AusPAR: Cabazitaxel - Therapeutic Goods Administration

AusPAR Jevtana Cabazitaxel Sanofi-Aventis Australia Pty Ltd PM-2010-02565-3-4
Final 9 February 2012
Therapeutic Goods Administration
The elimination profile of cabazitaxel has been shown to be triphasic, with rapid initial
and intermediate phases (half-life [t1/2]: 4.4 minutes [min] and 1.6 h respectively) followed
by a long terminal phase with a half-life of 95.1 h (Study POH 0124).
Renal clearance
Following a 1 h infusion of cabazitaxel, the clearance was a population value of 48.5 L/h
(for a patient with median BSA of 1.84 m 2). This was comparable with the clearance
estimated in patients with advanced solid tumours. However, it was more than twofold
higher than that estimated in patients with metastatic breast cancer in Study ARD 6191.
Pharmacokinetics in other special populations
Pharmacokinetics in subjects with impaired hepatic function
Cabazitaxel is mainly metabolized by the liver. However, the limited number of patients
with abnormal liver function prevents any conclusion being reached.
Pharmacokinetics in subjects with impaired renal function
Cabazitaxel is minimally excreted via the kidneys. In the population PK analysis, of the 170
patients, 14 patients had moderate renal impairment (creatinine clearance [CLcr] ≥30 to
≤50 mL/min) and 59 had mild renal impairment (CLcr ≥50 to ≤80 mL/min). Mild to
moderate renal impairment appears not to have significant effects on the PK of
cabazitaxel.
Pharmacokinetics according to age
The population PK analysis did not identify age as a significant factor in cabazitaxel PK.
Pharmacokinetics related to genetic factors (sex, ethnicity, genetic polymorphism)
Plasma clearance in studies of patients with advanced solid tumours was the same in both
males and females. In Study TCD 6945, the plasma clearance of cabazitaxel when used in
combination with capecitabine for the treatment of patients with metastatic breast cancer
was similar to that when cabazitaxel was used as monotherapy in patients with advanced
solid tumours. In Study ARD 6191 of cabazitaxel monotherapy in patients with metastatic
breast cancer, the clearance was much lower. The evaluator noted that it is possible that
tumour type rather than gender was the possible cause for the difference. The sponsor
indicated that the lower plasma CL value observed in study ARD6191 is most likely
attributed to a study effect rather than a tumour type effect or gender effect.
Pharmacokinetic interactions
Pharmacokinetic interactions demonstrated in human studies
In Study TCD 6945, cabazitaxel was used in combination with capecitabine in the
treatment of patients with metastatic breast cancer. Capecitabine is converted to 5fluorouracil
(5-FU) in tumours. The PK parameters for capecitabine at dose levels I and III
were (AUC: 6060 - 8870 ng.h/mL) and 5-FU (AUC: 334 - 495 ng.h/mL) and were similar to
that reported in the literature at the same dose. Cabazitaxel therefore does not appear to
alter the PK of capecitabine and 5-FU. Similarly capecitabine appears not to alter the PK of
cabazitaxel.
Evaluator’s overall conclusions on pharmacokinetics
Cabazitaxel exposure showed dose proportionality over the 10 - 30 mg/m 2 range infused
every 3 weeks. There was no difference in exposure between Cycle 1 and Cycle 2. The
pharmacokinetics of cabazitaxel showed a high clearance, a large volume of distribution at
steady state and a long terminal half-life. It was rapidly metabolised in the liver and
mainly excreted in faeces. Urinary excretion was low. The plasma clearance of cabazitaxel
Page 26 of 75