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Mechanism of Action
ABRAXANE is a microtubule inhibitor that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. This stability results in the inhibition of the normal dynamic reorganization of the microtubule network that is essential for vital interphase and mitotic cellular functions. Paclitaxel induces abnormal arrays or “bundles” of microtubules throughout the cell cycle and multiple asters of microtubules during mitosis.
The pharmacokinetics of total paclitaxel following 30 and 180-minute infusions of ABRAXANE at dose levels of 80 to 375 mg/m² were determined in clinical studies. Dose levels of mg/m² refer to mg of paclitaxel in ABRAXANE. Following intravenous administration of ABRAXANE, paclitaxel plasma concentrations declined in a biphasic manner, the initial rapid decline representing distribution to the peripheral compartment and the slower second phase representing drug elimination. The terminal half-life was approximately 27 hours.
The drug exposure (AUCs) was dose proportional over 80 to 375 mg/m² and the pharmacokinetics of paclitaxel were independent of the duration of ABRAXANE administration. At the dose of 260 mg/m² for metastatic breast cancer, the mean maximum concentration of paclitaxel, which occurred at the end of the infusion, was 18,741 ng/mL. The mean total clearance was 15 L/hr/m². The mean volume of distribution was 632 L/m² indicating extensive extravascular distribution and/or tissue binding of paclitaxel.
The pharmacokinetic data of 260 mg/m² ABRAXANE administered over a 30-minute infusion was compared to the pharmacokinetics of 175 mg/m² paclitaxel injection over a 3-hour infusion. The clearance was larger (43%) and the volume of distribution was also higher (53%) for ABRAXANE than for paclitaxel injection. Differences in the maximum concentration (Cmax) and dose-corrected Cmax reflected differences in total dose and rate of infusion. There were no differences in terminal half-lives.
In vitro studies of binding to human serum proteins, using paclitaxel concentrations ranging from 0.1 to 50 μg/mL, indicated that between 89% to 98% of drug is bound; the presence of cimetidine, ranitidine, dexamethasone, or diphenhydramine did not affect protein binding of paclitaxel.
In vitro studies with human liver microsomes and tissue slices showed that paclitaxel was metabolized primarily to 6α-hydroxypaclitaxel by CYP2C8; and to two minor metabolites, 3'-p-hydroxypaclitaxel and 6α, 3'-p-dihydroxypaclitaxel, by CYP3A4. In vitro, the metabolism of paclitaxel to 6α-hydroxypaclitaxel was inhibited by a number of agents (ketoconazole, verapamil, diazepam, quinidine, dexamethasone, cyclosporin, teniposide, etoposide, and vincristine), but the concentrations used exceeded those found in vivo following normal therapeutic doses. Testosterone, 17α-ethinyl estradiol, retinoic acid, and quercetin, a specific inhibitor of CYP2C8, also inhibited the formation of 6α-hydroxypaclitaxel in vitro. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with compounds that are substrates, inducers, or inhibitors of CYP2C8 and/or CYP3A4 [see DRUG INTERACTIONS].
After a 30-minute infusion of 260 mg/m² doses of ABRAXANE, the mean values for cumulative urinary recovery of unchanged drug (4%) indicated extensive non-renal clearance. Less than 1% of the total administered dose was excreted in urine as the metabolites 6α-hydroxypaclitaxel and 3'-p-hydroxypaclitaxel.
Fecal excretion was approximately 20% of the total dose administered.
Effect of Hepatic Impairment
The pharmacokinetic profile of ABRAXANE administered as a 30-minute infusion was evaluated in 15 out of 30 solid tumor patients with mild to severe hepatic impairment defined by serum bilirubin levels and AST levels. Patients with AST > 10 x ULN or bilirubin > 5 x ULN were not enrolled. ABRAXANE doses were assigned based on the degree of hepatic impairment as described:
- Mild (bilirubin > ULN to ≤ 1.25 x ULN and AST > ULN and < 10 x ULN): 260 mg/m²
- Moderate (bilirubin 1.26 to 2 x ULN and AST > ULN and < 10 x ULN): 200 mg/m²
- Severe (bilirubin 2.01 to 5 x ULN and AST > ULN and < 10 x ULN): 130 mg/m²
The 260 mg/m² dose for mild hepatic impairment and the 200 mg/m² dose for moderate hepatic impairment resulted in paclitaxel exposures within the range seen in patients with normal hepatic function (mean AUC0-∞ = 14,789 ± 6,703 hr*ng/mL). The 130 mg/m² dose in patients with severe hepatic impairment resulted in lower paclitaxel exposures than those seen in normal subjects. In addition, patients with severe hepatic impairment had higher mean cycle 1 absolute neutrophil count (ANC) nadir values than those with mild and moderate hepatic impairment. Table 6 summarizes the AUC values observed in the study. The 200 mg/m² dose has not been evaluated in patients with severe hepatic impairment, but it is predicted to adjust the paclitaxel AUC to the range observed in patients with normal hepatic function. There are no data for patients with AST > 10 x ULN or bilirubin > 5 x ULN [see DOSAGE AND ADMINISTRATION and Use In Specific Populations].
Table 6: Exposure (AUC0-∞) of ABRAXANE Administered
Intravenously over 30 Minutes in Patients with Hepatic Impairment
|Dose||260 mg/m²||200 mg/m²||130 mg/m²|
|Mean ± SD||17434 ± 11454||14159 ± 13346||9187 ± 6475|
|Median (range)||13755 (7618, 35262)||7866 (5919, 37613)||6134 (5627, 20684)|
|abilirubin 2.01 to 5 x ULN and AST > ULN and < 10 x ULN|
Effect of Renal Impairment
The effect of renal impairment on the disposition of ABRAXANE has not been studied [see Use In Specific Populations].
Pharmacokinetic Interactions between Carboplatin and ABRAXANE
Administration of carboplatin immediately after the completion of ABRAXANE infusion to patients with non-small cell lung cancer did not cause clinically important changes in paclitaxel exposure. The observed mean AUCinf of free carboplatin was approximately 23% higher than the targeted value (6 min*mg/mL) but its mean half life and clearance were consistent with those reported in the absence of paclitaxel.
Metastatic Breast Cancer
Data from 106 patients accrued in two single arm open label studies and from 460 patients enrolled in a randomized comparative study were available to support the use of ABRAXANE in metastatic breast cancer.
Single Arm Open Label Studies
In one study, ABRAXANE was administered as a 30-minute infusion at a dose of 175 mg/m² to 43 patients with metastatic breast cancer. The second trial utilized a dose of 300 mg/m² as a 30-minute infusion in 63 patients with metastatic breast cancer. Cycles were administered at 3-week intervals. Objective responses were observed in both studies.
Randomized Comparative Study
This multicenter trial was conducted in 460 patients with metastatic breast cancer. Patients were randomized to receive ABRAXANE at a dose of 260 mg/m² given as a 30-minute infusion, or paclitaxel injection at 175 mg/m² given as a 3-hour infusion. Sixty-four percent of patients had impaired performance status (ECOG 1 or 2) at study entry; 79% had visceral metastases; and 76% had > 3 sites of metastases. Fourteen percent of the patients had not received prior chemotherapy; 27% had received chemotherapy in the adjuvant setting, 40% in the metastatic setting and 19% in both metastatic and adjuvant settings. Fifty-nine percent received study drug as second or greater than second-line therapy. Seventy-seven percent of the patients had been previously exposed to anthracyclines.
In this trial, patients in the ABRAXANE treatment arm had a statistically significantly higher reconciled target lesion response rate (the trial primary endpoint) of 21.5% (95% CI: 16.2% to 26.7%), compared to 11.1% (95% CI: 6.9% to 15.1%) for patients in the paclitaxel injection treatment arm. See Table 7. There was no statistically significant difference in overall survival between the two study arms.
Table 7: Efficacy Results from Randomized Metastatic
Breast Cancer Trial
|ABRAXANE 260 mg/m²||Paclitaxel Injection 175 mg/m²|
|Reconciled Target Lesion Response Rate (primary endpoint)a|
|All randomized patients||Response Rate [95% CI]||50/233 (21.5%)||25/227 (11.1%)|
|[16.19% – 26.73%]||[6.94% – 15.09%]|
|Patients who had failed combination chemotherapy or relapsed within 6 months of adjuvant chemotherapyc||Response Rate [95% CI]||20/129 (15.5%)||12/143 (8.4%)|
|[9.26% – 21.75%]||[3.85% – 12.94%]|
|a Reconciled Target Lesion Response Rate (TLRR)
was the prospectively defined protocol specific endpoint, based on independent
radiologic assessment of tumor responses reconciled with investigator responses
(which also included clinical information) for the first 6 cycles of therapy.
The reconciled TLRR was lower than the investigator Reported Response Rates,
which are based on all cycles of therapy.
b From Cochran-Mantel-Haenszel test stratified by 1st line vs. > 1st line therapy.
c Prior therapy included an anthracycline unless clinically contraindicated.
Non-Small Cell Lung Cancer
A multicenter, randomized, open-label study was conducted in 1052 chemonaive patients with Stage IIIb/IV non-small cell lung cancer to compare ABRAXANE in combination with carboplatin to paclitaxel injection in combination with carboplatin as first-line treatment in patients with advanced non-small cell lung cancer. ABRAXANE was administered as an intravenous infusion over 30 minutes at a dose of 100 mg/m² on Days 1, 8, and 15 of each 21-day cycle. Paclitaxel injection was administered as an intravenous infusion over 3 hours at a dose of 200 mg/m², following premedication. In both treatment arms carboplatin at a dose of AUC = 6 mg•min/mL was administered intravenously on Day 1 of each 21-day cycle after completion of ABRAXANE/paclitaxel infusion. Treatment was administered until disease progression or development of an unacceptable toxicity. The primary efficacy outcome measure was overall response rate as determined by a central independent review committee using RECIST guidelines (Version 1.0).
In the intent-to-treat (all-randomized) population, the median age was 60 years, 75% were men, 81% were White, 49% had adenocarcinoma, 43% had squamous cell lung cancer, 76% were ECOG PS 1, and 73% were current or former smokers.
Patients received a median of 6 cycles of treatment in both study arms.
Patients in the ABRAXANE/carboplatin arm had a statistically significantly higher overall response rate compared to patients in the paclitaxel injection/carboplatin arm [(33% versus 25%) see Table 8]. There was no statistically significant difference in overall survival between the two study arms.
Table 8: Efficacy Results from Randomized Non-Small Cell
Lung Cancer Trial (Intent-to-Treat Population)
|ABRAXANE (100 mg/m²weekly) + carboplatin
(200 mg/m²every 3 weeks)
|Overall Response Rate (ORR)|
|Confirmed complete or partial overall response, n (%)||170 (33%)||132 (25%)|
|95% CI||28.6, 36.7||21.2, 28.5|
|P-value (Chi-Square test)||0.005|
|Median DoR in months (95% CI)||6.9 (5.6, 8.0)||6.0 (5.6, 7.1)|
|Overall Response Rate by Histology|
|Carcinoma/Adenocarcinoma||66/254 (26%)||71/264 (27%)|
|Squamous Cell Carcinoma||94/229 (41%)||54/221 (24%)|
|Large Cell Carcinoma||3/9 (33%)||2/13 (15%)|
|Other||7/29 (24%)||5/33 (15%)|
|CI = confidence interval; DoR= Duration of response|
Last reviewed on RxList: 10/19/2012
This monograph has been modified to include the generic and brand name in many instances.
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