Pharmacogenetic Profiling Assays (e.g. MDR1, CYP3A4, CYP2D6)
A drug’s effect depends on its concentration at the site of action. Since this in turn is influenced by the transport and metabolism of the drug, EPIDAUROS has developed a whole range of proprietary tests to detect polymorphisms in drug transporters and metabolizing enzymes.
One of these pharmacogenetic profiling assays, the MDR1 gene test, checks for a specific polymorphism in the drug transporter gene MDR1. The multi-drug resistance gene (MDR1) encodes P-glycoprotein that is responsible for the transport of more than 30% of all drugs and the majority of anti-cancer drugs. P-glycoprotein occurs in different tissues in the body, including the epithelial cells of the intestine, the tubuli of the kidney, and lymphocytes. Its primary task is to protect cells from toxic substances. EPIDAUROS has identified more than 50 polymorphisms in the MDR-1 gene. EPIDAUROS and its collaboration partners at the Institute of Clinical Pharmacology in Stuttgart and the University Hospital Charité in Berlin found in clinical studies that there is a causal correlation between one particular genetic variation (polymorphism) in the MDR1 gene and P-glycoprotein expression. This variable P-glycoprotein expression influences the uptake of drugs such as digoxin from the intestine into the blood and, in turn, their therapeutic effect (Proc. Natl. Acad. Sci. USA 2000; 97 (7):3473-3478). This polymorphism involves a single base change and patients with the TT-genotype showed lower amounts of P-glycoprotein expression and thus higher digoxin plasma levels than patients with the CC-genotype.
EPIDAUROS and its collaboration partners have further demonstrated that a low expression of MDR1 in the kidney represents a risk factor in the etiology of renal cell carcinoma. A low MDR1 expression results in higher concentrations of toxic and carcinogenic substances in the kidney since it takes longer to clear them.
A Swiss HIV Cohort Study (Lancet 2002;359:30-6) demonstrated that this particular polymorphism in the MDR1 gene also influences the therapeutic effect of protease and reverse-transcriptase inhibitors, both of which are components of standard HIV therapy. It showed for the first time that the polymor-phism in the MDR1 gene substantially influences the increase of lymphocytes and thus the success of treatment. EPIDAUROS' proprietary pharmacogenetic profiling assay MDR1 therefore indicates whether a patient will benefit from treatment with protease and reverse-transcriptase inhibitors or not.
In 2000, EPIDAUROS filed a patent application for this polymorphism. EPIDAUROS possesses the exclusive license to use the MDR1 gene for pharmacogenetic tests in Europe and the United States. In the fall of 2001, EPIDAUROS and its research partners were honored with the Prix Galien Germany Award and the German Urological Society presented them with the Bard Award for their outstanding achievements in the field of drug transporters.
EPIDAUROS has also developed a wide range of pharmacogenetic profiling assays for polymorphisms in those enzymes that play a critical role in the metabolism of drugs. Several of these tests, for instance, recognize polymorphisms in the CYP 3A4 gene that plays a crucial role in the metabolism of more than 50% of all drugs. EPIDAUROS succeeded in cloning and characterizing a new CYP3A gene, called CYP3A43. The EPIDAUROS team also discovered and characterized several polymorphisms that belong to the CYP3A family. These polymorphisms cause new protein variations which produce new metabolites, and can result in adverse reactions. Other polymorphisms affect the enzyme's metabolizing activity and thus drug concentration. The CYP2D6 gene is another example of the research at EPIDAUROS. The CYP2D6 gene is responsible for the metabolism of more than 25% of all drugs. EPIDAUROS discovered a new polymorphism that regulates gene expression and therefore the metabolism of important drugs.
EPIDAUROS Services:
Support of pharmaceutical and biotechnology companies throughout the entire drug development process
· Pharmacogenetic consultation
· Genotyping of volunteers and patients for the clinical trial phase I-IV according GLP and ISO 9001
· Characterization and validation of drug targets in different ethnic groups
· Implementation EPIDAUROS PHARMACOGENETIC PROFILING ASSAYS
· Written documentation for clinical trials
Enhancement of a drug's value by increasing its benefit-risk-ratio with the help of pharmacogenetics
· Resuscitation: Approval of drugs that have failed in Phase II/III of clinical development in combination with pharmacogenetic tests
· Repositioning of drugs through identification of non-responders and patients who will show adverse reactions
