Abstract
Fomepizole is a promising new treatment for preventing liver injury
following paracetamol (acetaminophen) overdose. However, we need robust
clinical trials to be performed to demonstrate its effect on clinical
outcomes that are important to our patients and important to healthcare
providers. Until such trials are performed, the toxicology community
should learn the lessons from the COVID pandemic – potential novel
therapeutic options may be theoretically appealing, but their
effectiveness needs to be assessed in robust clinical trials before they
are used in clinical practice.
The COVID-19 pandemic has dominated healthcare for the last couple of
years. The enormous challenge presented by the emergence of this new
infectious disease in late 2019 resulted in drug and vaccine development
being rapidly performed at ‘warp speed’ . When COVID was first
identified, clinicians searched for licenced medicines with mechanisms
of action consistent with a potentially effective treatment.
Hydroxychloroquine was identified as a potential treatment because it
has in vitro activity against SARS-CoV-2[1] and early small
observational studies suggested a possible benefit.[2] There were
high profile leaders who promoted using hydroxychloroquine to prevent
and treat COVID,[3] and doctors prescribed it based on this limited
evidence base. Fortunately, from the start of the pandemic, theRecovery platform trial tested multiple treatments in a large
randomised clinical trial that measured mortality as the primary
endpoint. Recovery conclusively demonstrated hydroxychloroquine
had no benefit when 1561 hospitalised patients with COVID were treated
with this drug compared to 3155 patients who received standard
care.[4] In fact, subsequent a meta-analysis suggests
hydroxychloroquine may harm patients.[5] Despite the initial hope
that resulted in doctors prescribing hydroxychloroquine, it proved
ineffective when tested in a robust large study. Fomepizole may be the
toxicology community’s hydroxychloroquine unless we learn the lessons of
COVID and come together to perform robust randomised trials before
prescribing an untested treatment.
Paracetamol (acetaminophen) overdose is common. There is a clear unmet
need for new treatments. Currently, the only effective treatment for
preventing liver injury after paracetamol overdose is acetylcysteine
(n-acetylcysteine, NAC). If treatment is commenced within 8 hours of the
overdose, then NAC is near 100% effective at preventing liver failure.
However, its effectiveness drops substantially when treatment is
delayed. NAC is near ineffective when treatment is delayed greater than
around 20 hours after overdose.[6] For patients who present to
hospital late following a significant paracetamol overdose we need
effective new treatment strategies to prevent liver injury in this high
risk group. Within this space, fomepizole has emerged as a potential new
candidate.
Fomepizole is well known to toxicologists as an effective treatment for
toxic alcohol poisoning due to its ability to inhibit the enzyme alcohol
dehydrogenase.[7] The potential as a treatment for paracetamol
overdose is unrelated to this mechanism of action. Fomepizole is a
potent inhibitor of the cytochrome P450 enzymes that produce the
paracetamol toxic metabolite (NAPQI) that is responsible for liver
injury. Furthermore, in mice, fomepizole prevents liver injury after the
metabolism phase of paracetamol mainly through the inhibition of c-Jun
N-terminal kinase activation. The pre-clinical evidence base for
fomepizole is impressive, largely due to the work of Hartmut Jaeschke’s
group.[8, 9] In humans, well performed clinical studies confirm that
fomepizole inhibits the oxidative metabolism of paracetamol.[10]
However, there is no trial evidence that fomepizole prevents liver
injury in man. These trials need to be performed. Sometimes it is
suggested that ‘trials cannot be performed in clinical
toxicology’. As paracetamol overdose is common this is untrue. In the
UK, every 5 minutes someone presents to hospital following a paracetamol
overdose – the same frequency as myocardial infarction. It is hard to
imagine cardiologists prescribing a medicine because it works in mouse
models and defending that position by saying clinical trials cannot be
performed in ischaemic heart disease.
There are a number of reasons to insist on robust, randomised trial
evidence for the clinical effectiveness of fomepizole before it is used
to treat paracetamol overdose in routine clinical practice. Advocates of
its use suggest it has a role in large overdoses when there is a high
concentration of paracetamol in the circulation. Given fomepizole’s
ability to inhibit the P450 enzymes this makes theoretical sense.
However, P450 enzyme inhibitors have been tested in this indication in
the past and failed to demonstrate clinical effectiveness.[11] If
P450 enzyme inhibition is the correct target for a new therapy, there
may be cheaper alternatives to the expensive option presented by using
fomepizole. Finally, and perhaps most importantly, we do not know
whether using a higher dose of NAC for larger overdoses will be
sufficient alone to prevent liver injury in this group of patients. This
approach is likely to be substantially cheaper than using fomepizole.
Currently, patients receive a dose of NAC that is based only on their
body weight. It is clear from the basic pharmacology, mathematical
modelling[12, 13] and observational studies[14, 15] [16]
that patients taking a large overdose may not be receiving enough NAC to
prevent liver injury. There are new regimens for administering NAC that
produce substantially lower rates of adverse drug reactions compared to
the standard 21-hour regimen.[17] These new regimes allow phase 2
clinical trials of high dose NAC treatment in selected patients with a
reasonable expectation of not producing dose-limiting toxicity. Before
advocating a new expensive treatment, the toxicology community should
focus on defining the optimal dose of NAC.
Fomepizole use in paracetamol overdose is occasionally defended as it is
claimed to have an excellent safety profile. This seems to be correct in
its licenced indication – treatment of toxic alcohol poisoning. We do
not know if it is safe in patients who have overdosed on paracetamol and
there are reasons for a degree of caution. A phase 1 trial of fomepizole
demonstrated a small increase in alanine transaminase (ALT) activity in
6 of 15 healthy subjects.[18] Although unlikely, when combined with
a potentially hepatotoxic dose of paracetamol this small ALT rise could
translate into increased cases of significant liver injury. A
fomepizole-induced increase in ALT, even if benign, may result in
patients having unnecessary prolonged treatment with NAC, as ALT is the
key biomarker which informs decisions to stop treatment. We do not have
robust data to know the answers to these questions about safety.
Fomepizole has promise as a treatment for paracetamol overdose. But we
do not have data from randomised trials about clinically important
outcomes such as liver injury, hospital length of stay and liver failure
and we do not have an adequate safety dataset. Now is the time for the
toxicology community to follow the example of the Recovery Trialand come together to perform large platform trials to evaluate new
treatments that have evidence of clinical efficacy from phase 2 trials.
Candidate treatments include high dose NAC and fomepizole. This is the
hard thing to do, the easier option is to start prescribing treatments
without a robust evidence base. The danger is fomepizole becomes like
hydroxychloroquine in COVID, advocated as a treatment without robust
evidence of benefit for our patients.
Conflict of interest:
JWD was the Chief Investigator on
the POP Trial of calmangafodipir in paracetamol overdose.