title: Irinophore C™, a lipid nanoparticle formulation of irinotecan, abrogates the gastrointestinal effects of irinotecan in a rat model of clinical toxicities.
abstract: 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.
authors: Experimental Therapeutics, BC Cancer Agency, Vancouver, BC, Canada.
authors: Dawn N
authors: DN
authors: Waterhouse
authors: Brent W
authors: BW
authors: Sutherland
authors: Nancy Dos
authors: ND
authors: Santos
authors: Dana
authors: D
authors: Masin
authors: Maryam
authors: M
authors: Osooly
authors: Dita
authors: D
authors: Strutt
authors: Christina
authors: C
authors: Ostlund
authors: Malathi
authors: M
authors: Anantha
authors: Natashia
authors: N
authors: Harasym
authors: Irina
authors: I
authors: Manisali
authors: Mohamed
authors: M
authors: Wehbe
authors: Marcel B
authors: MB
authors: Bally
authors: Murray S
authors: MS
authors: Webb
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D002784:Cholesterol / Q000737:chemistry; D003106:Colon / Q000473:pathology; D003967:Diarrhea / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D007421:Intestine, Small / Q000473:pathology; D000077146:Irinotecan; D008081:Liposomes; D053758:Nanoparticles / Q000008:administration & dosage*; D010713:Phosphatidylcholines / Q000737:chemistry; D017207:Rats, Sprague-Dawley
chemical_list: D000964:Antimetabolites, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D008081:Liposomes; D010713:Phosphatidylcholines; D000077146:Irinotecan; D002784:Cholesterol; C010942:1,2-distearoyllecithin; D005472:Fluorouracil; D002166:Camptothecin