Development and validation of a pharmacokinetically based fixed dosing scheme for XXXX .

@entity1 @entity137 @entity263 @entity228 @entity358 @entity74 @entity1576 @entity716 @entity1486 @entity158 @entity5747 @entity2359
PURPOSE: We used population pharmacokinetic-parameter estimates and designed a fixed dosing schedule to maintain plasma @entity5747 concentrations between 100 and 300 micrograms/mL and then evaluated its performance. MATERIALS AND METHODS: On day 1, @entity1 received a 200-mg test dose and 1,000-mg/m2 loading dose. On days 2, 3, 4, and 5, @entity1 received 1-hour infusions of 400, 300, 250, and 200 mg/m2, respectively. Subsequent 1-hour infusions of 275 mg/m2 were given on days 8, 11, 15, 19, 22, 29, 36, 43, 50, 57, 67, and 78. Therapy was discontinued for dose-limiting @entity137 (DLT) or @entity74 ( @entity74 ). @entity1 were to be removed from the fixed dosing schedule if, after day 5, three consecutive peak plasma @entity5747 concentrations were greater than 300 micrograms/mL. RESULTS: Forty-two @entity1 , including 40 with @entity263 ( @entity263 ), received 700 infusions. Forty @entity1 were assessable for @entity137 ; 38 were assessable for response. Two @entity1 with preexisting @entity358 died early of @entity1576 . Treatment was discontinued in five @entity1 due to DLT and in seven due to @entity74 . No @entity1 had treatment discontinued due to repeated peak plasma @entity5747 concentrations > or = 300 micrograms/mL. The fixed dosing schedule was precise, unbiased, and well tolerated. DLT consisted of grade 4 nephrotoxicity (n = 2), @entity2359 (n = 2), and @entity228 -induced @entity716 (n = 1). Three @entity1 , who received all 18 doses of @entity5747 per protocol, developed severe, but not dose-limiting, malaise, fatigue, and lethargy. Twenty-four of 36 assessable @entity1 with elevated serum @entity1486 levels had a > or = 50% reduction, lasting more than 4 weeks, and 18 had a > or = 75% reduction, lasting more than 4 weeks. Twelve of 23 (52%) symptomatic @entity263 @entity1 noted a subjective improvement in @entity158 . There were no measurable responses in four @entity1 with measurable disease. The estimated median survival time in 38 assessable @entity1 with @entity263 was 18.8 months. The estimated median time to progression in 35 @entity1 , for whom data were available, was 10.1 months. CONCLUSION: This easily implemented schedule allowed @entity5747 to be administered safely as an intermittent bolus injection. @entity137 was manageable and reversible.
