Study Helps Stop Drugs Slipping Through Safety Net

Growing use of pharamacogenetics will not just reduce side effects, but also speed up the process of drug development by helping eliminate unsuitable candidates at an earlier stage and enable researchers to concentrate on the most promising compounds. The potential benefits are therefore enormous, with pharmacogenetics playing a major role in the emerging era of personalized medicine where drugs and treatments are increasingly tailored to the circumstances and genetic makeup of individuals and sub-groups within populations. It will complement existing methods, in particular animal testing, which although valuable sometimes fails to identify critical side effects that may be caused by individual genetic traits, or combinations of genes specific to the human species as a whole.

"It was confirmed by the conference that we need to ensure we have the appropriate study designs including randomised controlled trials to unravel the complexity of variable drug responses, and we need to embrace the new technologies such as whole genome scans to identify novel and known genetic predisposing factors," said the conference chair Munir Pirmohamed from the University of Liverpool in the UK.

Side effects can be caused by many factors relating to drug transport, immune response, and sometimes unexpected metabolic pathways, but as Pirmohamed noted, they fall into two main categories, type A and type B. "The majority (80-90%) of adverse drug reactions are type A – they are predictable from the known pharmacology of the drug, are dose-dependent, and can be alleviated by reducing or identifying the correct dose for the patient," said Pirmohamed, who gave the example of the anti-coagulant warfarin, widely used to prevent thrombosis in susceptible patients by inhibiting blood clotting. But without any blood clotting, patients would sooner or later bleed to death, so clearly warfarin must be given in the correct dose, finding the tight window between dangerous clotting and unstoppable bleeding. The point is that the correct dose varies between individuals, and this is where pharamacogenetics comes in. "Genetic factors can be important here," said Pirmohamed. While Type A reactions can often be picked up in animal testing or from general clinical analysis before human trials begin, pharmacogenetics has an important future role to play in establishing the correct dose for individuals.

Type B accounts for most the remaining 10%-20% of adverse drug reactions, including a variety of bizarre or unexpected responses that may be genetically dependent or alternatively shared by all people who take the drug.

Animal testing and other existing methods are much less successful at identifying Type B reactions however, which are more likely to go undetected until human trials begin. Indeed pharmacogenetics will also play an important role in uncovering these potentially lethal Type B reactions, including those involving the immune system's memory cells.

"The immune system is important in adverse reactions, and this conference did focus on certain aspects of predisposition to immune mediated reactions," said Pirmohamed. There was particular interest in the role of the HLA (Human Leukocyte Antigen) system, which directs the production and operation of immunity proteins, and is the source of the individual variation in immune response that leads both to population-wide protection against disease, and rejection of incompatible blood, tissue, or donated organs. This variation in HLA genes can also cause adverse reactions to certain drugs in some individuals but not others, leading in some cases to liver damage for example. "It is clear from the conference, and from the findings over the last few years, that the HLA system plays a major role in predisposing to certain immune mediated adverse reactions," said Pirmohamed.

Some drugs cause adverse reactions much more commonly among particular ethnic groups, resulting from particular alleles of HLA genes whose selection has been favoured by conditions in a given part of the world. One example is the anticonvulsant drug carbamazepine used to treat epilepsy, which can cause Stevens-Johnson syndrome. This is a severe allergic reaction causing skin rashes and lesions.

The ESF conference set the stage for developing methods of identifying such adverse reactions in advance by seeking associations between genes that may indicate where unexpected problems or severe reactions may occur. In particular it helped identify future targets and research objectives, said Pirmohamed.

"As with any other conference, the aim is for world class scientists to present their latest work, and for the audience to then consider whether it would be appropriate to incorporate particular techniques or methodologies into their work, and to individually decide how to do it. I know for many attendees, this did happen. It certainly did for me!"

The ESF/University of Barcelona conference, Pharmacogenetics and Pharmacogenomics: Adverse Drug Reactions, was held in the Costa Brava, Spain, in July 2008.