Word of the week..idiosyncratic

As in idiosyncratic drug reaction…an unpredictable adverse drug reaction that occurs in a very small subset of patients. With the recent withdrawal from the market of a number of drugs in the last few years, the pharmaceutical industry has begun to focus its attention on finding ways to avoid this problem. If you want to witness a very spirited discussion (debate) amongst your colleagues simply mention idiosyncratic drug reactions and people will quickly divide up into groups based on what they believe causes idiosyncratic reactions and the value of the assays most research organizations are introducing to evaluate the risk of the event occurring.

The most accepted theory  (the “hapten hypothesis”) suggests that reactive drug metabolites covalently bind to proteins and act as haptens to effect an immune response to the drug and host-protein. There are a few problems with this theory one being that it fails to explain why the immune response only occurs in a very small subset of individuals. In order to explain the low frequency other researchers have invoked the “danger hypothesis”, which states that in order to activate the immune system towards a hapten it has to be accompanied by some sort of physical injury. But here again there are problems, the primary one being the the “danger hypothesis” is not well accepted by immunologists since it goes against the primary dogma of immune “self-tolerance” (Check out the review in Science by one of the proponents of this theory, Polly Matzinger). Last but not least, Werner Pichler has introduced the “PI” theory, which ignores reactive metabolites and covalent binding altogether and focuses on the parent drug. According to the PI theory the drug binds directly to the T-cell receptor, stimulating the cellular immune system.  T-cell receptors varyf from one individual to the next depending on genetics and other factors which would explain why only a small set of people would have receptors that bind to the drug. This hypothesis suggests that the immune reaction is caused by ‘off target’ binding of the drug and as such should be countered by increasing selectivity for the desired target and not by reducing metabolic stability.

Rather than adding my own opinion to this debate, I wanted to address a more fundamental issue…the definition of the word idiosyncratic. Unfortunately, based on the use of the word in the context of describing an unpredictable drug reaction that occurs with low frequency, most people assume that it means an unusual event. However, the true definition has more to do with the person…’idio’ comes from the Greek word idios which means “one’s own” or “personal”… and the definition of the word is more along the lines of  “characteristic, habit, mannerism, or the like, that is peculiar to an individual”

Actually, I prefer this definition, since I tend to think of idiosyncratic drug reactions as being a problem that resides with the affected patient, not necessarily with the drug. It is also the reason that I like Pichler’s PI theory since it addresses the patient’s susceptibility to an adverse drug reaction, rather than looking at the drug’s propensity to cause the reaction. The problem with focusing on the drug is that most, if not all drugs, will form reactive metabolites if they are metabolized in the body, therefore you can only reduce risk by removing those compounds that exhibit a certain level of covalent binding. The accepted level of covalent binding is subjectively determined and usually reflects the measure of risk one is willing to tolerate. With this paradigm you wind up tossing out a lot of potentially useful drugs, particularly if one is very conservative.

Unfortunately, we are not at the point where we are able to predict which patients will have a problem and it will be very difficult to get there. There is a lack of data due to the small number of patients affected and the inability to examine the issue prospectively in the clinic. Therefore, I have a few ideas/suggestions for speeding up research in this area;

1) Clinical data, be it from academia or pharmaceutical companies, should be pooled so that a sufficiently large database can be produced. This will help in probing for links in genetics or patient-histories with the frequency of the adverse drug reaction.

2) Would it be possible to expand the genetic diversity of the pre-clinical species that the drug is tested in? Although, more than one species of animals is employed in tox and safety studies, these are all derived from homogeneous colonies, so in reality the drug has only “seen” 2 to 3 different genotypes. Is it cost prohibitive to set up a panel of genetically diverse rats or dogs for screening?

3) Apply the same principle of genetic diversity for selecting patients for clinical trials, if possible, in order to increase the chance that a problem will be detected in early trials.

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2 Responses to “Word of the week..idiosyncratic”

  1. business|bytes|genes|molecules Says:

    […] new medicinal chemistry blog has an interesting post about “idiosyncratic” drug reactions, adverse reactions that occur in a small set of patients. For any number of reasons, trying to get […]

  2. business|bytes|genes|molecules Says:

    […] new medicinal chemistry blog has an interesting post about “idiosyncratic” drug reactions, adverse reactions that occur in a small set of patients. For any number of reasons, trying to get […]

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