Prescription Drug Information: Jevtana (Page 4 of 6)

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 [14 C]-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 α-, β-, and γ- 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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term animal studies have not been performed to evaluate the carcinogenic potential of cabazitaxel.

Cabazitaxel was positive for clastogenesis in the in vivo micronucleus test, inducing an increase of micronuclei in rats at doses ≥0.5 mg/kg. Cabazitaxel increased numerical aberrations with or without metabolic activation in an in vitro test in human lymphocytes though no induction of structural aberrations was observed. Cabazitaxel did not induce mutations in the bacterial reverse mutation (Ames) test. The positive in vivo genotoxicity findings are consistent with the pharmacological activity of the compound (inhibition of tubulin depolymerization).

In a fertility study performed in female rats at cabazitaxel doses of 0.05, 0.1, or 0.2 mg/kg/day there was no effect of administration of the drug on mating behavior or the ability to become pregnant. In repeat-dose toxicology studies in rats with intravenous cabazitaxel administration once every three weeks for up to 6 months, atrophy of the uterus was observed at the 5 mg/kg dose level (approximately the AUC in patients with cancer at the recommended human dose) along with necrosis of the corpora lutea at doses ≥1 mg/kg (approximately 0.2 times the AUC at the clinically recommended human dose).

In a fertility study in male rats, cabazitaxel did not affect mating performances or fertility at doses of 0.05, 0.1, or 0.2 mg/kg/day. In repeat-dose toxicology studies with intravenous cabazitaxel administration once every three weeks for up to 9 months, degeneration of seminal vesicle and seminiferous tubule atrophy in the testis were observed in rats at a dose of 1 mg/kg (approximately 0.2 times the AUC in patients at the recommended human dose), and minimal testicular degeneration (minimal epithelial single cell necrosis in epididymis) was observed in dogs treated at a dose of 0.5 mg/kg (approximately 0.1 times the AUC in patients at the recommended human dose).

14 CLINICAL STUDIES

14.1 TROPIC Trial (JEVTANA + prednisone compared to mitoxantrone)

The efficacy and safety of JEVTANA in combination with prednisone were evaluated in a randomized, open-label, international, multi-center study in patients with metastatic castration-resistant prostate cancer previously treated with a docetaxel-containing treatment regimen (TROPIC, NCT00417079).

A total of 755 patients were randomized to receive either JEVTANA 25 mg/m2 intravenously every 3 weeks for a maximum of 10 cycles with prednisone 10 mg orally daily (n=378), or to receive mitoxantrone 12 mg/m2 intravenously every 3 weeks for 10 cycles with prednisone 10 mg orally daily (n=377) for a maximum of 10 cycles.

This study included patients over 18 years of age with hormone-refractory metastatic prostate cancer either measurable by RECIST criteria or non-measurable disease with rising PSA levels or appearance of new lesions, and ECOG (Eastern Cooperative Oncology Group) performance status 0–2. Patients had to have neutrophils >1,500 cells/mm3 , platelets >100,000 cells/mm3 , hemoglobin >10 g/dL, creatinine <1.5 × upper limit of normal (ULN), total bilirubin <1 × ULN, AST <1.5 × ULN, and ALT <1.5 × ULN. Patients with a history of congestive heart failure, or myocardial infarction within the last 6 months, or patients with uncontrolled cardiac arrhythmias, angina pectoris, and/or hypertension were not included in the study.

Demographics, including age, race, and ECOG performance status (0–2) were balanced between the treatment arms. The median age was 68 years (range 46–92) and the racial distribution for all groups was 83.9% Caucasian, 6.9% Asian, 5.3% Black, and 4% Others in the JEVTANA group.

Efficacy results for the JEVTANA arm versus the control arm are summarized in Table 5 and Figure 1.

Table 5: Efficacy of JEVTANA in TROPIC in the Treatment of Patients with Metastatic Castration-Resistant Prostate Cancer (intent-to-treat analysis)
JEVTANA + Prednisonen=378Mitoxantrone + Prednisonen=377
*
Hazard ratio estimated using Cox model; a hazard ratio of less than 1 favors JEVTANA.
Overall Survival
Number of deaths (%)234 (61.9%)279 (74.0%)
Median survival (month) (95% CI)15.1 (14.1–16.3)12.7 (11.6–13.7)
Hazard Ratio * (95% CI)0.70 (0.59–0.83)
p-value<0.0001

Figure 1: Kaplan-Meier Overall Survival Curves (TROPIC)

Figure 1
(click image for full-size original)

Investigator-assessed tumor response of 14.4% (95% CI: 9.6–19.3) was higher for patients in the JEVTANA arm compared to 4.4% (95% CI: 1.6–7.2) for patients in the mitoxantrone arm, p=0.0005.

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