title: Preclinical safety, pharmacokinetics and antitumor efficacy profile of liposome-entrapped SN-38 formulation.
abstract: BACKGROUND
  SN-38, 7-ethyl-10-hydroxycamptothecin, is a biologically active metabolite of irinotecan. Its poor solubility restricted its development as an anticancer agent. We have developed an easy-to-use liposome-entrapped SN-38 (LE-SN38) and evaluated its toxicology, pharmacokinetics and antitumor efficacy profile.
  
  
  METHODS
  Toxicity and pharmacokinetics studies were conducted in CD2F1 mice and beagle dogs. Therapeutic efficacy studies were performed in murine leukemia (P388 and P388/ADR) and in a human pancreatic (Capan-1) tumor models.
  
  
  RESULTS
  Multiple dose administration (i.v. x 5) of LE-SN38 indicated a maximum tolerated dose (MTD) of 5.0 and 7.5 mg/kg/day for male and female mice, respectively. The MTD of LE-SN38 in dogs was 1.2 mg/kg. The elimination half-life (t1/2) of SN-38 in mouse plasma was 6.38 h with volume of distribution (VdSS) 2.55 L/kg. In dogs, t1/2 and VdSS were 1.38-6.42 h and 1.69-5.01 L/kg; respectively. P388 tumor-bearing mice dosed with LE-SN38 at 5.5 mg/kg (i.v. x 5) showed 100% survival. LE-SN38 at 4 or 8 mg/kg (i. v. x 5) inhibited 65% and 98% tumor growth, respectively, in a human pancreatic tumor model.
  
  
  CONCLUSIONS
  LE-SN38 showed a favorable pharmacokinetics profile and can be administered safely at therapeutically effective doses.
authors.affiliation: NeoPharm, Inc, Research and Development, Waukegan, IL 60085, USA.
authors.forename: Ajai
authors.initials: A
authors.lastname: Pal
authors.forename: Sumsullah
authors.initials: S
authors.lastname: Khan
authors.forename: Yue-Fen
authors.initials: YF
authors.lastname: Wang
authors.forename: Narayan
authors.initials: N
authors.lastname: Kamath
authors.forename: Asis K
authors.initials: AK
authors.lastname: Sarkar
authors.forename: Ateeq
authors.initials: A
authors.lastname: Ahmad
authors.forename: Saifuddin
authors.initials: S
authors.lastname: Sheikh
authors.forename: Shahid
authors.initials: S
authors.lastname: Ali
authors.forename: Danielle
authors.initials: D
authors.lastname: Carbonaro
authors.forename: Allen
authors.initials: A
authors.lastname: Zhang
authors.forename: Imran
authors.initials: I
authors.lastname: Ahmad
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002166:Camptothecin / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D000077146:Irinotecan; D007941:Leukemia P388 / Q000188:drug therapy* / Q000378:metabolism; D008081:Liposomes; D008297:Male; D051379:Mice; D016513:Mice, SCID; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D008081:Liposomes; D000077146:Irinotecan; D002166:Camptothecin