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).

Based on the population pharmacokinetic analysis, cabazitaxel has a plasma clearance of 48.5 L/h (CV 39%; 26.4 L/h/m2 for a patient with a median BSA of 1.84 m2) in patients with metastatic prostate cancer. 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.

Renal Impairment

Cabazitaxel is minimally excreted via the kidney. No formal pharmacokinetic trials have been conducted with cabazitaxel in patients with renal impairment. The population pharmacokinetic analysis carried out in 170 patients including 14 patients with moderate renal impairment (30 mL/min ≤ CLcr < 50 mL/min) and 59 patients with mild renal impairment (50 mL/min ≤ CLcr < 80 mL/min) showed that mild to moderate renal impairment did not have meaningful effects on the pharmacokinetics of cabazitaxel. No data are available for patients with severe renal impairment or end-stage renal disease [see Use in Special Populations (8.6)].

Hepatic Impairment

No formal trials in patients with hepatic impairment have been conducted. As cabazitaxel is extensively metabolized in the liver, hepatic impairment is likely to increase the cabazitaxel concentrations [see Warnings and Precautions (5.6), and Use in Special Populations (8.7)].

Drug interactions

As cabazitaxel is mainly metabolized by CYP3A in vitro, strong CYP3A inducers or inhibitors are expected to affect the pharmacokinetics of cabazitaxel.

Prednisone or prednisolone administered at 10 mg daily did not affect the pharmacokinetics of cabazitaxel.

In vitro, cabazitaxel did not inhibit the multidrug-resistance protein 1 (MRP1) or 2 (MRP2). In vitro cabazitaxel inhibited the transport of P-gp and BRCP, at concentrations at least 38 fold what is observed in clinical settings. Therefore, the in vivo risk of cabazitaxel to inhibit MRPs, P-gp, or BCRP is unlikely at the dose of 25 mg/m2.

In vitro, cabazitaxel is a substrate of P-gp, but not a substrate of MRP1, MRP2, or BCRP.

13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term animal studies have not been performed to eva luate the carcinogenic potential of cabazitaxel.

Cabazitaxel was positive for clastogenesis in the in vivo micronucleus test, inducing an increase of micronuclei in rats at doses ≥ 0.5 mg/kg. Cabazitaxel increased numerical aberrations with or without metabolic activation in an in vitro test in human lymphocytes though no induction of structural aberrations was observed. Cabazitaxel did not induce mutations in the bacterial reverse mutation (Ames) test. The positive in vivo genotoxicity findings are consistent with the pharmacological activity of the compound (inhibition of tubulin depolymerization).

Cabazitaxel may impair