Oral delivery of taxanes

• Published in: Investigational new drugs 2001-05, Vol.19 (2), p.155-162
• Main Authors: Malingré, M M, Beijnen, J H, Schellens, J H
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Antineoplastic Agents, Phytogenic - administration & dosage; Antineoplastic Agents, Phytogenic - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - pharmacology; ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors; Bioavailability; Biological Availability; Cancer therapies; Cell cycle; Cyclosporine - administration & dosage; Cyclosporins - administration & dosage; Cytochrome; Cytotoxicity; Drug dosages; Glycoproteins; Humans; Metabolism; Mice; Mice, Knockout; Neoplasms - drug therapy; Oral administration; Paclitaxel - administration & dosage; Paclitaxel - analogs & derivatives; Paclitaxel - pharmacokinetics; Patients; Pharmacokinetics; Quality of life; Rodents; Signal transduction; Taxoids
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1023/A:1010635000879

Oral treatment with cytotoxic agents is to be preferred as this administration route is convenient to patients, reduces administration costs and facilitates the use of more chronic treatment regimens. For the taxanes paclitaxel and docetaxel, however, low oral bioavailability has limited development of treatment by the oral route. Preclinical studies with mdr1a P-glycoprotein knock-out mice, which lack functional P-glycoprotein activity in the gut, 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 blockers such as cyclosporin A or the structurally related compound SDZ PSC 833. Based on the extensive preclinical research, the feasibility of oral administration of paclitaxel and docetaxel in cancer patients was recently demonstrated in our Institute. Co-administration of cyclosporin A strongly enhanced the oral bioavailability of both paclitaxel and docetaxel. For docetaxel in combination with cyclosporin A an oral bioavailability of 90% was achieved with an interpatient variability similar to that after intravenous drug administration; for paclitaxel the oral bioavailability is estimated at approximately 50%. The safety of the oral route for both taxanes is good. A phase II study of weekly oral docetaxel in combination with cyclosporin A is currently ongoing.