Irinophore C: A Liposome Formulation of Irinotecan with Substantially Improved Therapeutic Efficacy against a Panel of Human Xenograft Tumors

• Published in: Clinical cancer research Vol. 14; no. 4; pp. 1208 - 1217
• Main Authors: RAMSAY, Euan C, ANANTHA, Malathi, ZASTRE, Jason, MEIJS, Marieke, ZONDERHUIS, Jet, STRUTT, Dita, WEBB, Murray S, WATERHOUSE, Dawn, BALLYL, Marcel B
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.02.2008
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; Biological and medical sciences; Camptothecin - administration & dosage; Camptothecin - analogs & derivatives; Camptothecin - pharmacokinetics; cancer xenografts; CPT-11; Female; Humans; irinotecan; liposome; Liposomes; Medical sciences; Mice; Mice, Inbred BALB C; Neoplasms, Experimental - drug therapy; Pharmacology. Drug treatments; SN-38; Xenograft Model Antitumor Assays; Camptothecin derivatives; Antineoplastic agent; Human; Enzyme; Treatment efficiency; DNA topoisomerase; Enzyme inhibitor; Liposome; Drug carrier; Transplantation; Malignant tumor; Heterotransplantation; Irinotecan; Isomerases; Treatment; Surgery; Animal; Formulation; Graft; Topoisomerase I inhibitor; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-07-0780

Purpose: To assess the pharmacokinetics, tumor drug accumulation, and therapeutic activity of Irinophore C, a novel liposomal formulation of irinotecan (CPT-11). Experimental Design: The plasma lactone/carboxy levels of CPT-11 and SN-38 were determined in mice after a single i.v. dose of irinotecan (Camptosar), or Irinophore C, and the plasma t 1/2 , plasma area under the curve, plasma C max , and plasma clearance were calculated. Further, plasma and tumor drug levels were also measured in tumor-bearing mice following Irinophore C treatment. The efficacy of Irinophore C was compared with that of Camptosar in five s.c. human tumor xenografts using single-dose treatment (LS 180), a total of three doses administered at 4-day intervals (H460), or a total of three doses administered at 7-day intervals (Capan-1, PC-3, and HT-29). Results: Compared with Camptosar, Irinophore C mediated an 8-fold increase in t 1/2 , a 100-fold increase in C max , a 1,000-fold increase in area under the curve, and a 1,000-fold decrease in clearance for the active lactone form of CPT-11. Further, the plasma and tumor SN-38 lactone levels were consistent for at least 48 h post-Irinophore C injection. Camptosar treatment (40 mg/kg) mediated a delay in the time required for tumors to increase to four times their pretreatment size compared with controls (T-C). T-Cs ranged from 2 days (LS 180 model) to 18 days (PC-3 model). Irinophore C (40 mg/kg) engendered T-Cs ranging from 14 days (LS 180 model) to 87 days (Capan-1 model). Conclusion: Irinophore C improved CPT-11/SN-38 pharmacokinetics, promoted tumor drug accumulation, and increased therapeutic efficacy in a panel of five distinct human tumor xenografts.