Paclitaxel orally administered

Kimura, Y., et al. 2002. P-glycoprotein inhibition by the multidrug resistance-reversing agent MS-209 enhances bioavailability and antitumor efficacy of orally administered paclitaxel. Cancer Chemother Pharmacol 49 322. 

Two Phase III clinical studies of orally administered capecitabine in over 1,200 patients with untreated metastatic colorectal cancer demonstrated at least equal efficacy and improved tolerability versus the Mayo Clinic regimen of intravenous 5-fluorouracil/leucovorin administration. The overall response rate for patients taking capecitabine orally was 21%, versus 14% for the intravenous 5-FU/leucovorin regimen. A median 53-month follow-up revealed a three-year disease-free survival rate of 66% for capecitabine versus 63% for 5-FU/leucovorin patients. International Phase II trials also demonstrated therapeutic benefits of capecitabine monotherapy for women with metastatic breast cancer that was either resistant to both paclitaxel and anthracycline therapy. Orally administered at the twice-daily 1,250 mg/m2 regimen (cycles of two weeks of therapy followed by a week of rest), the tumor response rate was in the range of 20-25%. In addition, combination of capecitabine with a taxane yielded a unique survival benefit compared to the previous standard of taxane monotherapy for anthracycline-resistant breast cancer.13,14... 

In summary, capecitabine (1), an A -carbamate pyrimidine nucleoside prodrug of cytotoxic antimetabolite 5-fluorouracil, is an FDA-approved anticancer drug that can be administered orally. This compound uses a multilayer of prodrug strategies that not only avoids side effects arising from exposure of toxic metabolites to healthy tissue but is converted to 5-fluorouracil only by enzymes preferentially expressed in many cancer cell types, thus resulting in selective delivery of the drug to tumors. Capecitabine is marketed under the trade name of Xeloda for use in the treatment of metastatic colorectal and breast cancers and metastatic breast cancer that is resistant to paclitaxel or anthracycline therapies. 

There was a dramatic increase in the systemic availability of paclitaxel when ciclosporin was administered concomitantly (241) and in a phase I study of the pharmacokinetics of twice-daily oral paclitaxel 60-160 mg/m in 15 patients in combination with ciclosporin (15 mg/kg) there was a seven-fold increase in the systemic exposure to paclitaxel the plasma concentration increased from negligible to therapeutic concentrations (242). The inhibitory effect of ciclosporin on the gastrointestinal multidrug transporter P-glycoprotein was suggested to account for these interactions. 

Prepare and administer using glass or non-PVC IV bags and tubing Premedicate patients to prevent hypersensitivity reactions dexamethasone 20 mg IV or orally 12 hours and 6 hours prior to paclitaxel, and diphenhydramine 50 mg IV 30 minutes prior to paclitaxel, and ranitidine 50 mg IV or cimetidine 300 mg IV 30 minutes prior to paclitaxel Reduce dose in patients with elevated total bilirubin (>1.5 mg/dL) and/or elevated transaminases (guidelines not well established)... 

Premedication regimen for docetaxel oral dexamethasone 8 mg twice daily for 3 days starting 24 h prior to the commencement of infusion. For paclitaxel infused over 1, 3, and 24 h Hi antagonist diphenhydramine (50 mg) and an H2 antagonist (cimetidine 300 mg, ranitidine 50 mg, or famotidine 20 mg) given IV prior to infusion beginning. Oral dexamethasone 20 mg administered 12 and 6 h prior. 

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