Pharmacokinetic-pharmacodynamic modeling of @entity1499 -induced XXXX in @entity19 .

@entity19 @entity1499 @entity137 @entity1500
The prediction of chemotherapeutic efficacy is complicated by "protocol dependencies" in dose-effect and dose- @entity137 relationships. It has been proposed that pharmacokinetic-pharmacodynamic mathematical models may allow characterization of chemotherapeutic protocol dependencies, and may facilitate the prediction of chemotherapeutic efficacy; however, few demonstrations exist in the literature. The present study examines the pharmacokinetics and toxicodynamics of @entity1499 ( @entity1500 ), a commonly used anticancer agent, after intraperitoneal (i.p.) administration to @entity19 . @entity1500 was administered via bolus or infusion (24, 72, and 168 h), at doses of 2.5-1000 mg/kg. @entity1500 plasma and peritoneal pharmacokinetics were characterized through standard noncompartmental and compartmental techniques. Body weight loss was used as a measure of @entity1500 -induced @entity137 . We found that @entity1500 pharmacokinetics were independent of dose (over a range of 3-600 mg/kg) and independent of dosing mode (i.e., i.p. bolus vs. i.p. infusion). However, @entity1500 -induced @entity137 was shown to be highly dependent on the dosing protocol used. For example, the maximally tolerated dose (i.e., the dose related to a mean body weight loss of 10%) was 200-fold greater after bolus administration relative to that observed for 72-h infusion (760 mg/kg vs. 3.8 mg/kg). This profound protocol dependence in the relationship between @entity1500 -induced @entity137 and @entity1500 exposure was characterized through the use of a time-dissociated pharmacokinetic-pharmacodynamic model (median prediction error: 3.9%).
