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:
Regards
The authors