The formulation excipient Cremophor EL (CrEL) is known to limit absorption of oral paclitaxel given together with cyclosporin A (CsA). We hypothesized that the use of oral Genetaxyl, a paclitaxel formulation containing only 20% CrEL would have an improved oral bioavailability. Cohorts of 6 patients were treated with oral Genetaxyl at a dose of 60, 120, or 180 mg/m 2 and 10 mg/kg of oral CsA in cycle 1. In cycle 2, patients received intravenous (i.v.) Genetaxyl (175 mg/m 2 , 3-hour infusion). Three additional patients received one dose of generic i.v. paclitaxel (Genaxol, containing 50% CrEL; 175 mg/m 2 , 3-hour 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 2 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 µg×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 calculated either based on data for total paclitaxel (30.1%) or unbound paclitaxel (30.6%) when compared to i.v. Genetaxyl.

Paclitaxel (Taxol) is formulated in 50% Cremophor EL (CrEL)/absolute ethanol for clinical use. In order to reduce vehicle-related side effects, Genetaxyl was developed to have paclitaxel formulated in a solution containing lesser amounts of CrEL and ethanol plus 2 other solvents. The purpose of the study was to evaluate the efficacy and safety of Genetaxyl as first-line therapy to treat breast cancer patients. Patients with newly diagnosed stage III (N = 8) or IV (N = 10), or recurrent (N = 11) breast cancer received single-agent Genetaxyl at 175 mg/m(2) administered in a 3-h infusion every 3 weeks for 3-6 cycles. A total of 148 cycles were delivered to 29 patients. The overall response rate was 41.4% (95% confidence interval, 23.4 to 59.2%), and that of patients with metastatic disease (N = 20) was 30%. Median survival for all patients was 32.4 months and 24.3 months for patients having metastatic disease. The toxicity profile seems favorable, especially regarding myelosuppression and myalgia/arthralgia. No severe hypersensitivity reaction occurred. These phase II trial results demonstrate that a 60% reduction of CrEL by Genetaxyl's formulation does not affect the activity of paclitaxel and could allow for better control of several CrEL-related toxicities.

A sensitive and specific assay for paclitaxel in plasma has been developed to overcome limitations in previously published assays, using liquid chromatography with tandem mass spectrometric detection. Plasma samples (100 microL) were subjected to liquid-liquid extraction with 1-chlorobutane/acetonitrile (4:1, v/v), with [(2)H(5)]paclitaxel employed as the internal standard. Chromatography was carried out with a Waters SymmetryShield C8 column (50 x 2.1 mm, 3.5 microm). The total run time, including equilibration, was 8 min, using a gradient of acetonitrile and 10 mM ammonium formate, pH 4.0. The assay is accurate and precise over the range of 2-2500 ng/mL and has been successfully applied to study the clinical pharmacokinetics of two formulations of paclitaxel, Genaxol and Genetaxyl, given orally and intravenously.

12002 Background: Oral administration of paclitaxel given with CsA has shown promising activity in Phase II trials, but the apparent bioavailability is low and dose-dependent due to the presence of high concentrations of Cremophor EL (CrEL). We hypothesized that the use of a novel oral paclitaxel formulation containing only 20% CrEL (Genetaxyl [G]; Genovate Biotechnology Ltd., Taiwan), given with CsA is associated with an improved pharmacokinetic (PK) profile. Methods: Cohorts of 6 patients with cancer were treated with oral G at a dose of 60, 120, or 180 mg/m2 and 10 mg/kg of oral CsA in cycle 1. In cycle 2, patients received IV G (175 mg/m2, 3-h infusion). Three additional patients received generic IV paclitaxel (GIP). Serial blood samples were analyzed by LC/MS/MS and equilibrium dialysis, to determine total and unbound paclitaxel PK. Results: The mean (± SD) total paclitaxel AUCs were 1299±189, 1682±636, and 2204±1407 ng.h/mL at the 3 consecutive dose levels, suggesting nonlinear PK. However, based on unbound AUC, the oral bioavailability was dose-independent (P=.62), with a mean value of 37.2±18.6% (n=15). As expected, the total paclitaxel AUC following IV G (9024±4648 ng·h/mL) was lower than that for IV GIP (13,732±3983 ng·h/mL), as a result of increased clearance (39.6 vs 18.3 L/h) and a larger volume of distribution (768 vs 268 L). Interestingly, the unbound paclitaxel AUC was similar between the two IV formulations (P=.25), as the ratio of unbound/total paclitaxel for G was 2.5 times higher than that for GIP (12.5 vs 4.9%). Toxicity profiles were mild, with only 2 patients experiencing ≥ Gr 3 myelosuppression following oral G at 180 mg/m2. Conclusions: The mean bioavailability of paclitaxel following oral Genetaxyl with CsA was about 37%, which is higher than that observed previously with paclitaxel (range, 21–31%). Further clinical exploration of oral Genetaxyl in taxane-sensitive diseases is warranted. [Table: see text]