An open-label, pharmacokinetic study to determine the bioavailability, safety and tolerability of single dose oral docetaxel in metastatic prostate cancer (mPC) patients treated with IV docetaxel.

Abstract

5050 Background: Docetaxel has poor oral bioavailability in part due to extrusion by intestinal p-glycoprotein. To improve IV solubility, it is fomulated with the nonionic surfactant polysorbate 80, requiring steroid premedication to manage hypersensitivity type reactions. Oral administration has the potential to improve tolerability, reduce day-stay utilization and improve patient convenience and allows investigation of alternative dosing schedules. Oradoxel is a new combination of oral docetaxel capsules plus the novel gut-selective P-glycoprotein inhibitor encequidar (HM30181A). Methods: Patients with mPC receiving IV docetaxel were enrolled in 3 cohorts with a dose escalation schedule of Oradoxel 75 mg/m2 in Cohort 1, 150 mg/m2 in Cohort 2, 300mg/m2 in Cohort 3. Oradoxel was given 3 weeks before or after IV docetaxel treatment. Intensive PK samples were taken on days 1-5 for Oradoxel and days 1-4 for IV docetaxel. Dose limiting toxicity (DLT) or serious adverse events (SAE) were assessed per CTCAE v4.03. Results: 3 evaluable patients in each Cohort were studied. No DLT, MTD, or drug-related SAE were observed. PK parameters of Oradoxel vs IV docetaxel are summarized in the table below. Mean absolute bioavailability of Oradoxel was 15.9% (range 8-25%). PK became non linear at 300mg/m2. Conclusions: Oradoxel was well tolerated. Based on the results of this and related studies, Oradoxel 300mg/m2 in divided doses is being further evaluated in phase 2 studies. Clinical trial information: 12616000983404. [Table: see text]

A Sensitive Assay for Unbound Docetaxel Using Ultrafiltration plus HPLC-MS and Its Application to a Clinical Study

“…Nine patients with metastatic prostate cancer were recruited in a Phase I dose-escalation pharmacokinetic study for oDox+E [12]. Each patient had 24 and 23 plasma samples taken after administration of standard of care IV docetaxel and oDox+E, respectively.…”

“…Seven to eight samples after IV docetaxel administration and oDox+E administration were selected for unbound docetaxel analysis from each patient recruited in the Phase I trial [12]. The assay was implemented on these samples, and the quantified unbound docetaxel concentrations and the corresponding total docetaxel concentrations are shown in Figures 1 and 2.…”

“…Encequidar is a novel, well-tolerated intestine-specific P-glycoprotein inhibitor (with minimal systemic uptake) which increases the absorption of orally administered docetaxel [11]. oDox+E is a novel form of oral docetaxel that consists of oral docetaxel administered one hour after 15 mg of oral encequidar [12]. The total plasma concentration after oral oDox+E consists of protein-bound docetaxel and unbound docetaxel.…”

Minor Changes in Response Modules Leading to a “U-Shaped” Conversion Rate of Docetaxel Prodrug Nanoassemblies

“…With the advent of chemotherapy, the life expectancy of cancer patients has been extended . Docetaxel (DTX), a commonly prescribed chemotherapy drug for various types of cancer, inhibits the growth of tumor cells by disrupting microtubule dynamics. − The marketed formulation of Taxotere displays exceptional antitumor activity, but the clinical application is hindered by its unstable liquid form, severe hypersensitivity reactions, and grievous toxicity. , Numerous sophisticated DTX formulations and delivery techniques have been designed to surpass the restrictions, such as micelles, microcapsules, and polymeric nanoparticles. However, only a small number of them are currently listed in clinical trials. − The slow clinical progress may be due to the challenge of encapsulating DTX in traditional matrices.…”