Nanoparticle Albumin-bound Paclitaxel: a Novel Cremphor-EL®-free Formulation of Paclitaxel

Thomas E Stinchcombe

Disclosures

Nanomedicine. 2007;2(4):415-423. 

In This Article

Abstract and Introduction

Abstract

Standard formulation paclitaxel requires the use of solvents, such as Cremphor-EL®, which contribute to some of the toxicities commonly associated with paclitaxel-based therapy. Nanoparticle albumin-bound paclitaxel (nab™-paclitaxel) is a novel solvent-free formulation of paclitaxel. The formulation is prepared by high-pressure homogenization of paclitaxel in the presence of serum albumin into a nanoparticle colloidal suspension. The human albumin-stabilized paclitaxel particles have an average size of 130 nm. Nab-paclitaxel has several practical advantages over Cremphor-EL-paclitaxel, including a shorter infusion time (30 min) and no need for premedications for hypersensitivity reactions. The nab-paclitaxel formulation eliminates the impact of Cremphor-EL on paclitaxel pharmacokinetics and utilizes the endogenous albumin transport mechanisms to concentrate nab-paclitaxel within the tumor. A recent Phase III trial compared nab- and Cremphor-EL-paclitaxel in patients with metastatic breast cancer. Patients treated with nab-paclitaxel experienced a higher response, longer time to tumor progression and, in patients receiving second-line or greater therapy, a longer median survival. Patients treated with nab-paclitaxel had a significantly lower rate of severe neutropenia and a higher rate of sensory neuropathy. The preclinical and clinical data indicate that the nab-paclitaxel formulation has significant advantages over Cremphor-EL-paclitaxel.

Introduction

Paclitaxel was first identified as a crude extract from the bark of the North American pacific yew tree, Taxus brevifolia, and was subsequently found to have antineoplastic activity against a wide variety of malignancies.[1] Paclitaxel binds to tubulin, causing the development of excessively stable, nonfunctional microtubules. The development of these stable microtubules effectively inhibits mitosis, motility and intracellular transport within malignant cells.[2,3] Paclitaxel has been approved by the US FDA for the treatment of breast cancer, ovarian cancer and non-small-cell lung cancer (NSCLC). While highly effective, paclitaxel has several burdensome side effects, including hypersensitivity reactions, peripheral neuropathy, arthalgias, myalgias and neutropenia.[4,5] Paclitaxel is highly hydrophobic, and commercially available formulations require polyoxyethylated castor oil, Cremphor EL® (CrEL), and an ethanol vehicle to allow parental administration. The amount of CrEL required for paclitaxel is significantly higher than for other drugs containing CrEL.[6] The CrEL is responsible for the hypersensitivity reactions seen with paclitaxel and may contribute to the development of neuropathy.[7,8] The presence of the CrEL requires premedication with antihistamines and corticosteroids to prevent hypersensitivity reactions and, despite these premedications, approximately 40% of all patients will have minor reactions (e.g., flushing and rash) and 3% will have life-threatening reactions.[9,10] CrEL also causes leaching of the plasticizers from polyvinyl chloride (PC) bags and infusions sets, thus paclitaxel must be prepared and infused using non-PVC infusion systems and in-line filtration.

Nanoparticle albumin-bound paclitaxel (nab™-paclitaxel; ABI-007; Abraxane®) is a novel CrEL-free formulation of paclitaxel. This formulation is prepared by high-pressure homogenization of paclitaxel in the presence of serum albumin, resulting in a nanoparticle colloidal suspension.[11] The albumin concentration is 3-4%, which is similar to the albumin concentration in the blood.[12] The human albumin-stabilized paclitaxel particles have an average size of approximately 130 nm, which allows intravenous infusion without the risk of capillary blockage.[6]Nab-paclitaxel can be reconstituted in normal saline at concentrations of 2-10 mg/ml compared with 0.3-1.2 mg/ml for CrEL-paclitaxel; therefore, the volume and infusion time are reduced.[11] The nab-paclitaxel formulation provides several practical advantages over CrEL-paclitaxel: premedications for hypersensitivity reactions are not required, the infusion time is shorter (30 min for nab-paclitaxel vs 3 h for CrEL-paclitaxel) and conventional infusion equipment may safely be used since there is no danger of leaching plasticizers from infusion bags or tubing.

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