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Abraxane

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Abraxane

CLINICAL PHARMACOLOGY

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.

Pharmacokinetics

Absorption

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.

Distribution

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.

Metabolism

In vitro studies with human liver microsomes and tissue slices showed that paclitaxel was metabolized primarily to 6αhydroxypaclitaxel 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].

Excretion

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 11 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 11: Exposure (AUC0-∞) of ABRAXANE Administered Intravenously over 30 Minutes in Patients with Hepatic Impairment

  Mild
(n=5)
Moderate
(n=5)
Severea
(n=5)
Dose 260 mg/m² 200 mg/m² 130 mg/m²
AUCinf (hr*ng/mL)
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 and ABRAXANE and Carboplatin

Administration of carboplatin immediately after the completion of the ABRAXANE infusion to patients with NSCLC did not cause clinically meaningful 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.

Pharmacokinetic Interactions between and ABRAXANE and Gemcitabine

Pharmacokinetic interactions between ABRAXANE and gemcitabine have not been studied in humans.

Clinical Studies

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 12. There was no statistically significant difference in overall survival between the two study arms.

Table 12: 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%) [16.19% – 26.73%] 25/227 (11.1%) [6.94% – 15.09%]
p-valueb 0.003
Patients who had failed combination chemotherapy or relapsed within 6 months of adjuvant chemotherapyc Response Rate [95% CI] 20/129 (15.5%) [9.26% – 21.75%] 12/143 (8.4%) [3.85% – 12.94%]
aReconciled 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.
bFrom Cochran-Mantel-Haenszel test stratified by 1st line vs. > 1st line therapy.
cPrior 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 major 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 13]. There was no statistically significant difference in overall survival between the two study arms.

Table 13: Efficacy Results from Randomized Non-Small Cell Lung Cancer Trial (Intent-to-Treat Population)

  ABRAXANE (100 mg/m² weekly) + carboplatin
(N=521)
Paclitaxel Injection (200 mg/m² every 3 weeks) + carboplatin
(N=531)
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

Adenocarcinoma of the Pancreas

A multicenter, multinational, randomized, open-label study was conducted in 861 patients comparing ABRAXANE plus gemcitabine versus gemcitabine monotherapy as first-line treatment of metastatic adenocarcinoma of the pancreas. Key eligibility criteria were Karnofsky Performance Status (KPS) ≥ 70, normal bilirubin level, transaminase levels ≤ 2.5 times the upper limit of normal (ULN) or ≤ 5 times the ULN for patients with liver metastasis, no prior cytotoxic chemotherapy in the adjuvant setting or for metastatic disease, no ongoing active infection requiring systemic therapy, and no history of interstitial lung disease. Patients with rapid decline in KPS ( ≥ 10%) or serum albumin ( ≥ 20%) during the 14 day screening period prior to study randomization were ineligible.

A total of 861 patients were randomized (1:1) to the ABRAXANE/gemcitabine arm (N=431) or to the gemcitabine arm (N=430). Randomization was stratified by geographic region (Australia, Western Europe, Eastern Europe, or North America), KPS (70 to 80 versus 90 to 100), and presence of liver metastasis (yes versus no). Patients randomized to ABRAXANE/gemcitabine received ABRAXANE 125 mg/m² as an intravenous infusion over 30-40 minutes followed by gemcitabine 1000 mg/m² as an intravenous infusion over 30-40 minutes on Days 1, 8, and 15 of each 28-day cycle. Patients randomized to gemcitabine received 1000 mg/m² as an intravenous infusion over 30-40 minutes weekly for 7 weeks followed by a 1-week rest period in Cycle 1 then as 1000 mg/m² on Days 1, 8 and 15 of each subsequent 28-day cycle. Patients in both arms received treatment until disease progression or unacceptable toxicity. The major efficacy outcome measure was overall survival (OS). Additional outcome measures were progression-free survival (PFS) and overall response rate (ORR), both assessed by independent, central, blinded radiological review using RECIST (version 1.0).

In the intent to treat (all randomized) population, the median age was 63 years (range 27-88 years) with 42% ≥ 65 years of age; 58% were men; 93% were White and KPS was 90-100 in 60%. Disease characteristics included 46% of patients with 3 or more metastatic sites; 84% of patients had liver metastasis; and the location of the primary pancreatic lesion was in the head of pancreas (43%), body (31%), or tail (25%).

Results for overall survival, progression-free survival, and overall response rate are shown in Table 14.

Table 14: Efficacy Results from Randomized Study in Patients with Adenocarcinoma of the Pancreas (ITT Population)

  ABRAXANE(125 mg/m²) and gemcitabine
(N = 431)
Gemcitabine
(N = 430)
Overall Survival
Number of deaths, n (%) 333 (77) 359 (83)
  Median Overall Survival (months) 8.5 6.7
  95% CI 7.9, 9.5 6.0, 7.2
  HR (95% CI)a 0.72 (0.62, 0.83)
P-valueb < 0.0001
Progression-free Survivalc
Death or progression, n (%) 277 (64) 265 (62)
  Median Progression-free Survival (months) 5.5 3.7
  95% CI 4.5, 5.9 3.6, 4.0
  HR (95% CI)a 0.69 (0.58, 0.82)
  P-valueb < 0.0001
Overall Response Ratec
Confirmed complete or partial overall response, n (%) 99 (23) 31 (7)
  95% CI 19.1, 27.2 5.0, 10.1
  P-valued < 0.0001
CI = confidence interval, HR = hazard ratio of ABRAXANE plus gemcitabine / gemcitabine, ITT = intent-to-treat population.
aStratified Cox proportional hazard model.
bStratified log-rank test stratified by geographic region (North America versus Others), Karnofsky performance score (70 to 80 versus 90 to 100), and presence of liver metastasis (yes versus no).
cBased on Independent Radiological Reviewer Assessment.
dChi-square test.

In exploratory analyses conducted in clinically relevant subgroups with a sufficient number of subjects, the treatment effects on overall survival were similar to that observed in the overall study population.

Figure 1: Kaplan-Meier Curve of Overall Survival (Intent-to-treat Population)

Kaplan-Meier Curve of Overall Survival - Illustration

Last reviewed on RxList: 9/19/2013
This monograph has been modified to include the generic and brand name in many instances.

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