Journal
ANTI-CANCER DRUGS
Volume 19, Issue 3, Pages 275-281Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/CAD.0b013e3282f3fd2e
Keywords
cremophor; cyclosporin A; formulation; oral paclitaxel; pharmacokinetics
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Funding
- Intramural NIH HHS [NIH0011335962, Z01 BC010548-02] Funding Source: Medline
- NCI NIH HHS [N01CO12400, N01-CO-12400] Funding Source: Medline
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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/m(2) and 10mg/kg of oral cyclosporin A in cycle 1. In cycle 2, patients received intravenous (i.v.) Genetaxyl (1175 mg/m(2), 3-h infusion). Three additional patients received one dose of generic i.v. paclitaxel (Genaxol, containing 50% CrEL; 175 mg/m(2), 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/m(2), the median total paclitaxel AUCs were 1.29, 1.60, and 1.85 mu g 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%).
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