Pharmacokinetics in mice implanted with xenografted tumors after intravenous administration of tasidotin (ILX651) or its carboxylate metabolite.

The pharmacokinetics of tasidotin (ILX651), a depsipeptide currently in phase II for the treatment of advanced solid tumors, and tasidotin-C-carboxylate, the main metabolite, were characterized in male nude mice implanted with LOX tumors, which are sensitive to tasidotin, or H460 tumors, which are resistant to tasidotin. The pharmacokinetics of tasidotin and its metabolites were characterized after single-dose administration of tasidotin (20 and 120 mg/kg), tasidotin-C-carboxylate (150 mg/kg), or tasidotin (53 mg/kg) in the presence and absence of Z-prolyl prolinal (5 mg/kg administered 1 hour prior to tasidotin administration), a competitive antagonist of prolyl oligopeptidase, the enzyme responsible for the metabolism of tasidotin to tasidotin-C-carboxylate. A secondary study was done comparing tumor growth in tasidotin-treated mice with implanted LOX tumors in the presence and absence of Z-prolyl-prolinal.