The taxanes play an important role in treating adjuvant and metastatic breast cancer, but difficulties with their formulation have prompted research into alternative formulations. Abraxane has recently gained a favourable EMEA opinion for treating metastatic breast cancer
Pharmacy Clinical Trials Manager
Christie Hospital NHS Foundation Trust
The production unit can be likened to a workshop. The taxanes play an important role in the treatment of both adjuvant and metastatic breast cancer. However, the hydrophobic nature of taxanes makes formulation difficult causing problems with solubility and the vehicles used to overcome this are thought to be responsible for increased risk of hypersensitivity reactions. This has led to research into alternative formulations with reduced hypersensitivity and improved efficacy. Abraxane (ABI-007, nab-paclitaxel) has recently gained a favourable opinion from the EMEA for the treatment of metastatic breast cancer.
Formulation of paclitaxel
Standard formulations of paclitaxel contain polyethoxylated castor oil (Cremophor) as an excipient. The dose of Cremophor administered with paclitaxel at standard doses is high, at around 25ml (compared to approximately 5ml for other drugs formulated with it, such as etoposide). Although premedication with corticosteroids and antihistamines is standard practice, 1.5-3% of patients still experience severe hypersensitivity reactions.
Other disadvantages of this formulation are that Cremophor entraps paclitaxel in micelles formed in the plasma compartment. This leads to alteration of paclitaxel pharmacokinetics, possibly leading to a lack of dose-dependent antitumour activity. This entrapment of molecules may also affect other coadministered drugs. Cremophor also inhibits the transportation of albumin across endothelial cells, a process mediated by the gp60 receptor. Additionally Cremophor leaches plasticisers from administration systems, leading to the requirement for non-PVC equipment and inline filters.
Abraxane is a novel, solvent-free, albumin-bound nanoparticle form of paclitaxel designed to preferentially deliver paclitaxel to tumours by interacting with albumin receptors that mediate drug transport. The use of nanoparticles increases the solubility of poorly soluble drugs, and may allow targeting of some agents. Albumin is a naturally occurring vehicle for poorly soluble drugs. Binding paclitaxel to nanoparticles of albumin has been shown to produce a 4.5-fold increase in paclitaxel transport across endothelial cells for Abraxane. Additionally, SPARC (secreted protein, acidic and rich in cysteine), another albumin-binding protein expressed by tumour cells and secreted into the interstitium, is known to be overexpressed in breast cancer. This may account for preferential accumulation of albumin-bound drug at tumour sites.
The formulation of Abraxane allows it to be administered at significantly higher doses than standard paclitaxel. A phase I study established a maximum tolerated dose (MTD) of 300mg/m2. No hypersensitivity was observed. Antitumour activity at the MTD was confirmed in a phase II study. However, 25% of patients required dose reductions due to toxicity, notably neutropenia. The pivotal phase III study5 used a reduced dose of 260mg/m2 over 30 minutes every 21 days. This has become the licensed dose for Abraxane.
Abraxane has been shown to produce significantly higher response rates when compared with standard paclitaxel5 in advanced or metastatic breast cancer. The efficacy of Abraxane is summarised in Table 1.
Abraxane 260mg/m2 has a similar side-effect profile to standard paclitaxel 175mg/m.2, Hypersensitivity was not seen in the phase III study despite the lack of premedication and the reduced infusion time. However, postmarketing surveillance from other countries has noted the rare incidence of severe hypersensitivity reactions.
There is no mention of how to deal with extravasation of Abraxane in either the US9 or the EU1 datasheet, so one should assume this should be treated in the same manner as for standard paclitaxel. The most common side-effects of treatment with Abraxane are listed in Table 2.
Abraxane has been shown to exhibit linear pharmacokinetics over the dose range 135-300mg/m2, becoming nonlinear at higher doses. Standard paclitaxel has nonlinear pharmacokinetics, thought to be a result of the presence of Cremophor on the formulation. The major difference between the two agents is that Abraxane has approximately 50% higher plasma clearance and a higher volume of distribution. The high volume of distribution indicates widespread distribution and binding to tissue and extravascular proteins.
As expected, both formulations show the Cmax immediately after the end of infusion and have similar terminal half-lives (21 hours for Abraxane, 20 hours for paclitaxel). Due to the increased dose the Cmax for Abraxane was 6.5 times higher than for standard paclitaxel. However, there is little difference in the AUC. This may be explained by the formulation of Abraxane allowing rapid distribution out of the vascular compartment.
Abraxane has extensive nonrenal clearance less than 4% of unchanged drug is recovered from the urine. The principal methods of elimination are hepatic metabolism and biliary excretion.
Abraxane is presented as a white to yellow powder for suspension for infusion containing 100mg human albumin-bound paclitaxel bound per vial. It should be handled in accordance with local guidelines for handling cytotoxic drugs.
Each vial of Abraxane should be reconstituted with 20ml sodium chloride 0.9% to produce a 5mg/ml solution. Due to the risk of foaming the product requires careful handling and standing time to allow subsidence of foam.
The final solution requires no further dilution and should be added to an empty PVC bag. Inline filters should not be used during administration. Ideally, the prepared product should be used immediately, but must be used within eight hours of preparation and stored at a temperature below 25°C.
Abraxane should be infused over 30minutes. Care should be taken when calculating the infusion rate as the final volume of solution to be administered is not standard.
Abraxane appears to have many advantages for the treatment of patients with metastatic breast cancer. It has shown improved efficacy and reduced incidence of side-effects. It is a more convenient preparation to administer due to the reduced infusion time and absence of need for non-PVC equipment and inline filters.
1. European Medicines Evaluation Agency website: www.EMEA.europa.eu
2. Sparreboom A, et al. Paclitaxel repackaged in an albumin-stabilized nanoparticle: handy or just a dandy? J Clin Oncol 2005;23(31):7765-7.
3. Nyman DW, Campbell KJ, Hersh E, et al. Phase I and pharmacokinetics trial of ABI-007, a novel nanoparticle formulation of paclitaxel in patients with advanced nonhematologic malignancies. J Clin Oncol 2005;23(31):7785-93.
4. Sparreboom A, Scripture CD, Trieu V, et al.
Comparative preclinical and clinical pharmacokinetics of a Cremophor-free, nanoparticle albumin-bound paclitaxel (ABI-007) and paclitaxel formulated in Cremophor (taxol). Clin Cancer Res 2005;11(11):4136-43.
5. Gradishar WJ, Tjulandin S, Davidson N, et al. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol 2005;23(31):7794-803.
6. Adcock H. Using nanotechnology to improve drug therapy: what is all the fuss about? Pharm J 2003;271:362.
7. Ibrahim NK, Desai N, Legha S, et al. Phase I and pharmacokinetic study of ABI-007, a Cremophor-free, protein-stabilized, nanoparticle formulation of paclitaxel. Clin Cancer Res 2002;8:1038-44.
8. Ibrahim NK, Samuels B, Page R, et al. Multicenter phase II trial of ABI-007, an albumin-bound paclitaxel in women with metastatic breast cancer. J Clin Oncol 2005;23(25):6019-25.
9. Abraxane Pharmaceutical Information (US). Schaumburg (IL): Abraxis Oncology; 2005 Jan 7.