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

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. 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 1 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. After oral topotecan, the mean area under the plasma concentration-time curve (AUC) of total topotecan increased significantly from 32.4 +/- 9.6 microg.h/L without GF120918 to 78.7 +/- 20.6 microg.h/L when GF120918 was coadministered (P =.008). The mean maximum plasma concentration of total topotecan increased from 4.1 +/- 1.5 microg/L without GF120918 to 11.5 +/- 2.4 microg/L with GF120918 (P =.008). The apparent bioavailability 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 topotecan, 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. 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 GF120918.