Phase I and pharmacological study of oral topotecan and the BCRP and P-gp inhibitor elacridar

2003 Background: Oral topotecan has a moderate (∼ 40%) and variable bioavailability (F). Complete apparent F can be obtained by combining topotecan with elacridar which inhibits BCRP and P-gp in the gut wall. The OBJECTIVES were 1] to determine the lowest effective dose (LED) of elacridar resulting in complete apparent F of topotecan and the optimal schedule of elacridar and topotecan and 2] to determine the maximal tolerated dose (MTD) and dose-limiting toxicity (DLT) of topotecan in combination with the LED of elacridar at a dailyx5 schedule every 21 days. Methods of part 1: Patients (pts) were randomized to receive 1000, 700, 500, 300 or 100 mg of elacridar (tablets) plus 2 mg topotecan (capsules) after a standard breakfast. Elacridar was administered 60 minutes prior to topotecan or simultaneously with topotecan on day 1 and 8, which was randomized within patients. I.V. topotecan was given on day 15. Pharmacokinetics (PK) of topotecan (total and lactone form) and elacridar were obtained by validated L...