Irinophore C™, a lipid nanoparticle formulation of irinotecan, abrogates the gastrointestinal effects of irinotecan in a rat model of clinical toxicities.
In: Investigational New Drugs, Jg. 32 (2014-12-01), Heft 6, S. 1071-1082
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Zugriff:
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. [ABSTRACT FROM AUTHOR]
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Irinophore C™, a lipid nanoparticle formulation of irinotecan, abrogates the gastrointestinal effects of irinotecan in a rat model of clinical toxicities.
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Autor/in / Beteiligte Person: | Waterhouse, Dawn ; Sutherland, Brent ; Santos, Nancy ; Masin, Dana ; Osooly, Maryam ; Strutt, Dita ; Ostlund, Christina ; Anantha, Malathi ; Harasym, Natashia ; Manisali, Irina ; Wehbe, Mohamed ; Bally, Marcel ; Webb, Murray |
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Zeitschrift: | Investigational New Drugs, Jg. 32 (2014-12-01), Heft 6, S. 1071-1082 |
Veröffentlichung: | 2014 |
Medientyp: | academicJournal |
ISSN: | 0167-6997 (print) |
DOI: | 10.1007/s10637-014-0138-x |
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