What is the pharmacology of Colchicine (colchicine)?

From the Guidelines

Colchicine should be used at a loading dose of 1.2 mg followed by 0.6 mg one hour later for the treatment of acute gout, as recommended by the 2016 updated EULAR evidence-based recommendations for the management of gout 1.

Colchicine Pharmacology

Colchicine is an anti-inflammatory medication primarily used to treat gout attacks and prevent gout flares, with additional applications in familial Mediterranean fever, pericarditis, and Behçet's disease.

• The typical dosing for acute gout is 1.2 mg initially, followed by 0.6 mg one hour later, then 0.6 mg once or twice daily until symptoms resolve.
• For prophylaxis, 0.6 mg once or twice daily is common.
• Colchicine works by binding to tubulin, preventing microtubule assembly and thereby disrupting neutrophil function, migration, and the inflammatory cascade.
• It also inhibits NLRP3 inflammasome activation, reducing IL-1β production which is crucial in gout inflammation.

Important Considerations

• The medication has a narrow therapeutic window with common side effects including gastrointestinal disturbances (nausea, vomiting, diarrhea), which often limit dosing.
• Serious toxicities can include myelosuppression, neuropathy, and myopathy.
• Colchicine is metabolized by CYP3A4 and is a P-glycoprotein substrate, creating important drug interactions with inhibitors like clarithromycin, ketoconazole, and cyclosporine, which necessitate dose reduction.
• Caution is required in patients with renal or hepatic impairment, and dose adjustments are necessary in these populations to prevent toxicity, as noted in the 2017 systematic review in support of an American College of Physicians clinical practice guideline 1.

Dosing and Administration

• For patients already on prophylactic colchicine, the recommended dosing for acute gout is 1.2 mg initially, followed by 0.6 mg one hour later, as stated in the 2012 American College of Rheumatology guidelines for management of gout 1.
• Prophylaxis against flares should be fully explained and discussed with the patient, with recommended prophylactic treatment being colchicine, 0.5–1 mg/day, as recommended by the 2016 updated EULAR evidence-based recommendations for the management of gout 1.

From the FDA Drug Label

Colchicine is an alkaloid chemically described as (S)N- (5,6,7,9-tetrahydro- 1,2,3,10-tetramethoxy-9-oxobenzo [alpha] heptalen-7-yl) acetamide with a molecular formula of C 22H 25NO 6 and a molecular weight of 399. 4.

Following oral administration of Colchicine Tablets, USP given as 1.8 mg colchicine over one hour to healthy, young adults under fasting conditions, colchicine appears to be readily absorbed, reaching mean maximum plasma concentrations of 6.2 ng/mL at a median 1.81 hours (range: 1. 0 to 2.5 hours).

Absolute bioavailability is reported to be approximately 45%

Colchicine binding to serum protein is low, 39 ± 5%, primarily to albumin regardless of concentration.

Colchicine is demethylated to two primary metabolites, 2-O-demethylcolchicine and 3-O-demethylcolchicine (2- and 3-DMC, respectively) and one minor metabolite, 10-O-demethylcolchicine (also known as colchiceine).

In healthy volunteers (n=12), 40 to 65% of 1 mg orally administered colchicine was recovered unchanged in urine.

Colchicine is a substrate of P-gp.

Colchicine is not removed by hemodialysis.

Pharmacology of Colchicine:

• Absorption: Colchicine is readily absorbed after oral administration, with a mean maximum plasma concentration of 6.2 ng/mL at a median 1.81 hours.
• Bioavailability: The absolute bioavailability of colchicine is approximately 45%.
• Distribution: Colchicine binds to serum protein at a rate of 39 ± 5%, primarily to albumin.
• Metabolism: Colchicine is demethylated to two primary metabolites, 2-O-demethylcolchicine and 3-O-demethylcolchicine.
• Excretion: 40 to 65% of orally administered colchicine is recovered unchanged in urine.
• Transporter: Colchicine is a substrate of P-glycoprotein (P-gp).
• Elimination: Colchicine is not removed by hemodialysis. 2

From the Research

Colchicine Pharmacology

• Colchicine is a medication used to treat gout, a common rheumatic disease worldwide 3, 4, 5, 6.
• It has a narrow therapeutic-toxicity window and important variability in tolerance between subjects 6.
• Low-dose colchicine (1.8 mg over 1 h) is effective in reducing pain and is well tolerated in patients with acute gout 4, 6.

Efficacy of Colchicine

• Colchicine is an effective treatment for the reduction of pain and clinical symptoms in patients experiencing acute attacks of gout 3, 4.
• Low-dose colchicine may improve treatment outcome compared to placebo with little or no increased risk of adverse events 4.
• High-dose colchicine may improve symptoms, but with increased risk of harms 4.

Comparison with Other Treatments

• Colchicine may be used as a second-line therapy when NSAIDs or corticosteroids are contraindicated or ineffective 3.
• Low-dose colchicine may have a similar efficacy to NSAIDs in terms of treatment success and pain reduction 4, 5.
• There is limited evidence comparing colchicine to glucocorticoids or other treatments such as ACTH 3, 4, 5.

Safety and Tolerability

• Colchicine has a high frequency of gastrointestinal adverse events, such as diarrhea and vomiting 3.
• Low-dose colchicine has a comparable tolerability profile to placebo and a significantly lower side effect profile to high-dose colchicine 5, 6.
• The number needed to harm (NNH) with colchicine versus placebo was 1, indicating a high risk of adverse events 3.