Preclinical Safety, Pharmacokinetics and Antitumor Efficacy Profile of Liposome-entrapped SN-38 Formulation

• Published in: Anticancer research 2005-01, Vol.25 (1A), p.331-341
• Main Authors: PAL, Ajai, KHAN, Sumsullah, AHMAD, Imran, WANG, Yue-Fen, KAMATH, Narayan, SARKAR, Asis K, AHMAD, Ateeq, SHEIKH, Saifuddin, ALI, Shahid, CARBONARO, Danielle, ZHANG, Allen
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents, Phytogenic - administration & dosage; Antineoplastic Agents, Phytogenic - adverse effects; Antineoplastic Agents, Phytogenic - pharmacokinetics; Biological and medical sciences; Camptothecin - administration & dosage; Camptothecin - adverse effects; Camptothecin - analogs & derivatives; Camptothecin - pharmacokinetics; Dogs; Dose-Response Relationship, Drug; Female; Humans; Leukemia P388 - drug therapy; Leukemia P388 - metabolism; Liposomes; Male; Medical sciences; Mice; Mice, SCID; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - metabolism; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0250-7005; 1791-7530

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. Materials and 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 (t 1/2 ) of SN-38 in mouse plasma was 6.38 h with volume of distribution (Vd ss ) 2.55 L/kg. In dogs, t 1/2 and Vd ss 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. Conclusion: LE-SN38 showed a favorable pharmacokinetics profile and can be administered safely at therapeutically effective doses.