Oral bioavailability of a novel paclitaxel formulation (Genetaxyl) administered with cyclosporin A in cancer patients

Abstract

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.

In Vivo Evaluation of Paclitaxel-Loaded Lipid Nanocapsules After Intravenous and Oral Administration on Resistant Tumor

“…Unfortunately, standard LNCs and LNCs with chitosan presented no beneficial effect in reducing interindividual variability (variation of 69% in AUC for both LNCs vs. 49% for Ptx commercial formulation). After oral administration of a Taxol generic or a Ptx formulation with less Cremophor EL, associated with cyclosporin A, a high interindividual variability was observed in human (coefficient of variation in AUC varied from 14.5 to 63.9% according to the dose) [41]. On the opposite, PEG 2000 -amino postinserted LNCs present an effect on the reduction in interindividual variability (variation of 36% in AUC).…”

Low-Dose Metronomic Paclitaxel Chemotherapy Suppresses Breast Tumors and Metastases in Mice

“…A number of clinical trials have been reported in which orally bioavailable chemotherapeutic drugs such as cyclophosphamide, methotrexate, and capecitabine were given daily to treat patients with metastatic breast cancer (39,40). Several new formulations to enhance the oral bioavailability of paclitaxel and oral paclitaxel analogues have been invented (41)(42)(43).…”

Evaluation of the effect of food on the pharmacokinetics of axitinib in healthy volunteers

“…The spectrum of effects that has been associated with changes in formulation includes variable impact of food on drug absorption [10], altered bioavailability [11,12] including altered drug absorption [13,14], and even potential changes in the delivery to tumor target site [12,15]. Initial trials in the axitinib clinical development program were conducted using tablets containing crystal polymorph axitinib Form IV FCIR of axitinib drug substance [1,[3][4][5][16][17][18].…”