Skip to main content
Menu

Clinical Trials

Idiosyncratic Tox

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.

14 comments on “Idiosyncratic Tox”

  1. loupgarous says:

    One thing to look for might be “too much of a good thing” drug reactions.

    Odanacatib may have been an offender there – inhibiting cathepsin K, while it did reduce osteoporosis in Phase III trials, was also associated with an elevated risk of stroke. Inhibiting a major collagenase might reasonably be associated with intimal proliferation, implicated in vascular diseases, and a reason antiproliferatives are part of the treatment regimen for arterial disease, especially post-stenting. Restenosis of the stented part of the artery is a common problem directly traceable to proliferation of tissue – as the stenting procedure itself creates tears in the arterial intima that the body tries to mend with collagen deposits.

    The only way to find that out with odanacatib was to find it out, in the absence of a good screening test or a specific treatment-related injury in animals or early-phase clinical trials. But perhaps it’s a good idea to look at new drugs’ mechanism of action to see how it might make off-target conditions worse in the target population (as opposed to healthy volunteers presumably with no predisposition to stroke, in the case of odanacatib).

  2. cynical1 says:

    I think the IADRs in the biologics are also under appreciated. For instance, interferon-beta is associated with both hypothyroidism and hyperthyroidism in up to 30% of patients. And Rituximab, which targets CD20, has a rare but well-characterized late onset neutropenia which can occur up to a year after dosing. Funny thing is that neutrophils don’t have a CD20 receptor. Just weird.

    1. Ogamol says:

      Cynical1: Do the spawners* of neutrophils, or other cells in the excess-neutrophil feedback loop, have CD20 receptors?

      (* – Sorry, tired gamer brain.)

  3. random_french_person says:

    There are indeed so many things we ignore about the human body and its molecular process. New assays are required to better identified potential AE at an early stage. Maybe in silico methods could also be useful.

    I also wanted to let you know that we usually refer to the adverse event caused by hERG inhibition as “torsade de pointes” and not “torsade des points”

    1. Derek Lowe says:

      Thanks – that was a placeholder spelling as I wrote the post, but I never got back around to checking it!

      1. TroyBoy says:

        Derek, it was your German tendencies that overrode the French!

    2. loupgarous says:

      “There are indeed so many things we ignore about the human body and its molecular process. New assays are required to better identified potential AE at an early stage. Maybe in silico methods could also be useful.”

      Good idea. There’s no common architecture to do so, but perhaps it’d be worth making a “virtual patient” for every new drug, complete with all the receptors known to be problematic not just in the disease the new drug targets, but in every disease associated with the patient demographics of patients liable to be treated with the new drug.

      That’s an ambitious coding project, but no more ambitious than going in blind at Phase III and not knowing all the ways that (say, in my previous example) inhibiting cathepsin k might make comorbid conditions in the people we know will take the study drug much worse. As people get older, narrowing of arteries with deposits of calcium and fat happens. Cathepsin K and other collagenases probably reduce that narrowing to a level people can live with. If we inhibit one or more of those enzymes, knowing what else happens apart from the disease process targeted (osteoporosis) would be useful going into Phase III.

  4. Dutchy says:

    Indeed IADRs are an almost elusive problem!

    Although I can’t completely agree with your alcohol example in an overdose of acetaminophen.

    “Such damage is primed by conditions (alcohol, e.g.) that deplete the glutathione that would normally soak up the reactive metabolite.”

    In an acute acetaminophen intoxication/overdose alcohol is more or less a protective factor. Or at least not worsening. This is off course different when chronic alcohol abuse is involved.

    https://www.ncbi.nlm.nih.gov/pubmed/18211314

  5. milkshake says:

    do you remember the p38 fiasco? Every major pharma company had a late stage p38 antiinflammatory/pain medication compound in the clinic. After the coxib failures, p38 inhibitors looked like a good alternative for awhile (if only they could be made more isoform selective)… And there was always the unpredictable liver/GI tox in the patients. The nail in the coffin was a discovery that formation of unstable atherosclerotic plaque is linked to plaque infiltration by M2 macrophages and they are more likely to gorge up, turn into foam cells and die if p38 is inhibited

  6. Chris Phoenix says:

    And then of course there’s fluoroquinolones, a type of antibiotic that in some people, after some number of doses plus some number of months, makes the Achilles tendon rupture.

    1. loupgarous says:

      Not just Achilles tendon ruptures, but ruptures of other tendons and integumentary structures, and blood vessel damage all the way up to aortic aneurysms were discovered to occur in connection with the use of fluoroquinolone antibiotics, starting with a French study in the 1990s, but more famously in two retrospective studies of patient charts, one in and around Toronto, Canada and the other in Taiwan. Incidence increased with patient age, but the damage was seen across a spectrum of patient ages. This wasn’t picked up until years after marketing approval, and was idiosyncratic drug toxicity by any measure.

      IADR which don’t show up until after new drug approval is another issue we need to look at. All the hoopla about “big data” being able to turn up cures for cancer, Alzheimer’s disease and other horrible things aside, using our existing database of medical records for post-marketing safety monitoring would be vastly better than FDA’s current voluntary collection of adverse events associated with drugs and medical devices. That would probably have revealed the issue with the fluoroquinolones back in the early 1990s (when they saw wide use in URIs and other infections).

      Automated surveys of patient medical charts for toxicity and other adverse events are something the advocates of big data can do comparatively easily while they’re tooling up to look at more difficult patterns in patient data (say, to identify more older drugs that can be repurposed to treat the dementias or certain cancers).

    2. eub says:

      (This is idiosyncratic in that most people don’t flat-out rupture their Achilles, but systematic in that quinolones damage mitochondria by inhibiting topoisomerase 2 as well as bacterial gyrase, and apparently tendons in particular resent this, showing up with inflammation.)

  7. eub says:

    And what is going on with drug-triggered Stevens-Johnson and TEN and that whole crowd of nasty cytotoxic-T-cell freakouts? In the examples that show HLA allele specificity, it’s plausible that the drug is binding to the protein (like abacavir), but it’s still idiosyncratic even within an allele. Also we seem to have a correlation rather than a solid mechanism, because the same allele will behave differently between East Asian and European populations. Individual immune state matters, since HIV infection apparently increases SJS risk.

    Are there milder sub-SJS forms that occur on a continuum of severity, or is there some type of feedback loop or switch-flipping mechanism that results in a bimodal “no effect” / “severe effect”?

  8. junksciencepurveyor says:

    the primary reason for clinical trial failures is management doesn’t have the patience to keep making more molecules that might be better.
    They get something and decide there is more money in hyping initial clinical trials and acquisitions, manipulation of the markets is a better strategy etc etc etc.
    The fact is that a lot of these companies know full well their “clinical candidates” will never become drugs.
    If you took all these examples out of the pool of “failed clinical trials” you’d see a much higher success rate.
    Now all the boneheaded “senior scientists”, who’ve only ever worked one job, if any, can chime in and say NO… it can’t be.

Leave a Reply

Your email address will not be published. Required fields are marked *

Time limit is exhausted. Please reload CAPTCHA.