A Phase I, Randomized, Open-Label, Parallel-Cohort, Dose-Finding Study of Elacridar (GF120918) and Oral Topotecan in Cancer Patients

Abstract

Purpose: Breast cancer resistance protein (ABCG2) substantially limits the oral bioavailability of topotecan. Coadministration with elacridar, an inhibitor of breast cancer resistance proteinm ediated drug transport, increases the bioavailability of topotecan. The aim of this study was to establish the lowest effective dose of elacridar to obtain maximum oral bioavailability of topotecan and to determine the optimal schedule of coadministration of oral topotecan and elacridar. In the second part of this study, dose-limiting toxicities and maximum tolerated dose of oral topotecan coadministered with elacridar, at a daily times five regimen administered every 21 days, were established. Experimental Design: In part I, 20 patients were randomized to receive 100, 300, 500, 700, or 1,000 mg of elacridar on days 1 and 8 1 h before or simultaneously with 2.0 mg oral topotecan, which was also randomized. On day 15, all patients were treated with 1.5 mg/m 2 i.v. topotecan. In part II of the study, patients were treated daily with oral topotecan and with the lowest effective dose of elacridar following from part I. The maximum tolerated dose and dose-limiting toxicity were determined in cohorts of three patients. Blood samples were taken on days 1, 8, and 15 of part I and on day 1of cycles 1and 2 of part II. Results: Complete apparent oral bioavailability of topotecan (102 F 7%) for all treatment arms with elacridar in both schedules was seen in part I. In the topotecan dose escalation part, two dose-limiting toxicities were seen at the 2.5 mg topotecan dose level. Conclusion: The recommended schedule is 2.0 mg oral topotecan plus 100 mg elacridar administered concomitantly daily times five every 21days.

Inhibition of ABCB1 Overcomes Cancer Stem Cell–like Properties and Acquired Resistance to MET Inhibitors in Non–Small Cell Lung Cancer

“…Elacridar inhibited ABCG2 as well as ABCB1 and has been used in preclinical and clinical settings (38,39). Elacridar can also significantly increase plasma pharmacokinetics and brain distribution of several drugs, including dasatinib (40), gefitinib (41), and sunitinib (42).…”

Icariin Enhances Cytotoxicity of Doxorubicin in Human Multidrug-Resistant Osteosarcoma Cells by Inhibition of ABCB1 and Down-Regulation of the PI3K/Akt Pathway

“…[6][7][8][9] However, none of them was approved for clinical use due to their unwanted side effects.…”

PDZK1 Regulates Breast Cancer Resistance Protein in Small Intestine

“…Such intestinal drug efflux mediated by BCRP may hinder gastrointestinal absorption of certain therapeutic agents, including sulfasalazine and topotecan (Kuppens et al, 2007;Yamasaki et al, 2008), as suggested by analysis of ABCG2/BCRP gene polymorphisms in combination with the use of BCRP-inhibitory drugs. Nevertheless, there have been few reports regarding post-transcriptional regulatory mechanisms involving physical interaction with BCRP in the small intestine.…”

“…Membrane permeation of lipophilic drugs generally occurs by simple diffusion through the lipid bilayer, but absorption of some drugs is hindered by efflux transporters localized on the apical membranes. These include multidrug resistance protein (MDR1/P-glycoprotein/ABCB1) and breast cancer resistance protein (BCRP/ ABCG2), both of which are known to act a barrier against intestinal absorption of various therapeutic agents in vivo (Greiner et al, 1999;Kuppens et al, 2007;Schwarz et al, 2007;Yamasaki et al, 2008;Keskitalo et al, 2009). On the other hand, intestinal membrane permeation of some drugs is mediated by influx transporters that belong to the solute carrier (SLC) superfamily.…”