It’s our high failure rate in clinical trials that makes the drug industry what it is. And two of the biggest factors in that failure rate are picking the wrong targets/mechanisms, and unexpected toxicity. The first is clearly a failure of our understanding of human biology, and the only remedy I can see for that is for us to understand more about it. A slow process, that. The second would certainly benefit from more understanding as well, and a key question is whether “idiosyncratic tox” really is completely idiosyncratic. That is, are we bumping into a whole collection of unrelated things that are just waiting out there for us to trip over them, or are there some common mechanisms that we could prepare against?
There’s already evidence for the latter. Look at cardiac arrhythmia and its showstopping manifestation as torsade de pointes. This used to be Just One of Those Things That Happens, until we realized the connection to the hERG ion channel. Now hERG testing is a standard part of preclinical drug development. It’s not perfect, but the fit is good enough to be useful and has surely allowed us to not take compounds into the clinic that would have caused trouble later. What we need are more insights that are at least that useful.
This paper has some good background on the subject. It’s looking at idiosyncratic liver injury, the sort of thing that happens at the lower-than-1-per-ten-thousand-patients level, can kick in well after the exposure to the drug, and can also lead to serious damage. In short, a nightmare for drug development and the sort of thing that you might not even be able to notice until late in Phase III or even after the drug hits the market. What’s more, the data in this area can be pretty messy, because that time delay means that such idiosyncratic adverse drug reactions (IADRs) sometimes aren’t even correlated with a particular drug exposure.
There have been many efforts to find markers of this sort of thing, of course, but it’s tricky. Blood-test signs of liver injury (such as changes in ALT, AST, and bilirubin levels) are only vaguely correlated with these sorts of adverse events, and there are way too many false positives. There are some situations where blood samples from patients who’ve had an IADR will show effects (such as lymphocyte proliferation) on ex vivo exposure to the suspected drug, but that doesn’t always work, either. Such test can take weeks to perform and are pretty uncommon, so they’re not a great source of raw data.
A big reason for all this vagueness is that immunology is involved. It would be, wouldn’t it? Long and variable incubation time, extremely high patient-to-patient variability, sudden severe tissue damage, effects in high-exposure organs like the liver and immunologically-active ones like the skin (all those sudden-rash side effects): of course it’s the immune system. Indeed, there are specific human leukocyte antigen (HLA) alleles that have been associated with reactions to specific drugs, and you can bet that there are a lot more that we haven’t tracked down yet.
One way you can produce a new antigen is by reaction of a reactive covalent compound with some protein – that’s what’s going on with poison ivy, to pick an all-natural example. The urushiols in that plant (and in poison oak, etc.) get oxidized to reactive quinones in vivo, and those react with skin proteins to generate a neoantigen (usually after degradation to shorter peptides). You always want to be on the lookout for reactive metabolites, for just this reason. This sort of thing is of course one of the reasons that deliberately covalent compounds were avoided for so long in drug discovery, and it’s still something to you have to keep a careful eye out for. The less reactive and thus more selective covalent agents have less of a chance for this as opposed to red-hot stuff like quinones, but there are an awful lot of potential reactive sites out there. The fact that IADRs have also been associated in some cases with particular polymorphisms in metabolizing enzymes supports this mechanism.
The graphic at right is the current thinking about what’s going on, and while it makes sense, you’ll also note some rather fuzzy-sounding concepts. What exactly is that “underlying susceptibility to cell stress”, for example? The stress in this case is often oxidative. If the reactive-oxygen-species (ROS) levels in a cell exceed its capacity to deal with them through the normal routes, such compounds can start modifying proteins and generating neoantigens by that route. So anything that decreases the effectiveness of the heat shock proteins, the Nrf2 system, superoxide dismutase levels, and other such responses could be a problem. Nutritional state, co-morbidities, other drugs being taken simultaneously – there are a lot of possibilities.
As shown, it looks like the first step is an innate immune response, which gradually sets off that adaptive immune system (and this helps to account for the delay in IADRs showing up, since all this takes time and perhaps multiple cycles of injury to build up). That adaptive response will naturally get off the ground faster if it’s been primed by previous exposure, and to make things more complicated, there is always the possibility of immune crosstalk, where exposure to one agent also sensitizes things to a different species. Finally, there’s always that arrow from the “cell stress” box right to an IADR.
That’s similar to what you get with an overdose of acetaminophen, for example: direct damage and severe toxicity via a reactive intermediate. Such damage is primed by conditions (alcohol, e.g.) that deplete the glutathione that would normally soak up the reactive metabolite. The reason that acetaminophen isn’t really an IADR, though, is that it is the opposite of idiosyncratic: everyone who takes too much acetaminophen will destroy their liver, and everyone who washed it down with vodka will have accelerated the process. IADRs can be just as bad, but they’re just a lot harder to predict. I think it’s safe to say that that’s because most of them do involve the immune system, but there is always a possibility for a direct-damage route that takes place because of idiosyncratic factors, too. The problems with troglitazone, for example, seem to have been mediated by disruption of bile-acid homeostasis, a complex system involving several steps with opportunities for inter-patient variability.
The paper goes into detail on efforts to come up with predictive assays for this sort of thing. The best guess is that some combination of advanced sequencing (to look for known HLAs and metabolic variants and to expand both of those lists) and ex-vivo immunological assays will work out, but we have quite a ways to go. And by that I mean both to validate such assays (or assay systems) and to get them into a form where they can be much more widely used. Telling someone after they’ve had a bad IADR that we will only need a couple of weeks to figure out why it happened is not so useful, and neither is being able to assign a cause to a failed trial only after it’s failed. The sorts of assays it looks like we’ll need are not ones that have always been easy to reduce and speed up. For drug development purposes, we’ll need to come up with some sort of standard panel that can at least alert us to the more common IADR routes, and there will be quite a few of those to cover. We’re never going to be able to wring all the risk out of taken an investigational drug into humans – but we should be able to do a lot better than we can now.