AusPAR: Cabazitaxel - Therapeutic Goods Administration

Repeat dose toxicity
AusPAR Jevtana Cabazitaxel Sanofi-Aventis Australia Pty Ltd PM-2010-02565-3-4
Final 9 February 2012
Therapeutic Goods Administration
All toxicity studies were conducted with administration by the IV route which is the
proposed clinical route of administration. The duration of administration of the dose
varied between a short infusion (generally about 1 min) to a longer infusion (generally
about 1 h). Repeat dose toxicity studies were conducted in mice, rats and dogs.
As noted above, these species are acceptable models. Studies were generally adequate in
terms of duration, dosing frequency, animal numbers, the timing of investigations and
other aspects of study design. The doses chosen, limited by toxicity, were generally
acceptable, . Exposures at the highest adequately tested doses were >10 in mice and 2 in
rats but were subclinical in dogs. Different dosing schedules were tested including daily
administration (mice, rats and dogs), weekly administration (mice and dogs) and
administration once every 3 weeks (mice, rats and dogs). The latter, as this is proposed
clinical schedule, was chosen and cabazitaxel administered by 1 h infusion in these
studies. Additionally, in rats, a study with daily administration for 4 weeks provided
information for the selection of doses for the reproductive toxicity studies. The vehicle
used in most of these studies was prepared from a stock solution of cabazitaxel in
polysorbate 80 by dilution with 13% ethanol and then 5% glucose and was comparable to
that proposed for registration. As expected, in all species, lethality, as well as other toxic
effects, was influenced by dose, dosing frequency and dosing interval. Relative exposure of
cabazitaxel in repeat dose toxicity studies is shown in Table 1.
Table 1: Relative exposure of cabazitaxel in repeat dose toxicity studies
Species
(Strain)
Mouse
(CD-1)
Rat
(SD)
Dog
(Beagle)
Human
Duration/
frequency
5 cycles
(1h infusion/
3 weeks)
5 days
(1 min daily)
10 cycles
(1 h infusion/
3 weeks)
5 days
(1h infusion
daily)
13 cycles
(1h infusion/
3 weeks)
Dose
(mg/kg
/IV dose)
AUC0–24h
(ng·h/mL)
AUC over
3 weeks
(ng·h/mL)
5 5593 5593 6
10 14146 14146 15
15 13147 13147 14
0.25 11.2b 56 0.06
0.5 20.6 b 103 0.1
1 76.9 b 385 0.4
1 144 144 0.2
5 942 942 1.0
10 1910 1910 2
20 9445 9445 10d 0.1 6.7 c 34 0.04
0.1 9 9 0.01
0.25 49 49 0.05
0.5 157 157 0.2
2 cycles
(1h/3 weeks) [25 mg/m2] 953 953 –
Exposure ratio
based on AUC a
a calculated as animal:human AUC over 3 weeks; data are for the sexes combined, and averages across
sampling days;
b AUC0−6h
c AUC0−2h
d only one dose achievable at this level due to severe toxicity, dose was lowered to 10 mg/kg
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