Clinical pharmacodynamics of continuous infusion XXXX : systemic exposure as a determinant of response in a phase I trial.

@entity1 @entity137 @entity706 @entity2663 @entity33 @entity1778 @entity521
@entity2663 ( @entity2663 ) is an effective anticancer drug usually administered as a short infusion in doses of 150 to 165 mg/m2. The objectives of the trial reported here were to evaluate clinical responses and assess pharmacokinetic parameters as a determinant of outcome when @entity2663 was administered as a 72-hour continuous infusion (CI) with doses escalated from 300 to 750 mg/m2 per course. Twenty-eight @entity1 with recurrent @entity1778 , @entity706 , or @entity521 received 53 courses of CI @entity2663 and 16 had measurable responses. There were two partial remissions and one stable disease among seven @entity521 @entity1 and 13 of 21 @entity1778 / @entity706 @entity1 had oncolytic responses (greater than or equal to 75% decrease in circulating blasts). @entity137 included moderate to severe @entity33 and myelosuppression. Pharmacokinetic parameters determined during 35 courses administered to 23 @entity1 were highly variable. Clearance (CI) ranged between 3.7 and 43.8 ml/min/m2, resulting in @entity2663 plasma concentrations from 2.8 to 30.6 mg/L across all dose levels. The interpatient pharmacokinetic variability reflected in CI and @entity2663 steady state concentrations (Css), obscured any dose-response relationship. However, when pharmacokinetic parameters for responding and nonresponding @entity1 were compared, statistically significant relationships were observed. For responders, the mean Css was 15.2 mg/L and mean CI was 12.1 mL/min/m2; for nonresponders, mean Css was 6.2 mg/L (P less than .01) and mean CI was 21.3 mL/min/m2 (P less than .05). Thus, @entity1 with higher CI and lower Css were less likely to respond. Clinical responses occurred in ten of ten @entity1 with Css greater than 12 mg/L, and only five of 13 @entity1 with Css less than 12 mg/L (P less than .01). In this study, interpatient pharmacokinetic variability yielded a four- to sixfold difference in intensity of systemic exposure (Css) within the same dose level, which was an important determinant of clinical response. These data indicate that achieving a @entity2663 target concentration for individual @entity1 could ensure an increased intensity of systemic exposure in @entity1 with a high CI and improve the likelihood of effective therapy.
