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
cabazitaxel achievable in these studies, limited information or conclusions can be drawn
from the negative findings. 11
Supplementary safety pharmacology studies included investigation of effects on the renal
system (urine parameters and electrolyte excretion in saline loaded rats) and the
gastrointestinal system (in vivo transit time and in vitro response to ileal spasmogens),
with the in vivo studies at doses up to 5 mg/kg IV in rats and in vitro concentrations up to
10 µM. In all these studies, cabazitaxel showed no (or minimal) effects, except for a
significant reduction in urinary potassium excretion in the study of renal function. No
specific findings on the renal system were observed in rats or in dogs in other toxicity
studies. Histological changes to the intestines following a single IV dose of 5 or 10 mg/kg
to rats did not translate into a functional change in terms of gastrointestinal transit after
5 mg/kg.
Overall, the safety pharmacology studies indicate that cabazitaxel had a similar profile to
other taxanes on the cardiovascular, respiratory, renal and gastrointestinal systems. The
microscopic findings seen in the CNS of treated rats is not a common feature of the taxane
class.
Pharmacokinetics
Absorption
Clearance was high in all species investigated. Volume of distribution at steady state
appeared to be large (greater than body water) in all these species (although estimates in
mice and dogs varied considerably), consistent with wide tissue distribution of
cabazitaxel/metabolites to tissues. In humans, terminal half-life (123 hours [h]) was
longer than in the laboratory animal species (0.35-26 h), although estimates in mice and
dogs were variable.
There was no clear evidence of a sex difference in the absorption of cabazitaxel in either
rats or dogs (only females were investigated in mice), nor in the distribution kinetics in
rats. There was little evidence of accumulation following any of the repeated dosing
schedules investigated in mice, rats or dogs. Exposure to cabazitaxel increased in an
approximately dose proportional manner in mice but generally in a supra dose
proportional manner in rats and dogs, possibly due to saturation of metabolic pathways.
The proposed Product Information (PI) notes that there was no major deviation to dose
proportionality in patients with advanced solid tumours over the relatively narrow dose
range of 10 to 30 mg/m 2.
The cabazitaxel metabolites, docetaxel and RPR123142 were only detectable at high doses
(10 mg/kg IV, but not 1 mg/kg IV) in mice and rats. Docetaxel was not detectable in dogs
but only low doses were achievable in this species. These findings are consistent with
cabazitaxel being the main circulating drug related compound.
Distribution
In vitro protein binding was high in all species. At concentrations up to 10 µg/mL, protein
binding was >98% in mice, 96−97% in dogs, 95−97% in rats, 85−93% in rabbits and 89-
92% in humans , as determined by equilibrium dialysis using [14C]cabazitaxel and, with
the exception of mice, there was little evidence of saturation. Some concentration
dependent changes in protein binding were seen with mouse plasma, although protein
11 Masini E, Planchenault J, Pezziardi F, Gautier P, Gagnol JP. Histamine releasing properties of
polysorbate 80 in vitro and in vivo: correlation with its hypotensive action in the dog. Agents and
Actions 1985; 16: 470-477.
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