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Meds behaving badly – Exploring serious drug side-effects

13 Oct, 2009

TabletsUnwanted side-effects can be distressing, harmful and costly consequences of many common drugs. The Serious Adverse Events Consortium, an international collaboration, is leading the way in understanding the genetic background to these reactions, and has recently published its first results.

Medicines are meant to make us better, but, for a small proportion of the population, taking something as routine as a dose of aspirin or a course of antibiotics could trigger a potentially fatal reaction.

So-called serious adverse events are severely debilitating or life-threatening reactions to a normal dose of a drug, and usually require the medication to be stopped immediately.

Currently, it is almost impossible to tell which people are prone to these reactions, meaning that drug-induced serious adverse events continue to injure thousands across the world every year.

Enter the Serious Adverse Events Consortium, an international collaboration founded in August 2007 by Arthur Holden. The Consortium brings together the Wellcome Trust, medicines regulators, academic researchers and representatives from ten multinational pharmaceutical companies.

Its activities are based on the hypothesis that there is some genetic basis to drug-induced serious adverse events. Although this is little understood so far, Holden is confident about this approach.

“Serious adverse events lend themselves beautifully to genomics: their phenotypes [characteristics] are very clear, and you don’t have a lot of the complexity seen in studies that are looking for genetic links to common diseases.”

Genome screen

“The typical way to find out if genetic factors have a role in an outcome is to look in families,” says Professor Lon Cardon.

A former Wellcome Trust Principal Research Fellow and now Head of Genetics at GlaxoSmithKline, Professor Cardon sits on the Board of Directors of the Consortium. “We don’t have that option here because these adverse events are rare, and so we hardly ever see them in families.”

The involvement of genetics in these events is pure conjecture on some level, he adds, although their nature is “idiosyncratic enough” to be genetic.

He describes the results of the Consortium’s research so far1 – which show a strong link between a particular gene type and liver damage caused by the antibiotic flucloxacillin – as nothing short of remarkable.

Published in ‘Nature Genetics’, this research is the result of a genome-wide association study, an emerging technique that allows researchers to search for gene variants associated with a particular condition across the whole genome.

Drug-induced liver injury is rare, which adds an extra level of complexity to recruiting people for studies. What’s more, the cases collected need to represent people of different ethnic backgrounds, to understand the role of ethnicity in susceptibility to these events.

For the liver damage study, the Consortium used cases collected by academic researchers before the Consortium was established.

Retrospectively collected samples are not ideal: there is no set standard version of how the event under investigation is recognised and recorded in the patient’s notes, and permission to obtain and use blood samples from the patients must be sought – a potentially time-consuming and costly process.

“Serious adverse events lend themselves beautifully to genomics,” says Arthur Holden, founder of the Serious Adverse Events Consortium.

“Serious adverse events lend themselves beautifully to genomics,” says Arthur Holden, founder of the Serious Adverse Events Consortium.

To try to make sure that a particular event is defined consistently by hospital staff and researchers across the world, the Consortium is launching the Phenotype Standardization Project. It is also looking into how to achieve real-time identification of patients with a particular adverse event.

“We’re experimenting at the moment,” says Holden. “For example, we’re looking to see if we can pull patients in from pharmaceutical clinical development trials.”

He explains that, while there are sensitivities to commercial pressures, the opportunity to encourage different companies to share information on situations where these events occur, early in the process, is too good to miss.

The development of nationwide electronic patient records, as is planned for the UK, could be a massive boost to recruiting for research into serious adverse events.

It could also, Holden hopes, eventually help to prevent the events occurring. “Eventually we could be putting data into an electronic medical record before people get given drugs, to help tailor the drug both to the condition and the patient.”

In translation

How else might a better understanding of the genetics underlying serious adverse events help to prevent them happening? Well, as for many other research areas, translating laboratory findings into practice that will improve patient care is a priority for Consortium members.

Munir Pirmohamed is Professor of Clinical Pharmacology at the University of Liverpool and the NHS Chair of Pharmacogenetics. An adviser to the Consortium, he says that the translatability of its findings depends on how common and severe the individual events being studied are.

Still, he adds, the Consortium’s work could mark the first time that findings from genome-wide association studies have been translated into practical use.

Things look promising: there is already evidence that knowledge of genetic variants linked to serious adverse events can be used to help to prevent them.

In 2002, findings were published that linked certain genetic variants with susceptibility to a hypersensitivity reaction following treatment with the antiretroviral drug abacavir.

This variant, HLA-B*5701, lies on chromosome six, and is one version of a key immune gene called HLA-B. In the UK and across the EU, people are now routinely screened for the variant before being given abacavir.

The frequency of hypersensitivity reactions in those given the drug has since dropped from 5-7 per cent to less than 1 per cent.2,3,4

In its paper on flucloxacillin, the Consortium identified the same allele, HLA-B*5701, as conferring susceptibility to liver injury. However, this event occurs roughly once in 10 000 cases, so a predictive test may not be cost-effective.

“However, you could use it diagnostically, to determine if a patient’s acute liver injury is related to flucloxacillin, because of the high negative predictive value,” Professor Pirmohamed says.

“Nobody can have all the expertise, and Arthur Holden has had the foresight to bring together geneticists, clinicians, epidemiologists, academics and representatives from the pharmaceutical industry. It’s a global effort - that’s the only way we can crack this.” says Professor Munir Pirmohamed, an adviser to the Serious Adverse Events Consortium.

“Nobody can have all the expertise, and Arthur Holden has had the foresight to bring together geneticists, clinicians, epidemiologists, academics and representatives from the pharmaceutical industry. It’s a global effort – that’s the only way we can crack this.” says Professor Munir Pirmohamed, an adviser to the Serious Adverse Events Consortium.

The structure of the Consortium, now moving into its second phase, was informed by the SNP [single nucleotide polymorphism] Consortium, which Holden also organised and led. The SNP Consortium was a not-for-profit, international collaboration between the Trust, academic centres and industry established to identify common mutations in human DNA.

“For a long time, people have been discussing the need for a multi-centre, international collaboration to tackle serious adverse events,” says Professor Pirmohamed.

“Nobody can have all the expertise, and Arthur Holden has had the foresight to bring together geneticists, clinicians, epidemiologists, academics and representatives from the pharmaceutical industry. It’s a global effort – that’s the only way we can crack this.”

References

1. Daly AK et al. HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat Genet 2009;41(7):816-9.
2. Rauch A et al. Prospective genetic screening decreases the incidence of abacavir hypersensitivity reactions in the Western Australian HIV cohort study. Clin Infect Dis 2006;43:99-102.
3. Waters LJ et al. Prospective HLA-B*5701 screening and abacavir hypersensitivity: a single centre experience. AIDS 2007;21:2533-4.
4. Zucman D et al. Prospective screening for human leukocyte antigen-B*5701 avoids abacavir hypersensitivity reaction in the ethnically mixed French HIV population. J Acquir Immune Defic Syndr 2007;45:1-3.

Find out more on the SAEC’s website.

Getting serious

Common serious adverse events include:

  • DILI (drug-induced liver injury): Associated with over 30 medicines, the severity varies but can result in acute liver failure and death. Liver toxicity is also the most common reason for stopping clinical trials.
  • SSR (serious skin rash): For the Consortium, this refers to Stevens-Johnson syndrome and toxic epidermal necrolysis – related rare reactions that are associated with over 200 medicines. They cause severe blistering of the skin and mucous membranes and can be fatal.
  • Hypersensitivity syndrome: This affects the whole body, with symptoms including fever, rash and inflammation of internal organs (such as hepatitis).
  • Cardiac arrhythmias: These involve abnormal electrical activity in the heart.
  • Angioedema: Swelling of the lower layers of the skin.

At a glance

Serious adverse events are:

  • defined as severe, possibly life-threatening reactions to a normal
  • or ‘therapeutic’ dose of drug
  • often due to an immunological response but can also be due to non-immune
  • processes, for example, those that trigger abnormal activity in the heart
  • thought to have a genetic and an environmental component, i.e. are multifactorial.
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