AusPAR: Cabazitaxel - Therapeutic Goods Administration

More documents

Recommendations

Info

AusPAR Jevtana Cabazitaxel Sanofi-Aventis Australia Pty Ltd PM-2010-02565-3-4 Final 9 February 2012 Therapeutic Goods Administration of total faecal radioactivity) being detected in mice. In all species, unchanged drug also represented only a small proportion of total urinary radioactivity (
AusPAR Jevtana Cabazitaxel Sanofi-Aventis Australia Pty Ltd PM-2010-02565-3-4 Final 9 February 2012 Therapeutic Goods Administration In vitro, no clinically relevant inhibition of CYP1A2, 2B6, 2C9, 2C19, 2D6 or 2E1 enzyme activities was seen with cabazitaxel concentrations up to 200 µM. The only notable inhibition was on CYP3A (midazolam substrate; inhibitory rate constant [Ki] 2 µM, about 7× Cmax). The Ki for cabazitaxel inhibition of paclitaxel metabolism (mediated by CYP2C8) was 3.3 µM (about 12× the clinical Cmax). In human hepatocytes, there was no consistent evidence of the induction of CYP1A2, 2C9 or 3A4 (gene expression and marker enzyme activity), with cabazitaxel concentrations tested up to 10 µM. With the possible exception of CYP3A, cabazitaxel at the maximum recommended human dose (MRHD) is unlikely to cause any clinically relevant inhibition or induction of CYP450 enzymes. As cabazitaxel is mainly metabolised by CYP3A, its metabolism might be expected to be influenced by coadministered drugs that inhibit or induce CYP3A or are also primarily metabolised by CYP3A. This is noted in the PI. Inhibition of cabazitaxel metabolism by various drugs was investigated in human liver microsomes. The data suggested that there was unlikely to be inhibition by dexchlorpheniramine, granisetron, morphine, ondansetron, ranitidine, omeprazole, acetaminophen or warfarin. Cabazitaxel was found to be a highly permeable compound, as might be expected from its lipophilicity. It was shown to be a P-gp substrate at circulating concentrations in vivo. Cabazitaxel was found to be a P-gp inhibitor, but IC50 values (10‒17 µM) were well above the clinical Cmax (37 fold) and therefore inhibition of P-gp is unlikely to occur with the proposed clinical dose. Cabazitaxel was not a substrate for hMRP1, hMRP2 or hBCRP efflux transporters and no clinically relevant inhibition of the hMRP1, hMRP2 or hBCRP transporters was seen. Toxicology Single dose toxicity Single dose toxicity studies using only the intravenous route were conducted in mice, rats and dogs. Appropriate observation periods were included. The maximum non-lethal doses were 25 mg/kg (75 mg/m 2) in mice, 2.5 mg/kg (15 mg/m 2) in rats and 0.5 mg/kg (10 mg/m 2) in dogs. There was very little margin between non-lethal and lethal doses, suggesting a high order of toxicity in these species. In the rat and dog studies, deaths occurred at doses similar to the clinical dose (based on body surface area). The target organs for toxicity were the CNS (in mice), male reproductive organs (rats and dogs), bone marrow (rats and dogs), liver (rats and dogs) and the gastrointestinal tract (dogs only). Haematological changes associated with bone marrow toxicity (lymphopenia, neutropenia and anaemia) developed from Day 3 and showed a trend to recovery from Day 14. Page 15 of 75
Page 1 and 2: Australian Public Assessment Report
Page 3 and 4: Contents AusPAR Jevtana Cabazitaxel
Page 5 and 6: AusPAR Jevtana Cabazitaxel Sanofi-A
Page 7 and 8: Acetone Solvate AusPAR Jevtana Caba
Page 13: AusPAR Jevtana Cabazitaxel Sanofi-A
Page 17 and 18: Toxicological effects typical of th
Page 19 and 20: Reproductive toxicity AusPAR Jevtan
Page 21 and 22: Table 3: Details of impurities test
Page 29 and 30: Figure 1: Flow chart AusPAR Jevtana
Page 33 and 34: Figure 2: Overall survival (OS) - I
Page 55 and 56: Safety AusPAR Jevtana Cabazitaxel S
Page 59 and 60: NAME OF THE MEDICINE Non-proprietar
Page 61 and 62: CLINICAL TRIALS The efficacy and sa
Page 63 and 64: Table 2 Efficacy of Jevtana in the
Page 65 and 66:
Risk of cardiac arrhythmias Cardiac
Page 67 and 68:
co-administration with CYP3A induce
Page 69 and 70:
System Organ Class Adverse Reaction
Page 71 and 72:
none of which were Grade ≥3. The
Page 73 and 74:
Table 4 Recommended Dosage Modifica
Page 75:
Therapeutic Goods Administration PO
show all

AusPAR: Cabazitaxel - Therapeutic Goods Administration

Create successful ePaper yourself

Delete template?

Save as template?