Feeds:
Posts
Comments

Posts Tagged ‘Abraxane’


Author: Tilda Barliya PhD

Taxanes, are  diterpenes produced by the plants of the genus Taxus (yews), and are widely used as chemotherapy agents. Taxane agents include paclitaxel (Taxol) and docetaxel (Taxotere). The taxane class of drugs inhibit the microtubules by stabilizing GDP-bound tubulin in the microtubule, thereby inhibiting the process of cell division. Paclitaxel (trade name Taxol) is dissolved in Cremophor EL and ethanol, as a delivery agent and much of the clinical toxicity of paclitaxel is associated with the solvent Cremophor EL in which it is dissolved.

Albumin-bound paclitaxel (trade name Abraxane, also called nab-paclitaxel) is an alternative formulation where paclitaxel is bound to albumin nano-particles (particle size of approximately 130 nanometers). nab-Paclitaxel utilises the natural properties of albumin to reversibly bind paclitaxel, transport it across the endothelial cell and concentrate it in areas of tumour. The proposed mechanism of drug delivery involves, in part, glycoprotein 60-mediated endothelial cell transcytosis of paclitaxel-bound albumin and accumulation in the area of tumor by albumin binding to SPARC (secreted protein, acidic and rich in cysteine).

When evaluating paclitaxel vs the albumin-bound paclitaxel in Pharmacokinetics (PK) clinical trials, few important questions are raised:

  • What is the total paclitaxel?
  • How much  FREE  paclitaxel is generated by each type of drug (Taxol vs Abraxane)?
  • Do they have a linear or non-linear PK curves?

 

Few differences between Taxol (paclitaxel) and Abraxane (albumin-bound paclitaxel) are:

  • Time of administration; Taxol (3hrs) and Abraxane (30min)
  • PK curves; Taxol (non-linear and therefore less predictable) and Abraxane (linear and therefore more predictable)
  • Doses; Taxol (175 mg/m2) and Abraxane (260 mg/m2)

These differences affect the analysis of the results obtained from many clinical trials conducted in multiple clinical centers and need to be taken into consideration.

In 2006: single arm phase II safety study was conducted to support the approval of adjuvant breast cancer. The FDA published the Clinical PK Comparison of Total Paclitaxel Study c008-0
Sparreboom A. et al  Clin Cancer Res 2005; 11:4136-4143
Study Design:
  • Randomized, Phase 3, open label
  • Sample size: 460 patients
  • 70 sites: Russia (77%), UK (15%), Canada and US (9%)
  • 2 Arm: Abraxane 260 mg/m2 as a 30-minute infusion and Taxol 175 mg/m2  as a 3-hour infusion
  • 59% second line or greater and 77% previous anthracycline exposure
  • Designed to show non inferiority in RR
Parameter

(mean ± %CV)

Abraxane

260 mg/m2

(n=14)

Taxol

175 mg/m2

(n=12)

Abraxane/taxol

Ratio

Abraxane*

Dose-adjusted

(n=14)

 

Taxol*

Dose-adjusted

(n=12)

Abraxane/taxol

Ratio

Cmax

(ng/ml)

22969 3543 6.5 x 89 20 4.4 X
AUC0-∞

(ng-hr/ml)

14789 12603 1.17 x 57 72 0.80 x
CL

(L/hr*m2)

21 15 1.43 x

(43%)

21 15 1.43 x

(43%)

Vz

(L/m2)

664 433 1.53 x

(53%)

664 433 1.53 x

(53%)

FREE paclitaxel was NOT measured!!!!

Toxicity profile:

  • Taxol has a higher incidence of neutropenia and hypersensitivity reactions
  • Abraxane has a higher incidence of peripheral neuropathy, nausea, vomiting, diarrhea and asthenia

Overall Survival:

  • There was no difference in overall survival between the Abraxane and Taxol treatment groups. HR (Abraxane/Taxol) was 0.90, p=0.348 (log rank).
  • No conclusions can be drawn from a subgroup analysis when the main analysis was not statistically significant.
  • Multiple subgroup analyses using different criteria without p value adjustments
  • P-values are not interpretable

 

In the presentation at the American Society of Clinical Oncology (ASCO) meeting in Chicago, many eyebrows have been raised over Abraxane vs Paclitaxel study (http://www.pharmatimes.com/article/12-06 05/Eyebrows_raised_at_ASCO_over_Abraxane_vs_paclitaxel_study.aspx)

The Phase III study enrolled 799 patients with locally advanced or metastatic breast cancer who were randomised to receive one of the three therapies – paclitaxel (the standard of care), Abraxane (nanoparticle albumin bound -‘nab’ – paclitaxel) or Ixempra (ixabepilone) – on a weekly basis with each cycle consisting of three weeks of treatment followed by a one-week break. Some 98% of patients also received Roche’s Avastin (bevacizumab), which had its approval for breast cancer revoked by the US Food and Drug Administration in November 2011.

The data from the study, presented at ASCO by lead investigator Hope Rugo at the University of California, San Francisco, stated that median progression-free survival was 10.6 months for those receiving paclitaxel, 9.2 months for nab-paclitaxel, and 7.6 months for ixabepilone.       Abraxane was NO better than paclitaxel !  The major surprise was over the  150mg high does chosen for the Abraxane arm, well above the 100mg for which Abraxane is approved in over 40 or so countries,

However, when searching the literature and evaluating multiple publications, Abraxane seems to be more efficacious over Taxol

Benefits of Abraxane vs. Taxol or Onxal are:
– more effective at treating tumors because a higher dosage can be delivered.
– decrease in side effects from solvent related hypersensitivity reactions.
– decreased use of medications to combat the solvent related hypersensitivity reactions.
– decreased time of administration.

 

In summary,

Abraxane (the albumin-bound paclitaxel) seems to have better benefits over the free paclitaxel as stated above. However, due to the differences in PK properties and lack of FREE drug measurements, more clinical studies needs to be conducted in order the understand the true values and differences between the two drug.

 

 

 

Read Full Post »