Posts Tagged ‘side effects’

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

(mean ± %CV)


260 mg/m2



175 mg/m2















22969 3543 6.5 x 89 20 4.4 X


14789 12603 1.17 x 57 72 0.80 x


21 15 1.43 x


21 15 1.43 x




664 433 1.53 x


664 433 1.53 x


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 ( 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 »

Reported & Curated by: Dr. Venkat S. Karra, Ph.D.

Predicting Potential Cardiac Events

One of the leading causes of drug attrition during development is cardiac toxicity, which has a serious impact on cost and can impact getting new drugs to patients. Detecting cardiovascular safety issues earlier in the drug development program would produce significant benefits for pharmaceutical companies and, ultimately, public health.

Comprehensive cardiovascular and electrophysiology assessments are routinely conducted in vivo and in vitro early in the preclinical or lead optimization phases of drug development. For example, the isolated perfused guinea pig heart preparation (classically called the Langendorff preparation) can be used to screen a series of related new chemical entities (NCE) in the lead optimization phase for preliminary information on the relative effects on contractility and rhythm. Additionally, intact animal non-GLP studies—generally conducted in anesthetized, non-recovery models—are designed to assess effects of NCEs on a range of acute hemodynamic and cardiac parameters such as heart rate, blood pressure, electrocardiogram (ECG), ventricular contractility, vascular resistance, cardiac output, etc. These studies employ small numbers of animals, but by allowing scientists to terminate research into NCEs with obvious cardiovascular side effects, they can eliminate the need for larger animal studies later in the development process. These preparations also provide information on the involvement of the autonomic nervous system in the cardiovascular responses of the NCE. Such effects can be important determinants in the total cardiovascular response to an NCE, and this information cannot be obtained with any known in vitro method.

The ICH S7A and ICH S7B guidelines provide guidance on important physiological systems and assessment of pharmaceuticals on ventricular repolarization and proarrhythmic risk. The guidelines were designed to protect patients from potential adverse effects of pharmaceuticals. Since these guidelines were issued in 2000 and 2005, respectively, cardiac safety study designs have been realigned to identify potential concerns prior to administering the first dose to humans. It is now routine for all NCEs to be evaluated using an in vitro Ikr assay such as the hERG voltage patch clamp assay to assess for the potential for QT interval prolongation. Systems have evolved to screen large numbers of compounds using automated high-throughput patch clamp systems early in the lead optimization/drug discovery phase. This is a cost effective method for determining an initial go/no-go gate. Once a compound has progressed to the development phase, it can once again be assessed with the hERG assay utilizing the gold standard manual patch clamp assay.

If the NCE under investigation is a cardiovascular therapy, then pharmacological characterization should also occur early in the lead development process. In addition to some of the techniques already discussed, a variety of disease models are available to help determine if the NCE will be efficacious in a clinical setting. However sound the in vitro data used in screening and selection process (e.g., receptor-binding studies), NCEs that have been shown to be active in at least one in vivo model (e.g,. salt-sensitive Dahl rat model) have a higher likelihood of clinical success. Once a lead is identified, it should still go through the generalized safety characterization discussed earlier.

The in vivo study designs for NCEs reaching the development phase to support the Investigational New Drug (IND) application (just prior to the first human dose) require acquisition of heart rate, blood pressure, and ECG data using an appropriate species at and above clinically relevant doses.

The trend in the industry for these regulatory-driven studies has been to utilize animals surgically instrumented with telemetry devices that can acquire the required parameters. The advantage of using instrumented animals over anesthetized animals is that data can be acquired from freely moving animals over greater periods of time without anesthetic in the test system, which has the potential to confound and perturb results interpretation. Appropriate dose selection relative to those used in the clinic provides valuable information about potential acute cardiac events and how they may impact trial participants.

Animal studies
Telemetry-instrumented animals can be used as screening tools earlier in the drug selection phase. Colonies of animals that can be reused, following a suitable wash-out period, provide an excellent resource for screening compounds to detect unwanted side effects. The use of these animals coupled with recent advances in software-analysis systems allow for rapid data turnaround, which enables scientists to quickly determine if there are any potentially unwanted signals. If any effects are detected on, for example, blood pressure or QT interval, then the decision to either shelve the drug or conduct additional studies can be made before advancing any further in the developmental phase.

Interestingly, the experience that has been acquired since the approval of the ICH guidelines has allowed pharmaceutical companies to temper their response to finding a potentially unwanted signal. Rather than permanently shelve libraries of compounds that, for example, were found to be positive in the hERG assay—common practice when the 2005 guidelines came into being—companies can now determine a risk potential based on knowledge gained with the intact animal studies.

Similarly, if changes in hemodynamic parameters are detected, there are follow-up experiments employing anesthetized or telemetry models that include additional measurements like left ventricular pressure. These experiments can be utilized to further assess their potential clinical impact by examining effects on myocardial contractility, relaxation, and conduction velocity.

These techniques primarily address acute effects: those following a single exposure. Chronic effects—those seen with long-term administration of the NCE to an intact organism—are difficult to obtain in early development, but are routinely monitored during safety studies, which are conducted non-clinically during Phase 1 and 2 of the development process. ECGs typically are collected to evaluate the chronic cardiac effects in non-rodent species during these studies. While traditional ECGs can be taken, it is recommended that JET (jacketed external telemetry) techniques, which permit the recording of ECG’s—but not blood pressure—in freely moving animals, be applied. If chronic effects are discovered, follow-up experiments can be conducted with any of the techniques mentioned in this article.

As the focus on cardiac safety has matured over the last 10 years, the Safety Pharmacology Society has led efforts to establish an approach to determine best practices for conducting key preclinical cardiovascular assessments in drug development. From this, the hope is to provide sensitive preclinical assays that can detect high-probability safety concerns. Parallel efforts have been made to more accurately assess the translation of preclinical cardiovascular data into clinical outcomes and to encourage collaborations between preclinical and clinical scientists involved in cardiac safety assessment.

This has been conducted under the umbrella of the International Life Science Institute–Health and Environmental Services Institute (ILSI-HESI) consortium, which has bought together industrial, academic, and government scientists to discuss and determine what steps are necessary to establish an integrated cardiovascular safety assessment program. The goal is to provide better ways of predicting potential adverse events, allowing for earlier detection of cardiovascular safety issues and reducing the number of clinical trial failures.

Another possibility is genetic testing to determine the likelihood of stroke, for example Corus CAD is a shoebox-size kit that uses a simple blood draw to measure the RNA levels of 23 genes. Using an algorithm, it then creates a score that determines the likelihood that a patient has obstructive coronary artery disease.

“By providing Medicare beneficiaries access to Corus CAD, this coverage decision enables patients to avoid unnecessary procedures and risks associated with cardiac imaging and elective invasive angiography, while helping payers address an area of significant healthcare spending,” CardioDx President and CEO David Levison said in a press release.

Read Full Post »