Increased oral bioavailability of topotecan in combination with the breast cancer resistance protein and P-glycoprotein inhibitor GF120918

Purpose: We discovered that breast cancer resistance protein (BCRP), a recently identified adenosine triphosphate-binding cassette drug transporter, substantially limits the oral bioavailability of topotecan in mdr1a/1b(-/-) P-glycoprotein (P-gp) knockout and wild-type mice. GF120918 is a potent inhibitor of BCRP and P-gp. The aim was to increase the bioavailability of topotecan by GF120918. Patients and Methods: In cohort A, eight patients received 1.0 mg/m(2) oral topotecan with or without coadministration of one single oral dose of 1,000 mg GF120918 (day I or day 8). In cohort B, eight other patients received 1.0 mg/m(2) intravenous topotecan with or without 1,000 mg oral GF120918 to study the effect of GF120918 on the systemic clearance of topotecan. Results: After oral topotecan, the mean area under the plasma concentration-time curve (AUC) of total topotecon increased significantly from 32.4 +/- 9.6 mug.h/L without GF120918 to 78.7 +/- 20.6 mug.h/L when GF120918 was coadministered (P = .008). The mean maximum plasma concentration of total topotecon increased from 4.1 +/- 1.5 mug/L without GF120918 to 11.5 +/- 2.4 mug/L with GF120918 (P = .008). The apparent bicavoilability in this cohort increased significantly from 40.0% (range, 32% to 47%) to 97.1% (range, 91% to 120%) (P = .008). Interpatient variability of the apparent bioavailability was 17% without and 11% with GF120918. After intravenous administration of topotecon, coadministration of oral GF120918 had a small but statistically significant effect on the AUC and systemic clearance of total topotecan but no statistically significant effect on maximum plasma concentration and terminal half-life of total topotecan. Conclusion: Coadministration of the BCRP and P-gp inhibitor GF120918 resulted in a significant increase of the systemic exposure of oral topotecan. The apparent oral bioavailability increased from 40.0% without to 97.1% with GF12091 S. (C) 2002 by American Society of Clinical Oncology.