Taxanes: Old Drugs, New Oral Formulations

Oral administration of anticancer drugs is most often preferred over intravenous administration, as it is convenient for patients, prevents hospitalisation and reduces costs of the therapy. However, the oral route is often hampered by low oral bioavailability, for instance of the taxanes paclitaxel and docetaxel. Limited oral bioavailability can be due to pharmaceutical as well as pharmacological reasons. Taxanes are poorly water-soluble drugs and do not sufficiently dissolve when administered in their crystalline form. Furthermore, affinity for drug transporters highly expressed in the epithelial layer of the gastro-intestinal tract, such as the drug efflux pump P-glycoprotein (P-gp, ABCB1), and presystemic elimination by the cytochrome P450 (CYP) metabolic enzymes, especially CYP3A4, present in liver and gut wall, further hamper oral application of these important anticancer drugs. Preclinical studies with knockout mice lacking functional Pgp and CYP3A4 metabolic enzymes show a significant increase in the bioavailability of orally applied taxanes. Enhancement of oral bioavailability of both taxanes was shown also in wild-type mice using P-gp and CYP3A4 blockers such as cyclosporine A (CsA) and ritonavir (RTV). Subsequently, in clinical studies enhancement of the oral bioavailability of paclitaxel and docetaxel was established when administered orally in combination with CsA or ritonavir. Initially, in preclinical and clinical studies drinking solutions based on the intravenous formulations were applied for oral administration of taxanes. Because these solutions had several disadvantages, solid pharmaceutical formulations of paclitaxel and docetaxel were developed. Clinical studies with these novel formulations in combination with ritonavir are currently ongoing at our Institute.