Tyler Perry’s Colchicine Part 2

In a previous post, I discussed the use of colchicine following acute MI in the COLCOT study. Leading up to the discussion, I briefly touched on the pharmacology of colchicine. But since this drug is so unique and fascinating, particularly with regards to its toxicology, I wanted to have a separate post to discuss just that.

It often seems as though the interest in a given xenobiotic is proportional to its use in history. Colchicine is a prime example, in that it has an incredibly complex mechanism that offers the opportunity for some deep learning, and its history goes back pretty much as far as history goes.

History

According to Goldfranks, colchicine can be traced as far back as stories from Greek mythology around 700 BC.[1] Madea, (not to be confused with the other Madea), was a sorceress and avid user of potions (ie poisons). From the story describing Jason of the Argonauts’ quest for the Golden Fleece, Madea is described as assisting Jason by using several different poisons. After winning the Golden Fleece, Jason and Madea were married and had numerous children. But as often occurred in these stories, Jason was off with some other hussie and Madea was having none of it. So she killed some of their children and his lover (allegedly) using a potion concocted from plants belonging to the same family as Colchicum autumnale.

Later in the 6th century AD, the use of colchicine (in the form of Colchicum autumnale) for arthritic conditions was documented by Alexander of Tralles.[2] As history evolved, so too did the experience with colchicine, particularly its toxicity. Intolerable GI effects and alopecia limited its use, which likely explains the peaks and troughs of its popularity. Benjamin Franklin was even reported using Colchicum autumnale for conditions resembling Gout. 

Colchicine was once used regularly for the treatment of gout, among other indications. I recall having rotations during APPEs, and PGY1 where almost every male over 55 was or had been taking colchicine at some point. Colchicine is rarely used in practice today. This is because of the FDA unapproved drug initiative of 2006 which sought formal regulatory review of medications that previously fell under “grandfather” laws. Since colchicine was available prior to the 1938 Food, Drug, and Cosmetic Act, it was never required to establish safety and efficacy for FDA approved indications.[3,4] The goal of this FDA program was to modernize and test these drugs, without “imposing undue burdens on consumers, or unnecessarily disrupting the market.” 

When it came to calling on colchicine to produce safety and efficacy data, most manufacturers dropped the product or were forced to stop producing the drug altogether by 2011, creating catastrophic shortages. The single producer remaining conducted the required research and won regulatory approval for Colcrys. Unfortunately in the process, these actions by the FDA caused the price of colchicine to rise from $0.07 per tablet to more than $5 per tablet. The price increase, coupled with the extended shortage/unavailability forced providers to simply move on from the therapy. 

Recent studies have now begun to re-introduce colchicine into clinical practice. Indications including post-MI, Afib, diabetes, and rheumatic diseases have all used colchicine in new investigations. With this resurgence in use, are we primed to start seeing colchicine toxicity once again?

Pharmacology/Toxicology

To understand colchicine, you have to recall the function of a specific intracellular structure: microtubules. We recall that microtubules are composed of repeating alpha and beta-tubulin subunits aligned in such a way that they create a polar structure resembling a hollow tube.  These microtubules are created by adding these alpha/beta units at one end and then disassembled at the other. In some tissues, microtubules form stable structures, while others exist in a transient state. Transient microtubules, as the name would suggest assemble and disassemble at a much faster rate when compared to stable microtubules (if it occurs at all). 

At normal doses, when colchicine binds to its particular site at the end of developing a microtubule, its assembly at the positive end is halted. The normal process of disassembly is unaffected at normal doses. Without the function of transient intracellular microtubules, colchicine causes inhibition of neutrophil activity (chemotaxis, adhesiveness, mobility, degranulation of lysosomes). The inhibition of chemotaxis of leukocytes, inflammatory cytokines, glycoproteins is the primary mechanism for the treatment of gout.

Colchicine also alters the regulation of microtubule formation. Because of the above action, colchicine actually increases the number of available tubulin dimers available, initiating negative feedback by inhibiting further production by binding to ribosomes and halting mRNA production. So while there is no direct effect on the disassembly of microtubules, their disassembly is enhanced while further production is impaired.

As the concentration of colchicine increases, so do the actions on these cell structures. In toxic concentrations, colchicine leads to microtubule depolymerization through disassociation of tubulin dimer. In other words, it now affects disassembly, assembly and further formation of microtubules. These effects not only affect transient microtubules but also stable ones as well.

Colchicine shares these actions with other xenobiotics. The vinca alkaloids (vincristine, vinblastine), podophyllins (mayapple or mandrake, and etoposide) share similar effects on microtubules. In rapidly dividing tissues (such as tumors) these agents can prevent or slow tumor formation. Interestingly it is also a GABA-antagonist (a good list to know when studying for tox boards).

In the absence of renal or liver impairment, the toxic doses of colchicine ofter are quoted between 0.5-0.8 mg/kg. While the range of toxic doses is debated, as the toxic dose approaches 0.8 mg/kg, mortality approaches 100%. It should be noted that fatalities have occurred in ingestions under 0.5 mg/kg. Although histories, patient reports, and a lack of rapid turnaround in serum level testing, in patients with a story consistent with a toxic ingestion, aggressive therapy should be considered.

PK/PD

The complex mechanism of action pairs well with the unique pharmacokinetics of colchicine. When taken orally, colchicine has a range of bioavailability between 25-50% with peak concentrations occurring in 30 minutes to 3 hours and undergoes extensive 1st pass metabolism in the process. It has a large and wide-ranging volume of distribution from 2 to 12 L/kg and is 10-50% bound to albumin (primarily). Colchicine is metabolized hepatically by CYP3A4 to two active and on inactive metabolites. Finally, about 20-40% of the drug is eliminated in the urine unchanged with a terminal half-life of.

Of note, colchicine was once available in an IV form. Needless to say, it is no longer available.

As a result of its CYP3A4 metabolism, and being a p-glycoprotein substrate, colchicine is subject to a myriad of drug interactions. When coadministered with a PGP inhibitor, colchicine could experience several fates. In the gut, a PGP inhibitor will enhance the absorption of colchicine. For example, a patient on colchicine in the ED for Afib with RVR and received either amiodarone, digoxin, diltiazem, or verapamil- the PGP inhibition would increase the absorption of colchicine. Since PGP also exists in the liver, pancreas, kidney and on the blood-brain barrier, the ultimate consequence may not just be increased absorption of colchicine, but also increased concentrations in target tissues. Concerningly PGP inhibition would certainly worsen colchicines action as a GABA-antagonist in the CNS.

Clinical Course

Should you be unlucky enough to be poisoned by Madea, or ingest colchicine on your own accord, the toxicity can be predicted as an extension of its pharmacology. GI irritant effects occur early, generally within the first 24 hours after ingestion. As one would expect, volume depletion and electrolyte abnormalities could be predicted to occur in this phase. Recalling the MOA, these rapidly dividing cells are the first to manifest clinically observable insult. 

As the toxicity progresses, these cellular toxic effects extend to cause expansive multiorgan injury. Renal injury, hepatic injury, ARDS and sepsis can occur between 1 and 7 days post-ingestion. But the hallmark of this phase is the onset of bone marrow suppression. Alopecia and myoneuropathy mark the onset of the third phase (beyond 7 days). As with all tox: seizure coma death can sum up the final phase.

Management

The detailed and complete workup and management of colchicine overdose can be summarized as the words-that-shall-not-be-spoken of supportive care. While clinically paramount to provide good supportive care, I’d rather talk about a specific element of care that may yet see the light of day: anti-colchicine Fab.

The interest and availability of anti-colchicine fab has fluctuated over time. Animal models and some human case reports of the use of anti-colchicine fab from the 1980s and 1990s showed promise. In a case report describing a 25-year-old female presenting 24 h after ingesting 0.96 mg/kg of Colchimax (colchicine), 900 mg of phenobarbital, and 750 mg of opium extract.[5] She initially presented with tachycardia (HR 110) and hypotensive (unmeasurable) requiring a 500mL saline bolus and vasopressor support (dobutamine… which is interesting). Of note, at this time she had marked WBC elevation (68,300). The patient’s clinical status continued to decline, requiring higher doses of dobutamine (maybe try something else) and a respectable fluid resuscitation of 4.4L but yielding a paultry 20mL of urine output in the first 4 hours. At this time (now 40 h after the ingestion), goat derived anti-colchicine Fab fragments were administered intravenously. Her vasopressor requirement after 30 minutes of the Fab infusion began to improve and the patient’s clinical picture continued this trend.  The patient was discharged hospital on day 25 and followup demonstrated no sequelae. 

However, this n=1 did not lead to further use or investigation. The odd case report and animal model would appear in the literature every once in a while. But now that there is a sustained resurgence in colchicine, and Fabs are all the rage these days, a renewed interest in this drug has developed.

A new producer of ant-colchicine fab has emerged. According to the product website, human studies of ColchiBIND should have started at some point in 2019. While we wait for those results, this product was studied in a minipig model of colchicine toxicity.[6] When a full neutralizing dose was administered within 3 hours of the end of an IV colchicine dose, marked increased in colchicine elimination and absence of free colchicine until 20 hours after exposure.

Administration of a full neutralizing dose of Fab within 3 h of the end of colchicine administration resulted in marked increases in plasma colchicine and urinary elimination, and absence of free colchicine from plasma until 20 h after colchicine exposure. However, the investigators cautioned the administration beyond 6 hours from exposure. When a half-neutralizing dose of the Fab was delayed until 6 h after the end of colchicine administration, there was a reduced effect on urinary elimination and only a modest increase in time to euthanasia. So it’s unclear whether this is due to the dose, or delay to administration. Based on the clinical case report previously described, which suggested Fab efficacy up to 24 hours post-ingestion, the treatment window is likely beyond 6 hours.

While we await the forthcoming evidence of ColchiBIND, I’m certain that the use of colchicine for various indications will continue to expand. If there’s sure to be therapeutic misadventures, drug interactions, and outright overdoses with this most recent colchicine renaissance. For the time being, we can only speculate what cool brand name derived from Greek mythology ColchiBIND may have.

 

 

Reference

  1. D. Santos C, Schier CG. Colchicine, Podophyllin, and the Vinca Alkaloids. In: Nelson LS, Howland M, Lewin NA, Smith SW, Goldfrank LR, Hoffman RS. eds. Goldfrank’s Toxicologic Emergencies, 11e New York, NY: McGraw-Hill; . http://accesspharmacy.mhmedical.com.ezproxy.uttyler.edu:2048/content.aspx?bookid=2569&sectionid=210270571. Accessed December 08, 2019.
  2. Snow JW, Kao LW, Furbee B. Chapter 71, Antitubulin Agents: Colchicine, Vinca Alkaloids, and Podophyllin. In:  J. Brent et al. (eds.), Critical Care Toxicology,DOI 10.1007/978-3-319-17900-1_138
  3. Gupta R, Dhruva SS, Fox ER, Ross JS. The FDA Unapproved Drugs Initiative: An Observational Study of the Consequences for Drug Prices and Shortages in the United States. J Manag Care Spec Pharm. 2017 Oct;23(10):1066-1076
  4. Kesselheim AS, Franklin JM, Kim SC, et al. Reductions in Use of Colchicine after FDA Enforcement of Market Exclusivity in a Commercially Insured Population. J Gen Intern Med. 2015 Nov; 30(11): 1633–1638.
  5. Baud FJ, Sabouraud A, Vicaut E, et al. Brief report: treatment of severe colchicine overdose with colchicine-specific Fab fragments. N Engl J Med. 1995;332:642–645
  6. Eddleston M, Fabresse N, Thompson A, et al. Anti-colchicine Fab fragments prevent lethal colchicine toxicity in a porcine model: a pharmacokinetic and clinical study. Clin Toxicol (Phila). 2018 Aug;56(8):773-781