Abstract C218: Antitumor activities of a novel oral formulation of SN38

Abstract

Background: Novel formulations of SN38 were developed and screened in vitro. The efficacy and tolerability of the best formulation was evaluated in vivo. SN38 is the active metabolite of irinotecan (CPT-11) a potent TOPO-I inhibitor. Despite its poor and variable hydrolysis into SN38 by carboxylesterases, CPT-11 is still a drug of choice for the treatment of metastatic colorectal cancer. Until now, the poor aqueous solubility of SN38 has precluded its development. To address this formulation challenge, we used our library of block copolymers of polyethyleneglycol-polymethacrylate (PEG-PMA) to prepare pH-sensitive micellar formulations of SN38 for oral administration. Material and Methods: Formulations were screened in vitro for their ability to improve SN38 permeability using Caco-2 monolayers. The pharmacokinetics of SN38 as delivered by oral DDS-06E (50mg/kg) or by IV CPT11 (6.2 (mg/kg) were evaluated in fasted Sprague Dawley rats. Plasma profile of CPT11, SN38 and SN-38 glucuronide were determined. DDS-06E was evaluated in tolerability studies conducted in HCT-116 tumor bearing Swiss nude mice (Q1Dx5) × 2 weeks. Chronic toxicity of the excipient PEG-PMA given orally daily was also evaluated in Swiss nude mice for 28 days. Efficacy studies were performed in HCT-116 and Mia-PaCa-2 xenografts (n = 12/group). Micellar SN38 (50 and 75 mg/kg/d) and vehicle control were administered orally [(Q1Dx5) × 2 weeks] every 21 days for at least 2 cycles. CPT-11 was administered IV at 50 mg/kg [(Q7D) × 2 weeks] every 21 days for at least 2 cycles. Body weights and tumor volumes were monitored thrice a week. Results: Permeability of SN38 was significantly increased in 4 out of 6 micellar formulations compared to SN38 in DMSO. The best formulation (DDS-06E) was selected based on its in vitro behavior and in vivo studies were performed. Intravenous (IV) administration of CPT-11 to rats resulted in extensive metabolism to SN38 and SN38-Glu (AUCSN38-Glu/AUCSN38 = 2.60). Conversely, when DDS-06E was administered orally, negligible conversion to SN38-Glu occurred (AUCSN38-Glu/AUCSN38 = 0.03). Orally administered DDS-06E was well tolerated after single dose (> 200 mg/kg) and repeated doses (between 50 and 100 mg/kg/d). Body weights and hematologic/biochemical parameters did not reveal any sign of toxicity after administration of PEG-PMA alone for doses up to 2700 mg/kg/d. Overall, DDS-06E was well tolerated after repeated administration to animal bearing colon (HCT-116) and pancreatic (Mia-PaCa-2) tumors. Significant reductions in relative tumor growth were observed in the HCT-116 and Mia-Pa-Ca model compared to vehicle control (p<0.05). In these models, DDS-06E displayed equivalent efficacy than CPT-11 given IV (p>0.5). Conclusions: Labopharm has developed an oral micellar formulation of SN38 that is well tolerated in tumor-bearing animals and displays efficacy equivalent to CPT-11 given IV. These results suggest that DDS-06E is a promising agent and should be evaluated in clinical trials. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C218.

Prodrug and nanomedicine approaches for the delivery of the camptothecin analogue SN38

“…The MTD of a single oral dose of DDS-06E (without SN38) was more than 200 mg/kg and repeated oral doses were more than 100 mg/kg/day for Sprague Dawley rats. The PEG-PMA copolymer was found to be safe up to 2700 mg/kg/day after oral doses to laboratory animals [106]. However, the potential presence of free SN38 in the intestine due to the drug dissociation from the micelles and the related side effects need to be considered in the further development of DDS-06E.…”

Lipophilic Prodrugs of SN38: Synthesis and in Vitro Characterization toward Oral Chemotherapy

“…Recently, pH sensitive polymeric micelles (DDS-06E) of SN38 were developed with drug loading up to 80%, and these improved Caco-2 permeability. 17,18 Oral delivery of DDS-06E to an animal model resulted in similar tumor growth regression compared to intravenous CPT-11 at an identical dose. In another study, SN38 was encapsulated into chitosan modified poly lactic-coglycolic acid nanoparticles (PLGA-SN38) with drug loading of 6.8%.…”

“…For instance, a hydrophilic prodrug was synthesized by conjugating SN38 to a macromolecular polyamidoamine (PAMAM) dendrimer; this was stable in simulated gastrointestinal fluids, showed improved aqueous solubility, and enhanced in vitro Caco-2 permeability compared to SN38. , Roger et al encapsulated SN38 into lipid nanoparticles with >90% encapsulation efficiency; these were stable in simulated gastrointestinal fluids and showed higher permeation across Caco-2 cell lines; however, the drug loading was too low (0.04%) for practical use. Recently, pH sensitive polymeric micelles (DDS-06E) of SN38 were developed with drug loading up to 80%, and these improved Caco-2 permeability. , Oral delivery of DDS-06E to an animal model resulted in similar tumor growth regression compared to intravenous CPT-11 at an identical dose. In another study, SN38 was encapsulated into chitosan modified poly lactic- co -glycolic acid nanoparticles (PLGA-SN38) with drug loading of 6.8% .…”

Oral administration of irinotecan in patients with solid tumors: an open-label, phase I, dose escalating study evaluating safety, tolerability and pharmacokinetics

“…Drug release was 10%, 20% and 56%, respectively, in simulated gastric, intestinal and liver environments [ 22 ]. Finally, pH-sensitive polymeric micelles of SN38 have been developed to improve permeability [ 23 ].…”