Oral bioavailability of a novel paclitaxel formulation (Genetaxyl) administered with cyclosporin A in cancer patients.
The formulation excipient Cremophor EL (CrEL) is known to limit the absorption of oral paclitaxel given together with cyclosporin A. We hypothesized that the use of oral Genetaxyl, a paclitaxel formulation containing only 20% CrEL would have an improved oral bioavailability. Cohorts of six patients were treated with oral Genetaxyl at a dose of 60, 120, or 180 mg/m2 and 10 mg/kg of oral cyclosporin A in cycle 1. In cycle 2, patients received intravenous (i.v.) Genetaxyl (175 mg/m2, 3-h infusion). Three additional patients received one dose of generic i.v. paclitaxel (Genaxol, containing 50% CrEL; 175mg/m2, 3-h infusion). The median area under the plasma concentration-time curve (AUC) and peak concentration of total paclitaxel following i.v. Genetaxyl were lower than those for i.v. Genaxol, as a result of significantly increased clearance (P = 0.017), and the AUC ratio for unbound to total paclitaxel for i.v. Genetaxyl was about two times higher than that for i.v. Genaxol (P = 0.0077). After oral administration of Genetaxyl at doses of 60, 120, and 180 mg/m2, the median total paclitaxel AUCs were 1.29, 1.60, and 1.85 microg x h/ml, respectively, suggesting a less than proportional increase in systemic exposure with increasing doses. The corresponding median values for the apparent bioavailability of oral Genetaxyl were similar when compared with i.v. Genetaxyl, when calculated either on the basis of data for total paclitaxel (30.1%) or unbound paclitaxel (30.6%).
Chu
Zyting
Z
Department of Medical Research, China Medical University Hospital, Taichung, Taiwan.
Chen
Jen-Shi
JS
Liau
Chi-Ting
CT
Wang
Hung-Ming
HM
Lin
Yung-Chang
YC
Yang
Muh-Hwa
MH
Chen
Po-Min
PM
Gardner
Erin R
ER
Figg
William D
WD
Sparreboom
Alex
A
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D016572:Cyclosporine / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D005990:Glycerol / Q000031:analogs & derivatives / Q000737:chemistry; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics*
D000972:Antineoplastic Agents, Phytogenic; D007166:Immunosuppressive Agents; C000515:cremophor EL; D016572:Cyclosporine; D017239:Paclitaxel; D005990:Glycerol