Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

12.2 Pharmacodynamics
Cardiac Electrophysiology
The effect of cabazitaxel following a single dose of 25 mg/m2 administered by intravenous infusion on QTc interval was evaluated in 94 patients with solid tumors. No large changes in the mean QT interval (i.e., >20 ms) from baseline based on Fridericia correction method were detected. However, a small increase in the mean QTc interval (i.e., <10 ms) cannot be excluded due to study design limitations.

Pharmacokinetic Properties

12.3 Pharmacokinetics
A population pharmacokinetic analysis was conducted in 170 patients with solid tumors at doses ranging from 10 to 30 mg/m2 weekly or every three weeks.
Absorption
Based on the population pharmacokinetic analysis, after an intravenous dose of cabazitaxel 25 mg/m2 every three weeks, the mean Cmax in patients with metastatic prostate cancer was
226 ng/mL (CV 107%) and was reached at the end of the one-hour infusion (Tmax). The mean
AUC in patients with metastatic prostate cancer was 991 ng∙h/mL (CV 34%).
No major deviation from the dose proportionality was observed from 10 to 30 mg/m² in patients with advanced solid tumors.
Distribution
The volume of distribution (Vss) was 4,864 L (2,643 L/m² for a patient with a median BSA of 1.84 m²) at steady state.
In vitro, the binding of cabazitaxel to human serum proteins was 89% to 92% and was not saturable up to 50,000 ng/mL, which covers the maximum concentration observed in clinical trials. Cabazitaxel is mainly bound to human serum albumin (82%) and lipoproteins (88% for HDL, 70% for LDL, and 56% for VLDL). The in vitro blood-to-plasma concentration ratio in human blood ranged from 0.90 to 0.99, indicating that cabazitaxel was equally distributed between blood and plasma.
Metabolism
Cabazitaxel is extensively metabolized in the liver (>95%), mainly by the CYP3A4/5 isoenzyme (80% to 90%), and to a lesser extent by CYP2C8. Cabazitaxel is the main circulating moiety in human plasma. Seven metabolites were detected in plasma (including the 3 active metabolites issued from O-demethylation), with the main one accounting for 5% of cabazitaxel exposure.
Around 20 metabolites of cabazitaxel are excreted into human urine and feces.
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 -, β-, and - half-lives of 4 minutes, 2 hours, and 95 hours, respectively.
Renal Impairment
Cabazitaxel is minimally excreted via the kidney. A 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. This was confirmed by a dedicated comparative pharmacokinetic study in patients with solid tumors with normal renal function (n=8, CLCR >80 mL/min/1.73 m2), or moderate (n=8, 30 mL/min/1.73 m2 ≤ CLCR <50 mL/min/1.73 m2) and severe (n=9, CLCR <30 mL/min/1.73 m2) renal impairment, who received several cycles of cabazitaxel in single IV infusion up to 25 mg/m2. Limited pharmacokinetic data were available in patients with end-stage renal disease (n=2, CLCR <15 mL/min/1.73 m2).
Hepatic Impairment
Cabazitaxel is extensively metabolized in the liver.


A dedicated study in 43 cancer patients with hepatic impairment showed no influence of mild (total bilirubin >1 to ≤1.5 × ULN or AST >1.5 × ULN) or moderate (total bilirubin >1.5 to ≤3.0 × ULN) hepatic impairment on cabazitaxel pharmacokinetics. The maximum tolerated dose (MTD) of cabazitaxel was 20 and 15 mg/m2, respectively.
In 3 patients with severe hepatic impairment (total bilirubin >3 × ULN), a 39% decrease in clearance was observed when compared to patients with mild hepatic impairment (ratio=0.61, 90% CI: 0.36-1.05), indicating some effect of severe hepatic impairment on cabazitaxel pharmacokinetics. The MTD of cabazitaxel in patients with severe hepatic impairment was not established. Based on safety and tolerability data, cabazitaxel dose should be maintained at 20 mg/m2 in patients with mild hepatic impairment and reduced to 15 mg/m2 in patients with moderate hepatic impairment [see Warnings and Precautions (5.8) and Use in Specific Populations (8.7)]. Cabazitaxel is contraindicated in patients with severe hepatic impairment [see Contraindications (4) and Use in Specific Populations (8.7)].
Drug Interactions
A drug interaction study of JEVTANA in 23 patients with advanced cancers has shown that repeated administration of ketoconazole (400 mg orally once daily), a strong CYP3A inhibitor, increased the exposure to cabazitaxel (5 mg/ m2 intravenous) by 25%.
A drug interaction study of JEVTANA in 13 patients with advanced cancers has shown that repeated administration of aprepitant (125 or 80 mg once daily), a moderate CYP3A inhibitor, did not modify the exposure to cabazitaxel (15 mg/m2 intravenous).
A drug interaction study of JEVTANA in 21 patients with advanced cancers has shown that repeated administration of rifampin (600 mg once daily), a strong CYP3A inducer, decreased the exposure to cabazitaxel (15 mg/m2 intravenous) by 17%.
A drug interaction study of JEVTANA in 11 patients with advanced cancers has shown that cabazitaxel (25 mg/m2 administered as a single 1-hour infusion) did not modify the exposure to midazolam, a probe substrate of CYP3A.
Prednisone or prednisolone administered at 10 mg daily did not affect the pharmacokinetics of cabazitaxel.
Based on in vitro studies, the potential for cabazitaxel to inhibit drugs that are substrates of other CYP isoenzymes (1A2, -2B6, -2C9, -2C8, -2C19, -2E1, -2D6, and CYP3A4/5) is low. In addition, cabazitaxel did not induce CYP isozymes (-1A, -2C9 and -3A) in vitro.
In vitro, cabazitaxel did not inhibit the multidrug-resistance protein 1 (MRP1), 2 (MRP2) or organic cation transporter (OCT1). In vitro, cabazitaxel inhibited P-gp, BRCP, and organic anion transporting polypeptides (OATP1B1, OATP1B3). However, the in vivo risk of cabazitaxel inhibiting MRPs, OCT1, P-gp, BCRP, OATP1B1 or OATP1B3 is low at the dose of 25 mg/m2.
In vitro, cabazitaxel is a substrate of P-gp, but not a substrate of MRP1, MRP2, BCRP, OCT1, OATP1B1 or OATP1B3.