WHAT IS pharmacokinetics - I thought to take the definition from wikipedia and copy here. Please read this in conjuction with Starpharma market sensitive announcement below to get an appreciation of fantastic initial phase I clinical result
Pharmacokinetics, sometimes abbreviated asPK (from Ancient Greekpharmakon "drug" andkinetikos "moving, putting in motion"; seechemical kinetics), is a branch of pharmacologydedicated to determining the fate of substances administered externally to a living organism. The substances of interest include pharmaceutical agents, hormones, nutrients, and toxins. It attempts to discover the fate of a drug from the moment that it is administered up to the point at which it is completely eliminated from the body. Pharmacokinetics describes how the body affects a specific drug after administration through the mechanisms of absorption and distribution, as well as the chemical changes of the substance in the body (e.g. by metabolic enzymes such as cytochrome P450 or glucuronosyltransferase enzymes), and the effects and routes of excretion of the metabolites of the drug.[1]Pharmacokinetic properties of drugs may be affected by elements such as the site of administration and the dose of administered drug. These may affect the absorption rate.[2] Pharmacokinetics is often studied in conjunction with pharmacodynamics, the study of a drug's pharmacological effect on the body.
A number of different models have been developed in order to simplify conceptualization of the many processes that take place in the interaction between an organism and a drug. One of these models, the multi-compartment model, gives the best approximation to reality; however, the complexity involved in using this type of model means that monocompartmental models and above all two compartmental models are the most-frequently used. The various compartments that the model is divided into is commonly referred to as the ADME scheme (also referred to as LADME if liberation is included as a separate step from absorption):
Absorption - the process of a substance entering the blood circulation.
Distribution - the dispersion or dissemination of substances throughout the fluids and tissues of the body.
Metabolization (or biotransformation, or inactivation) – the recognition by the organism that a foreign substance is present and the irreversible transformation of parent compounds into daughter metabolites.
Excretion - the removal of the substances from the body. In rare cases, some drugsirreversibly accumulate in body tissue.
The two phases of metabolism and excretion can also be grouped together under the title elimination. The study of these distinct phases involves the use and manipulation of basic concepts in order to understand the process dynamics. For this reason in order to fully comprehend the kinetics of a drug it is necessary to have detailed knowledge of a number of factors such as: the properties of the substances that act asexcipients, the characteristics of the appropriate biological membranes and the way that substances can cross them, or the characteristics of the enzyme reactions that inactivate the drug.
All these concepts can be represented through mathematical formulas that have a corresponding graphical representation. The use of these models allows an understanding of the characteristics of a molecule, as well as how a particular drug will behave given information regarding some of its basic characteristics. Such as its acid dissociation constant (pKa), bioavailability and solubility, absorption capacity and distribution in the organism.
The model outputs for a drug can be used in industry (for example, in calculatingbioequivalence when designing generic drugs) or in the clinical application of pharmacokinetic concepts. Clinical pharmacokinetics provides many performance guidelines for effective and efficient use of drugs for human-health professionals and inveterinary medicine.
DEP™ docetaxel shows intended longer duration and increased exposure
20 October 2014 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 Cmax[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 Cmax) of docetaxel is substantially (~50-100 times) lower than the Cmax of an equivalent dose of docetaxel administered as Taxotere®. The lower Cmax 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 Cmax 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. [1] Equivalent with respect to dose (mg/m2) of docetaxel. [2] Cmax is the maximum plasma concentration of the drug. [3]Plasma half-life for the purposes of these analyses is defined as the time required for the concentration of the drug to fall to half of its concentration in the blood after reaching a steady-state. [4] Taxotere® parameters based on published data (Bruno et al, 1996). [5]Area under the curve, or AUC, is a measure of total drug exposure. It is derived from plasma drug concentration and time so reflects how much and for how long a drug stays in a body.
SPL Price at posting:
64.0¢ Sentiment: Buy Disclosure: Held
