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01.12.2014 | PRECLINICAL STUDIES | Ausgabe 6/2014 Open Access

Investigational New Drugs 6/2014

Irinophore C™, a lipid nanoparticle formulation of irinotecan, abrogates the gastrointestinal effects of irinotecan in a rat model of clinical toxicities

Zeitschrift:
Investigational New Drugs > Ausgabe 6/2014
Autoren:
Dawn N. Waterhouse, Brent W. Sutherland, Nancy Dos Santos, Dana Masin, Maryam Osooly, Dita Strutt, Christina Ostlund, Malathi Anantha, Natashia Harasym, Irina Manisali, Mohamed Wehbe, Marcel B. Bally, Murray S. Webb

Summary

Irinotecan is a water-soluble camptothecin derivative with clinical activity against colorectal and small cell lung cancers and is currently a standard of care therapeutic in the treatment of colorectal cancer in combination with 5-fluorouracil. One of the major clinical issues limiting the use of irinotecan is gastrointestinal toxicity manifested as life-threatening diarrhea which is reported in up to 45 % of treated patients. The studies summarized here tested, in a rat model of irinotecan-associated gastro-intestinal toxicity, whether a lipid nanoparticle formulation of irinotecan, Irinophore C™, mitigated early-onset or late-onset diarrhea when given at doses equivalent to unformulated irinotecan that engenders both early- and late-onset diarrhea. Specifically, rats administered intravenously on two consecutive days with unformulated irinotecan at 170 mg/kg then 160 mg/kg experienced transient early-onset diarrhea after each administration and then experienced significant late-onset diarrhea peaking 4 days after treatment. Irinophore C™ given at the identical dose and schedule did not elicit either early- or late-onset diarrhea in any animals. When Irinophore C™ was combined with 5-fluorouracil there was also no early- or late-onset diarrhea observed. Histopathological analysis of the gastro-intestinal tract confirmed that the effects associated with irinotecan treatment were absent in rats given Irinophore C™ at the identical dose. Pharmacokinetic analysis demonstrated significantly higher systemic concentrations of irinotecan in rats given the nanoparticle formulation compared to those given unformulated irinotecan. These results demonstrate that the Irinophore C™ formulation is significantly less toxic than irinotecan, used either as a single agent or in combination with 5-fluorouracil, in a rat model of irinotecan-induced gastrointestinal toxicity.

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