Phase I clinical and pharmacokinetic study of @entity2600 in adults with recurrent XXXX .

@entity1 @entity137 @entity2600 @entity1313 @entity11 @entity14 @entity54473
PURPOSE: A preliminary evaluation of the efficacy of @entity2600 in @entity1 with @entity11 demonstrated modest activity. A markedly lower than expected incidence of drug-related @entity137 was also noted. This was consistent with pharmacokinetic data indicating that the total body clearance (CL) of @entity2600 in this @entity1 population was considerably greater than in @entity14 @entity1 . Concomitant medications used chronically in @entity1313 @entity1 , especially glucocorticoids and anticonvulsants that induce hepatic enzymes involved in the metabolism or excretion of drugs, were believed to be the cause of the alteration in pharmacokinetic behavior. A Phase I study was therefore undertaken in @entity1 with recurrent @entity11 to independently determine the maximum tolerated dose (MTD) of @entity2600 in @entity1 stratified according to the use of enzyme-inducing anticonvulsants (EIAs). EXPERIMENTAL DESIGN: @entity1 with recurrent @entity11 received @entity2600 as a weekly 90-min i.v. infusion for four consecutive weeks, with additional cycles of treatment repeated every 6 weeks. The starting dose was 125 mg/m(2)/week for both groups of @entity1 (+/-EIA). Groups of >/==" BORDER="0">3 @entity1 were evaluated at each dose level, and the modified continual reassessment method was used for dose adjustments. The plasma pharmacokinetics of @entity2600 , its active metabolite, @entity2600 ( @entity2600 ), and the glucuronide conjugate of @entity2600 , @entity2600 glucuronide, were determined in all @entity1 during treatment with the first weekly dose. RESULTS: Forty @entity1 were enrolled into the study and treated with a total of 135 cycles of @entity2600 . The MTD was determined to be 411 mg/m(2)/week in the +EIA cohort and 117 mg/m(2)/week in the -EIA cohort for the weekly x 4 every 6 weeks schedule. Pharmacokinetic studies showed that the CL of @entity2600 was distinctly dose dependent in the @entity1 receiving EIAs, decreasing from approximately 50 liters/h/m(2) at the lower dose levels (125-238 mg/m(2)) to a mean +/- SD value of 29.7 +/- 9.0 liters/h/m(2) (n = 7) at the MTD. The grand mean CL for a group of 13 @entity1 who were not taking EIAs, 18.8 +/- 10.6 liters/h/m(2), was significantly different from the mean CL at the MTD of the +EIA cohort (P = 0.033). Mean values of the AUC of @entity2600 (P = 0.4) and @entity54473 (P = 0.55) were not significantly different at the MTDs for the two cohorts of @entity1 . CONCLUSIONS: The MTD of @entity2600 was 3.5 times greater in @entity1 with @entity11 who were concurrently receiving EIAs than in those who were not. This study has also served to confirm that the concomitant administration of EIAs results in marked enhancement in the CL of @entity2600 . These findings have important implications for subsequent clinical trials to further evaluate @entity2600 in @entity1313 @entity1 and underscore the importance of assessing the potential for pharmacokinetic interactions between concurrent medications and chemotherapeutic agents.
