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. After
tasidotin administration, the pharmacokinetics of
tasidotin and
tasidotin-C-carboxylate were similar in plasma and
tumors in LOX- and H460-implanted mice, indicating the resistance was not due to pharmacokinetic factors.
Tumor carboxylate concentrations were much higher than in plasma after
tasidotin administration. The metabolite appeared to contribute approximately 17% to 33% to the total exposure in LOX
tumors and 20% to 49% in H460
tumors but <5% in plasma. Less than 5% of the administered
tasidotin dose was converted to
tasidotin-C-carboxylate, with no apparent differences between LOX- and H460-treated animals. The presence of Z-prolyl-
prolinal decreased the amount of
tasidotin converted to
tasidotin-C-carboxylate from 5.5% to 0.90%, a reduction of almost 80%. After
tasidotin-C-carboxylate administration, the half-life was on the order of minutes compared with hours when observed after
tasidotin administration.
Tasidotin-C-carboxylate elimination was not dependent on
tasidotin pharmacokinetics, suggesting that the rate of efflux from cells into plasma was the rate-limiting step in its elimination.
Tasidotin-C-carboxylate was also further metabolized to desprolyl-
tasidotin-C-carboxylate, although the metabolite ratios were <10%. Pretreatment with Z-prolyl-
prolinal completely abolished the antitumor activity of
tasidotin, indicating that the metabolite is the main moiety responsible for activity and that, despite
tasidotin itself having activity in vitro,
tasidotin is acting mainly as a
prodrug.