Aspects of clinical pharmacology and safety considerations
Although colchicine at low doses (0.5-1 mg per day) was found to be safe
even if administered continuously for decades, there are possible side
effects, more common, as the gastrointestinal ones found in 5-10% of
cases, less common to consider as the bone marrow suppression,
hepatotoxicity, myotoxicity. The dose in the three stages of SARS-CoV-2
infection in patients should however be modified depending on the
clinical condition of the patient, especially renal and hepatic
function. The simultaneous administration of colchicine and cytochrome
P450 3A4 (CYP3A4) or glycoprotein P (P-gp) inhibitors increases the
potential toxicity of colchicine. A patient with SARS-CoV-2 infection is
a complex patient who may have various organ dysfunctions and take
several medications. A patient with SARS-CoV-2 infection could be on
therapy with cytochrome P450 3A4 (CYP3A4) inhibitors such as macrolides,
this interaction may decrease the metabolization and excretion of
colchicine, increasing the risk of severe adverse reactions, currently
it seems reasonable to avoid co-administration of colchicine and
macrolides. The macrolides as the clarithromycin are P-gp inhibitors,
for this, concomitant administration with such as could increase the
risk of toxicity. A SARS-CoV-2 patient may be in therapeutic treatment
with antivirals such as Ritonavir lopinavir darunavir and ribavirin. Due
to inhibition of P-gp and/or CYP3A4 by ritonavir/lopinavir, a reduction
in colchicine dose or discontinuation of treatment (in patients with
regular renal or hepatic function) would be appropriate to avoid
accumulation of toxic doses and serious adverse reactions such as
rhabdomyolysis. Same interactions also for darunavir. Ribavirin does not
inhibit cytochrome P450 enzymes. There is no evidence from toxicity
studies that ribavirin induces liver enzymes or interferes with gl-P, so
there is a minimal possibility of P450 and gl-P-based interactions with
colchicine. The expression of CYP450 liver enzymes is suppressed by
cytokines, such as IL-6, which stimulate chronic inflammation.
Therefore, the expression of CYP450 can be reversed when used a powerful
cytokine inhibition therapy with tocilizumab or sarilumab. In vitro
studies with cultured human hepatocytes have shown that IL-6 causes a
reduction in expression of the enzymes CYP1A2, CYP2C9, CYP2C19 and
CYP3A4. In phase three, IL-6 is present at high levels. Tocilizumab or
sarilumab can normalize the expression of these enzymes by inhibiting
IL-6. Based on this, if colchicine is administered in phase three in
combination with Tocilizumab or sarilumab, a decrease in colchicine
concentrations may occur compared to when tocilizumab or sarilumab is
not administered. No particular pharmacokinetic interaction seems
instead to be found between colchicine and the following drugs, LWHM,
immunostimulants, plasma derivatives or hydroxychloroquine. However, in
any polytherapy it is always important to refer to the RCP of medicines
to avoid unpleasant interactions. The most common adverse reactions with
colchicine are related to the gastrointestinal tract, diarrhea is the
most commonly reported symptom, followed by vomiting and nausea. Adverse
events of the gastrointestinal tract can be a problem for the patient
SARS-CoV-2 which can presents symptoms such as diarrhea, nausea and
vomiting due to infection, in these patients a decrease in the dose of
colchicine could be considered to avoid electrolyte imbalance. In
addition, drugs such as hydroxychloroquine, ritonavir/lopinavir or
macrolides can cause gastrointestinal symptoms such as diarrhea with
common or very common frequency, this could be a problem with possible
co-administration between these drugs and colchicine. In addition,
concomitant therapy with colchicine hydroxychloroquine and darunavir or
lopinavir / ritonavir could increase the risk of serious adverse
reactions affecting the musculoskeletal system and connective tissue.
Finally, in a polytherapy with colchicine, IL-6 inhibitors,
hydroxychloroquine, and possibly glucocorticoids it should be monitored
continuously the patient’s inflammatory/immune status and to verify
laboratory parameters. However, each patient should be carefully
monitored for possible side effects, including blood tests
(transaminases, serum creatinine, creatin kinase, creatin kinase and
blood cell count), renal and liver function and possible drug
interactions The SARS-CoV-2patient is to be considered a complex
patient, the benefit-risk ratio in that specific patient with those
specific clinical conditions should always be considered in any
politherapy. Colchicine does not have a wide therapeutic window,
treatment with this drug should be managed well, however, clinical
studies and stronger evidence are needed to validate the use of
colchicine in SARS-CoV-2 infection. (14-27)
CONCLUSIONS
SARS-CoV-2 infection
can be divided into three phases: phase 1, an asymptomatic or slightly
symptomatic incubation period with or without detectable virus; phase 2,
slightly symptomatic period with presence of virus; phase 3, severely
symptomatic respiratory phase with high viral load and generalized
hyperinflammatory state. The third is the most severe and dangerous
described by a generalized hyperinflammatory state, a sudden release of
cytokines into the circulation defined as ”cytokine storm” (CS). Waiting
to find antivirals directed against SARS-CoV-2, evidence has shown that
reducing or stopping the hyperinflammatory state that occurs in some
infected patients is effective in improving health. We believe that it
is of utmost importance to properly manage the inflammatory/immune
status of the infected patient. The use of colchicine, as well as its
proven efficacy in the prophylaxis and treatment of autoinflammatory
diseases such as FMF or pericarditis, could be considered in all three
stages of SARS-CoV-2 infection, especially in those patients at high
risk of developing serious lung complications in a dramatically short
time, in monotherapy or in combination, carefully monitoring possible
drug interactions. Colchicine, if used in the recommended doses, could
be in monotherapy or in combination a safe and effective treatment for
the prevention or reduction of cytokine storm in patients with
SARS-CoV-2. However, we believe that a combination of several drugs,
each at a lower dosage than monotherapy, may be the most effective and
tolerable solution to manage the patient’s inflammatory state,
particularly in phases two and three.
MAIN STATEMENTS
I, the undersigned, Francesco Ferrara and any other author, declare
that:
- We have no conflict of interest;
- We have not received funding;
- There are no sensitive data and no patients were recruited for this
study;
- The document does not conflict with ethical legislation.
Regards
The authors