Co-administration of GF120918 significantly increases the systemic exposure to oral paclitaxel in cancer patients

Oral bioavailability of paclitaxel is very low, which is due to efficient transport of the drug by the intestinal drug efflux pump P-glycoprotein (P-gp). We have recently demonstrated that the oral bioavailability of paclitaxel can be increased at least 7-fold by co-administration of the P-gp blocker cyclosporin A (CsA). Now we tested the potent alternative orally applicable non-immunosuppressive P-gp blocker GF120918. Six patients received one course of oral paclitaxel of 120 mg/m(2)in combination with 1000 mg oral GF120918 (GG918, GW0918). Patients received intravenous (i.v.) paclitaxel 175 mg/m(2)as a 3-hour infusion during subsequent courses. The mean area under the plasma concentration-time curve (AUC) of paclitaxel after oral drug administration in combination with GF120918 was 3.27 +/- 1.67 microM x h. In our previously performed study of 120 mg/m(2)oral paclitaxel in combination with CsA the mean AUC of paclitaxel was 2.55 +/- 2.29 microM x h. After i.v. administration of paclitaxel the mean AUC was 15.92( )+/- 2.46 microM x h. The oral combination of paclitaxel with GF120918 was well tolerated. The increase in systemic exposure to paclitaxel in combination with GF120918 is of the same magnitude as in combination with CsA. GF120918 is a good and safe alternative for CsA and may enable chronic oral therapy with paclitaxel.