Full-profile pharmacokinetics, anticancer activity and toxicity of an extended release trivalent PEGylated irinotecan prodrug

Irinotecan is an anticancer topoisomerase I inhibitor that acts as a prodrug of the active metabolite, SN-38. Unfortunately, the limited utility of irinotecan is attributed to its pH-dependent stability, short half-life and dose-limiting toxicity. To address this problem, a novel trivalent PEGylated prodrug (PEG-Irinotecan₃) has been synthesized and its full-profile pharmacokinetics, antitumor activity and toxicity compared with those of irinotecan. The results show that after intravenous administration to rats, PEG-Irinotecan₃ undergoes stepwise loss of irinotecan to form PEG-Irinotecan_3-x (x=1,2) and PEG-linker during which time the released irinotecan undergoes conversion to SN-38. As compared with conventional irinotecan, PEG-Irinotecan₃ displays extended release of irinotecan and efficient formation of SN-38 with significantly improved AUC and half-life. In a colorectal cancer-bearing model in nude mice, the tumor concentrations of irinotecan and SN-38 produced by PEG-Irinotecan₃ were respectively 86.2 and 2293 times higher at 48 h than produced by irinotecan. In summary, PEG-Irinotecan₃ displays superior pharmacokinetic characteristics and antitumor activity with lower toxicity than irinotecan. This supports the view that PEG-Irinotecan₃ is a superior anticancer drug to irinotecan and it has entered the phase II trial stage.