Cabazitaxel (Jevtana) is a semi-synthetic derivative of a natural taxoid. Cabazitaxel (Jevtana) increases CYP3A enzyme activities in rat hepatocytes. The mean ex-vivo human plasma protein binding of Cabazitaxel (Jevtana) is 91.6%. Cabazitaxel (Jevtana) is rapidly and extensively metabolised into numerous metabolites. Cabazitaxel (Jevtana) demonstrates activity in several murine and human resistant cell lines. With a 4-day exposure to cabazitaxel, cytotoxicity is noted with relatively low cabazitaxel concentrations. Cabazitaxel (Jevtana) shows high antitumor activity in 3 human colorectal cell lines (HCT-116, HCT-8, and HT-29). In accompanying models, Cabazitaxel (Jevtana) has significant antitumor activity. In murine tumor xenografts (colon C38 and pancreas P03), Cabazitaxel (Jevtana) causes complete tumor regressions. Using SF-295 and U251 human glioblastoma cell lines, both orthotopic and subcutaneous murine xenografts are generated. Cabazitaxel (Jevtana) treatment leads to complete regression in the majority of subcutaneously implanted tumors. Cabazitaxel (Jevtana) has entered in a phase I clinical trial in the treatment of solid cancer. Cabazitaxel (Jevtana) plus Prednisone, Carboplatin has entered in a phase II clinical trial in the treatment of prostate cancer. Cabazitaxel is a semi-synthetic derivative of a natural taxoid.
 |
Source | Mol Pharm (2015). Figure 2. Cabazitaxel |
| Method | Plasma Pharmacokinetics | |
| Cell Lines | Abcb1a/1b-/-, Abcg2-/- and Abcb1a/1b;Abcg2-/- mice | |
| Concentrations | 10 mg/kg | |
| Incubation Time | 8 h | |
| Results | Absorption of cabazitaxel was rapid, with a Tmax occurring at or before 30 minutes in all strains. |
 |
Source | Mol Pharm (2015). Figure 1. Cabazitaxel |
| Method | Transport Assays | |
| Cell Lines | MDCK-II parental cells | |
| Concentrations | 5 μM | |
| Incubation Time | 8 h | |
| Results | In MDCKII parental cells, there was modest but significant apically directed transport of cabazitaxel, which was completely inhibited by the ABCB1 inhibitor zosuquidar, suggesting some transport by the low-level endogenous canine ABCB1. In MDCKII-hABCB1 cells. |
| Cell Experiment | |
|---|---|
| Cell lines | MCF-7 cells |
| Preparation method | Parallel drug selections were initiated using 0.1 nmol/L cabazitaxel, a concentration that would inhibit growth in MCF-7 cells by 50% (IC50 value) with and without 2 μmol/L PSC-833. Selections continued by increasing the drug concentration in a stepwise manner up to a final concentration of 5 nmol/L cabazitaxel. |
| Concentrations | 5 nmol/L |
| Incubation time | 72 h |
| Animal Experiment | |
|---|---|
| Animal models | Male nude mice |
| Formulation | 1% medium /0.1% Tween-20 |
| Dosages | 30 mg/kg |
| Administration | i.v. |
| Molecular Weight | 835.93 |
| Formula | C45H57NO14 |
| CAS Number | 183133-96-2 |
| Solubility (25°C) | DMSO 90 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
[2] Duran GE, et al. Mol Cancer Ther. Mechanisms of resistance to cabazitaxel.
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