Melbourne, Australia; Starpharma Holdings Ltd (ASX: SPL, OTCQX: SPHRY) today announced it has completed preliminary analyses of the pharmacokinetics (PK) of DEP™ docetaxel from the ongoing Phase 1 human clinical trial using results from the first cycle of dosing for several patients.  

The preliminary PK findings confirm in humans a number of beneficial product features that were also seen in earlier preclinical studies. These beneficial features of DEP™ docetaxel, when compared with the reference drug, Taxotere^®, include a very substantially extended duration of exposure, greatly increased extent of total exposure to drug, and reduced peak levels of drug.

DEP™ docetaxel is Starpharma’s patented formulation of the widely used cancer drug docetaxel and utilises the Company’s proprietary dendrimers to improve its delivery. In preclinical studies DEP™ docetaxel demonstrated significantly improved anti-cancer efficacy and reduced toxicity and the current clinical trial is being conducted to assess DEP™ docetaxel in cancer patients.

Starpharma CEO, Dr Jackie Fairley, said:

“The PK profile seen with DEP™ docetaxel in humans is very pleasing. It fits very well with our preclinical data and these findings also support the likely explanations for the improved efficacy and improved tolerability previously seen with DEP™ docetaxel in animal models. It’s really pleasing to see the PK results in humans lining up so well in this respect.

To date in the trial, there have been no reports of drug-induced nausea, hair loss, fluid retention, or indeed neutropenia, which is the most important dose-limiting toxicity for Taxotere^®.”

These PK data indicate that when equivalent[1] doses of Taxotere^® and DEP™ docetaxel are intravenously administered to patients, DEP™ docetaxel results in a much greater exposure to the cancer drug, docetaxel.  This outcome could be expected to result in higher levels of exposure of cancer tissue to the drug.  This increased drug exposure is in addition to the significant cancer-tissue targeting observed with DEP™ docetaxel in preclinical studies.

In addition, the peak level (or C_max[2]) of docetaxel achieved with DEP™ docetaxel administration is lower, as intended, and exposure to docetaxel occurs over a much longer period of time, due to release of docetaxel from the dendrimer occurring gradually. This gradual release PK profile afforded by DEP™ docetaxel indicates that the dendrimer is acting as a depot for docetaxel, avoiding the initial excessive spike in plasma docetaxel levels observed following dosing with Taxotere^®.

Key findings of the pharmacokinetic analyses include:

Extended duration of exposure with DEP™ docetaxel

The plasma half-life[3] of docetaxel when administered as DEP™ docetaxel is substantially longer (~8 times on average) than the plasma half-life of the equivalent dose of the approved form of docetaxel, Taxotere^®.[4]  When compared with the initial rapid phases of docetaxel (Taxotere^®) plasma clearance, the current data show that the plasma half-life of DEP™ docetaxel is approximately 150 times longer.  Plasma half-life is a parameter used to evaluate the duration of drug level in the blood. 

The extended plasma half-life of docetaxel when administered as DEP™ docetaxel reflects the gradual release of docetaxel from the dendrimer and indicates that there is an extended duration of exposure to docetaxel compared with Taxotere^®.

Increased extent of exposure with DEP™ docetaxel

For a given dose of DEP™ docetaxel, the extent of drug exposure, measured as the Area Under the Curve[5] for total docetaxel, is ~500-800 times higher for DEP™ docetaxel than the extent of drug of exposure (AUC) for an equivalent dose of docetaxel administered as Taxotere^®.

This finding reflects the gradual release of docetaxel from the dendrimer and indicates that the DEP™ docetaxel molecule is a ‘depot’ of docetaxel (i.e., dendrimer-bound docetaxel) circulating for an extended period of time.

Reduced peak drug levels with DEP™ docetaxel

For a given dose of DEP™ docetaxel, the peak blood level (or C_max) of docetaxel is substantially (~50-100 times) lower than the C_max of an equivalent dose of docetaxel administered as Taxotere^®.  The lower C_max for docetaxel administered as DEP™ docetaxel compared to an equivalent dose of docetaxel administered as Taxotere^® avoids the sometimes problematic “spike” in drug levels (see schematic representation below). The lower C_max is due to the gradual release of docetaxel from the dendrimer).

Schematic Illustration: Drug levels over time with a dendrimer version

(e.g. DEP™ docetaxel) and reference drug alone (ie. Taxotere^®)

Docetaxel is a leading cancer drug used to treat a wide range of solid tumours including breast, lung and prostate.  It is marketed by Sanofi Aventis as Taxotere^® and generated sales in excess of US$3 billion in 2010.  

In earlier preclinical studies, Starpharma’s DEP™docetaxel demonstrated the significantly superior anti-cancer effectiveness compared to Taxotere^® across a range of important cancer types including breast, prostate, lung and ovarian cancer.  In addition, DEP™ docetaxel exhibited a lack of the severe toxicity, neutropenia, which is the most important dose-limiting side effect of Taxotere^®. Use of Starpharma’s DEP™ technology also improved the water solubility and tissue targeting of docetaxel. This improvement means that unlike Taxotere^® and other marketed formulations of docetaxel, Starpharma’s DEP™ docetaxel is also detergent (polysorbate 80) free, delivering a number of potential patient tolerability and safety advantages compared to other formulations.