Abraxane (Paclitaxel) - Description and Clinical Pharmacology

CLINICAL PHARMACOLOGY

Mechanism of Action

ABRAXANE for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) is an antimicrotubule agent 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.

Human Pharmacokinetics

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 about 27 hours.

The drug exposure (AUCs) was dose proportional over 80 to 375 mg/m² and the pharmacokinetics of paclitaxel for ABRAXANE^® were independent of the duration of administration. At the recommended ABRAXANE clinical dose, 260 mg/m², 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; the large volume of distribution indicates extensive extravascular distribution and/or tissue binding of paclitaxel.

The pharmacokinetic data of 260 mg/m² ABRAXANE administered over 30 minutes was compared to the pharmacokinetics of 175 mg/m² paclitaxel injection over 3 hours. The clearance of ABRAXANE was larger (43%) than for the clearance of paclitaxel injection and the volume of distribution of ABRAXANE was also higher (53%). Differences in C_max and C_max corrected for dose 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, indicate that between 89% to 98% of drug is bound; the presence of cimetidine, ranitidine, dexamethasone, or diphenhydramine did not affect protein binding of paclitaxel.

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.

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 PRECAUTIONS: Drug Interactions). The effect of renal or hepatic dysfunction on the disposition of ABRAXANE^® has not been investigated.

Possible interactions of paclitaxel with concomitantly administered medications have not been formally investigated.

CLINICAL STUDIES

Metastatic Breast Carcinoma

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

Table 1: Efficacy Results from Randomized Trial

		ABRAXANE 260 mg/m2	Paclitaxel Injection 175 mg/m2
Reconciled Target Lesion Response Rate (primary endpoint) 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.
All randomized patients	Response Rate [95% CI]	50/233 (21.5%) [16.19% – 26.73%]	25/227 (11.1%) [6.94% – 15.09%]
	P-value From Cochran-Mantel-Haenszel test stratified by 1st line vs. > 1st line therapy.	0.003
Patients who had failed combination chemotherapy or relapsed within 6 months of adjuvant chemotherapyPrior therapy included an anthracycline unless clinically contraindicated.	Response Rate [95% CI]	20/129 (15.5%) [9.26% – 21.75%]	12/143 (8.4%) [3.85% – 12.94%]