Colchicine - How It Works
Clinical pharmacology details from the US FDA-approved label: how Colchicine works in your body, how it's absorbed, how long it stays active, and how it's eliminated.
Mechanism of Action
12.1 Mechanism of Action The mechanism by which colchicine tablets exert its beneficial effect in patients with FMF has not been fully elucidated; however, evidence suggests that colchicine may interfere with the intracellular assembly of the inflammasome complex present in neutrophils and monocytes that mediates activation of interleukin-1β. Additionally, colchicine disrupts cytoskeletal functions through inhibition of β-tubulin polymerization into microtubules and consequently prevents the activation, degranulation and migration of neutrophils thought to mediate some gout symptoms.
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism by which colchicine tablets exert its beneficial effect in patients with FMF has not been fully elucidated; however, evidence suggests that colchicine may interfere with the intracellular assembly of the inflammasome complex present in neutrophils and monocytes that mediates activation of interleukin-1β.
Additionally, colchicine disrupts cytoskeletal functions through inhibition of β-tubulin polymerization into microtubules and consequently prevents the activation, degranulation and migration of neutrophils thought to mediate some gout symptoms.
12.3 Pharmacokinetics Absorption In healthy adults, colchicine tablets are absorbed when given orally, reaching a mean C max of 2.5 ng/mL (range 1.1 to 4.4 ng/mL) in one to two hours (range 0.5 to 3 hours) after a single dose administered under fasting conditions.
Following oral administration of colchicine tablets 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).
Following administration of the nonrecommended high-dose regimen (4.8 mg over six hours), mean maximal plasma concentrations were 6.8 ng/mL, at a median 4.47 hours (range: 3.1 to 7.5 hours).
After ten days on a regimen of 0.6 mg twice daily, peak concentrations are 3.1 to 3.6 ng/mL (range 1.6 to 6.0 ng/mL), occurring 1.3 to 1.4 hours postdose (range 0.5 to 3.0 hours).
Mean pharmacokinetic parameter values in healthy adults are shown in Table 5.
Mean (% CV) Pharmacokinetic Parameters in Healthy Adults Given Colchicine Tablets C max (Colchicine ng/mL) T max T max mean (range) CL = Dose/AUC 0-t (calculated from mean values) Vd = CL/Ke (calculated from mean values) (h) Vd/F (L) CL/F (L/hr) t 1/2 (h) Colchicine Tablets 0.6 mg Single Dose (N = 13) 2.5 1.5 (1.0 - 3.0) 341.5 54.1 -- Colchicine Tablets 0.6 mg Twice Daily x 10 Days (N = 13) 3.6 1.3 (0.5 - 3.0) 1150 30.3 26.6 In some subjects, secondary colchicine peaks are seen, occurring between three and 36 hours postdose and ranging from 39 to 155% of the height of the initial peak.
These observations are attributed to intestinal secretion and reabsorption and/or biliary recirculation.
Absolute bioavailability is reported to be approximately 45%.
Administration of colchicine tablets with food has no effect on the rate of colchicine absorption but does decrease the extent of colchicine by approximately 15%.
This is without clinical significance.
Distribution The mean apparent volume of distribution in healthy young volunteers is approximately 5 to 8 L/kg.
Colchicine binding to serum protein is low, 39 ± 5%, primarily to albumin regardless of concentration.
Colchicine crosses the placenta (plasma levels in the fetus are reported to be approximately 15% of the maternal concentration).
Colchicine also distributes into breast milk at concentrations similar to those found in the maternal serum [see Use in Specific Populations (8.1 , 8.2) ] .
Metabolism 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 colchicine).
In vitro studies using human liver microsomes have shown that CYP3A4 is involved in the metabolism of colchicine to 2- and 3-DMC.
Plasma levels of these metabolites are minimal (less than 5% of parent drug).
Elimination/Excretion In healthy volunteers (n = 12), 40 to 65% of 1 mg orally administered colchicine was recovered unchanged in urine.
Pharmacokinetics
12.3 Pharmacokinetics Absorption In healthy adults, colchicine tablets are absorbed when given orally, reaching a mean C max of 2.5 ng/mL (range 1.1 to 4.4 ng/mL) in one to two hours (range 0.5 to 3 hours) after a single dose administered under fasting conditions. Following oral administration of colchicine tablets 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). Following administration of the nonrecommended high-dose regimen (4.8 mg over six hours), mean maximal plasma concentrations were 6.8 ng/mL, at a median 4.47 hours (range: 3.1 to 7.5 hours). After ten days on a regimen of 0.6 mg twice daily, peak concentrations are 3.1 to 3.6 ng/mL (range 1.6 to 6.0 ng/mL), occurring 1.3 to 1.4 hours postdose (range 0.5 to 3.0 hours). Mean pharmacokinetic parameter values in healthy adults are shown in Table 5. Table 5. Mean (% CV) Pharmacokinetic Parameters in Healthy Adults Given Colchicine Tablets C max (Colchicine ng/mL) T max T max mean (range) CL = Dose/AUC 0-t (calculated from mean values) Vd = CL/Ke (calculated from mean values) (h) Vd/F (L) CL/F (L/hr) t 1/2 (h) Colchicine Tablets 0.6 mg Single Dose (N = 13) 2.5 1.5 (1.0 - 3.0) 341.5 54.1 -- Colchicine Tablets 0.6 mg Twice Daily x 10 Days (N = 13) 3.6 1.3 (0.5 - 3.0) 1150 30.3 26.6 In some subjects, secondary colchicine peaks are seen,