Improvement of the antitumor activity of intraperitoneally and orally administered XXXX by optimal scheduling.

@entity137 @entity19 @entity5 @entity25218 @entity694
PURPOSE: @entity25218 ( @entity25218 ), a new anticancer drug that has recently completed Phase I clinical trial, is effective against transplantable @entity19 @entity5 with established vasculature. We wished to determine the relationship between administration schedule and antitumor activity. EXPERIMENTAL DESIGN: C57Bl/6 @entity19 with s.c. implanted @entity694 were used for determination of maximal tolerated doses and @entity5 growth delay. Plasma and tissue @entity25218 concentrations were measured by high-performance liquid chromatography. RESULTS: Continuous infusion (30 mg/kg/day for 3 days) and daily i.p. administration schedules (7.5 mg/kg) were ineffective. A pharmacokinetically guided schedule was developed to increase @entity5 tissue drug concentrations without increasing the maximal plasma concentration. A schedule comprising a loading dose (25 mg/kg, i.p.) followed by supplementary doses (5 mg/kg after 4 and 8 h) provided a 1.6-fold increase in @entity5 tissue area under the concentration-time curve, no increased @entity137 , and superior antitumor activity (100% cure rate, as compared with 55% for a single i.p. dose of 25 mg/kg). A similar strategy was developed for oral administration with a loading dose (30 mg/kg) and supplementary doses (15 mg/kg after 4 and 8 h). It provided a 90% cure rate, in contrast to a single oral dose (0% cure rate). CONCLUSIONS: The antitumor action of @entity25218 is schedule dependent, and the achievement of an adequate @entity5 tissue @entity25218 concentration above a threshold value appears to be critical for activity. The use of a pharmacokinetically guided schedule provides excellent oral activity against @entity694 and provides a basis for developing more effective administration schedules in clinical trials.
