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 LC/MS/MS on days 1, 8 and 15. Part 2: The LED of elacridar was combined with increasing doses of topotecan in patient cohorts of 3 to determine MTD and DLT of the regimen. Results Part 1: 23 pts with advanced cancer (age range 27-75) were included in part 1. Three pts were not evaluable for PK and were replaced. There was no statistically significant effect of the elacridar dose or administration schedule on the apparent F of topotecan, which was 102 ± 7 % (range 94-111%). Part 2: 15 pts were included with age range 27-71 yrs. Dose levels of topotecan evaluated were 1.0, 1.5, 2.0, and 2.5 mg/day for 5 days. DLTs consisting of CTC Grade 4 leukocytopenia, neutropenia and thrombocytopenia were observed at 2.5 mg/d of topotecan. The MTD (6 pts) was 2.0 mg plus 100 mg elacridar. GI toxicity was minimal and the combination was well tolerated.

CONCLUSIONS: 100 mg elacridar given simultaneously was sufficient to provide maximal apparent F of topotecan. The recommended oral dose of topotecan in this combination and schedule is 2.0 mg. [Table: see text].