Using Genotoxicity Tests to Push Drug Development Forward



Pharma IQ
09/14/2010


When it comes to the production of quality drugs and medicines, safety is arguably the fundamental concern of pharmaceutical companies based across the globe.

So many of the regulatory standards and guidelines put in place by authorities such as the US Food and Drug Administration are there to ensure that every possible test has been carried out and all products are suitable for public use. There could be major consequences if such evaluations are not carried out and after all, one of the key aims of all drug developers is to ensure that all of their research projects become both safe and profitable.

Tests for genotoxic and carcinogenic impurities play a key role in this respect, as they can be used to assess the safety of drug ingredients and produce data that can be used to support applications for regulatory approval.

[inlinead]

Such assessments are a fundamental part of drug development, with research organisations focusing on ensuring that they can accurately produce information that shows carcinogens and genotoxins are not present in their latest work. The importance of testing for such impurities was recently highlighted by global pharmaceutical firm Merck, which has published details on its new oral antifungal agent named Posaconazole.

The company's latest update on the agent revealed it is hoping to launch a Phase II clinical study to discover whether the compound would be suitable for the treatment of chronic Chagas disease, which can occur in regions where biting insects are common. Regarded by the World Health Organisation as a neglected tropical disease, there are only two drugs approved for treatment despite the massive impact of the condition on people in Latin American countries.

Dr. Roger J Pomerantz, global franchise head for infectious diseases and senior vice-president of Merck Research, said: "While significant progress has been made in recent years in the prevention of the transmission of this potentially life-threatening disease, no new drugs have been approved for the treatment of chronic Chagas disease in over three decades."

While Merck is looking ahead to the future of Posaconazole, plenty of work has already been carried out to test its safety in relation to a range of other factors.  One area which the research has touched upon is carcinogenicity and genotoxicity.

A two-year carcinogenicity study was carried out on the drug, which saw female and male rats given it orally at doses up to 20 and 30mg/kg respectively. According to Merck, the doses were equivalent to 3.9 or 3.5 times the exposure achieved with a 400mg BID regimen.

During the research, no drug-related neoplasms were recorded in the animals, while Posaconazole was also found to not be genotoxic or clastogenic when evaluated in line with bacterial mutagenicity. Best known as Ames testing, such studies assess the mutagenetic activity in chemicals and whether they pose a risk of causing cancer in subjects.

The drug also passed a chromosome aberration study in human peripheral blood lymphocytes, a Chinese hamster ovary cell mutagenicity and a mouse bone marrow micronucleus study.

All of the information on the previous tests that Posaconazole has had to go through, despite only just approaching the Phase II point of the development, showcases how seriously issues related to drug safety are taken by Merck and the pharmaceutical industry as a whole.

Consideration of the issue has become a vital cog in the machinery of the sector, ensuring that all items which consumers see on the shelves of their local pharmacies meet good quality standards and are completely safe for use. With Merck and other drug development firms being so transparent over their use of such assessment policies, it is likely that such high standards will be maintained for a long time to come.