-SRN given orally once a day for 5 consecutive days. All dosages were well tolerated without any loss of weight and no mortality. The maximum tolerated dose of IRN-SRN was not achieved even at the highest feasible dose of 300 mg/kg. In opposition, the MTD for free IRN given orally following the same protocol was 100 mg/kg with an important weight loss (15%). As the IRN-SRN oral formulation was well tolerated, we evaluated the efficacy of the formulation on tumor growth. Nude mice bearing HT29 tumors were treated with IRN-SRN (30, 100, 300 mg/kg), free IRN (100 mg/kg) given orally once a day for 5 consecutive days and free IRN (20 mg/kg) given iv (once a week during 2 weeks). The oral formulation of IRN-SRN shows a significant dose dependent inhibition of tumor growth with 84 % of tumor growth inhibition at 300 mg/kg and 75% at 100 mg/kg (Day 11). These results are similar to the inhibition of tumor growth of 88% observed with free IRN, or with iv administration of free IRN. Conclusions: This new oral formulation of IRN-SRN demonstrates a better tolerance compared to free IRN and a similar antitumor efficacy. Furthermore, this study IRN-SRN allows higher oral dosing of IRN without any sign of adverse effect. The pharmacokinetic study ongoing will lead to better understand the kinetic and metabolic profile of this new formulation of IRN-SRN for oral use.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1563.