Toxicokinetic Evaluation of A Novel Anti-Tumor Agent, Zalypsis (R) (pm00104), in Dogs

3095 Zalypsis® (PM00104) is a new synthetic alkaloid related to Jorumycin and Renieramycins. Preliminary insights into the mechanism of action of Zalypsis® suggested cell cycle changes, DNA binding properties, and transcriptional inhibition. Zalypsis® has demonstrated a significant in vitro activity against solid and non-solid tumor cell lines as well as significant in vivo activity in several xenografted human cell lines in mice, such as breast and prostate. Our recent efforts have focused on the toxicokinetic evaluation of Zalypsis® to support multi-cycle toxicology studies. The toxicokinetics of Zalypsis® have been investigated in beagle dogs following either intravenous bolus doses or 24-hour infusion. The plasma samples were processed by liquid-liquid extraction and analyzed by a validated LC/MS/MS method. To assess its toxicokinetic profile in dogs, Zalypsis® was administered as two i.v. bolus injections 14 days apart. A separate study was performed as 5 consecutive days of i.v. bolus dosing. The mean maximum plasma concentrations (C max s) and AUCs increased in a dose-proportional manner over the dose range studied (from 0.008 to 0.08 mg/kg for two-cycle study and from 0.004 to 0.032 mg/kg for the QD x 5 study). The exposure was similar in both sexes, indicating no sex-differences. Also, no differences were observed between the first and last dose suggesting the pharmacokinetics of Zalypsis® were time-independent. The toxicokinetics of Zalypsis® have also been studied in dogs following multiple doses (ranging from 0.008 to 0.08 mg/kg) administered as a two-cycle 24-hour i.v. infusion schedule. The C max s were generally observed at the end of the infusion period, and the plasma levels declined rapidly after the infusion was stopped, displaying multiple compartmental kinetics without notable gender differences. Overall, Zalypsis® plasma levels were fairly comparable among different dose cycles and exposures or C max s appeared to increase proportionally over the investigated dose range.No significant Zalypsis® accumulation was observed after multiple doses. In addition, the results from these toxicokinetic studies confirm previous findings that Zalypsis® has moderate to high systemic clearance, a large volume of distribution, a long half-lives, and linear pharmacokinetics.