Pharmacokinetic/pharmacodynamic study of ZD9331, a nonpolyglutamatable inhibitor of thymidylate synthase, in a murine model following two curative administration schedules

ZD9331 is a nonpolyglutamatable antifolate inhibitor of thymidylate synthas e currently in clinical development. This enzyme is crucial for DNA synthes is and catalyzes the reductive methylation of dUMP to form thymidylate, whi ch is subsequently converted to dTTP. The pharmacokinetics of two curative antitumor doses of ZD9331 administered by either a single i.p. bolus inject ion (50 mg/kg) or by 24-h s.c. infusion (3 mg/kg) have been measured in a t hymidine salvage-incompetent murine lymphoma model (L5178Y) using a sensiti ve and specific ELISA. To gain an understanding of the relationship between the pharmacokinetics of ZD9331 and antitumor activity perturbations in tum or, dTTP and dUMP concentrations were also determined. After bolus administ ration, ZD9331 was eliminated from plasma and tissues relatively rapidly, w ith terminal elimination (lambdaz 0-24 h) of 4-6 h. Liver concentrations we re 8-fold higher than those measured in the plasma. Kidney and lymphoma dru g concentrations were similar to those of plasma, although there was eviden ce of a slower overall elimination of drug at later time points. Steady-sta te concentrations of ZD9331 were obtained 4-5 h after the start of the 24 h s.c. infusion. At the end of infusion, elimination rates were similar for plasma and tissues (similar to3.5 h) but appeared to be slower in the tumor at later time points. Liver concentrations were similar to4-fold higher, a nd kidney and tumor concentrations were similar to those in the circulation . Depletion of dTTP and elevation in dUMP in the tumor were consistent with inhibition of thymidylate synthase after both administration schedules, al though the time for which dTTP was decreased was longer (similar to 24 h) f or the infusional route than for the bolus injection (< 16 h). The results suggest that antitumor activity is dependent on attaining adequate drug con centrations to affect dTTP pools as well as on the duration of effective dr ug levels.