Oral delivery of taxanes

Oral treatment with cytotoxic agents is to be preferred as this administrat ion route is convenient to patients, reduces administration costs and facil itates the use of more chronic treatment regimens. For the taxanes paclitax el and docetaxel, however, low oral bioavailability has limited development of treatment by the oral route. Preclinical studies with mdr1a P-glycoprot ein knock-out mice, which lack functional P-glycoprotein activity in the gu t, have shown significant bioavailability of orally administered paclitaxel . Additional studies in wild-type mice revealed good bioavailability after oral administration when paclitaxel was combined with P-glycoprotein blocke rs such as cyclosporin A or the structurally related compound SDZ PSC 833. Based on the extensive preclinical research, the feasibility of oral admini stration of paclitaxel and docetaxel in cancer patients was recently demons trated in our Institute. Co-administration of cyclosporin A strongly enhanc ed the oral bioavailability of both paclitaxel and docetaxel. For docetaxel in combination with cyclosporin A an oral bioavailability of 90% was achie ved with an interpatient variability similar to that after intravenous drug administration; for paclitaxel the oral bioavailability is estimated at ap proximately 50%. The safety of the oral route for both taxanes is good. A p hase II study of weekly oral docetaxel in combination with cyclosporin A is currently ongoing.