indication

For treatment of patients with hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing treatment regimen.

pharmacology

After an intravenous dose of cabazitaxel 25 mg/m2 every three weeks to a population of 170 patients with solid tumors, the mean Cmax in patients with metastatic prostate cancer was 226 ng/mL (CV 107%) and was reached at the end of the one-hour infusion (Tmax). The mean AUC in patients with metastatic prostate cancer was 991 ng.h/mL (CV 34%).

mechanism of action

Cabazitaxel is a microtubule inhibitor. Cabazitaxel binds to tubulin and promotes its assembly into microtubules while simultaneously inhibiting disassembly. This leads to the stabilization of microtubules, which results in the inhibition of mitotic and interphase cellular functions.

toxicity

Cabazitaxel may cause serious side effects including neutropenia, hypersensitivity reactions, gastrointestinal symptoms, and renal failure. Anticipated complications of overdose include exacerbation of adverse reactions such as bone marrow suppression and gastrointestinal disorders. Cabazitaxel penetrates the blood-brain barrier.

biotransformation

Cabazitaxel is extensively metabolized in the liver (>95%), mainly by the CYP3A4/5 isoenzyme (80% to 90%), and to a lesser extent by CYP2C8. Cabazitaxel is the main circulating moiety in human plasma. Seven metabolites were detected in plasma (including the 3 active metabolites issued from O-demethylation), with the main one accounting for 5% of cabazitaxel exposure.

half life

Following a one-hour intravenous infusion, plasma concentrations of cabazitaxel can be described by a three-compartment pharmacokinetic model with α-, β-, and γ- half-lives of 4 minutes, 2 hours, and 95 hours, respectively.

route of elimination

After a one-hour intravenous infusion [14C]-cabazitaxel 25 mg/m2, approximately 80% of the administered dose was eliminated within 2 weeks. Cabazitaxel is mainly excreted in the feces as numerous metabolites (76% of the dose); while renal excretion of cabazitaxel and metabolites account for 3.7% of the dose (2.3% as unchanged drug in urine).