The Influence of Patient Factors on the Population Pharmacokinetics of Colchicine: Implications for Safe and Effective Dosing.

Background And Objectives: The factors that predict colchicine plasma concentrations and the impact on safety and efficacy are under-researched. We aimed to determine the probability of achieving steady-state plasma concentrations within the nominal therapeutic range of 0.5-3 ng/mL.

Methods: Colchicine plasma concentrations from 78 people with gout were analysed using non-linear mixed effects. Body size, kidney function, concomitant drugs, ethnicity, sex, age and adherence were tested as covariates in the model. Simulations were conducted to determine the probability of achieving steady-state minimum, maximum and average concentrations within the therapeutic range of 0.5-3 ng/mL under different doses and for different patient characteristics. We considered colchicine doses that produced > 80% of steady-state average concentrations < 3 ng/mL and > 0.5 ng/mL to have a reasonable probability of safety and efficacy.

Results: A two-compartment pharmacokinetic model with zero-order absorption was the best fit. Body weight, sex and statin use were significant predictors of colchicine pharmacokinetics, reducing the between-subject variance on clearance by about 40%. The model predicted that colchicine dosages of ≤ 1.5 mg daily carry a low risk of toxicity based on the criteria defined here. Efficacious concentrations were achieved for all dosages tested except 0.5 mg daily, where concentrations below the proposed therapeutic range may occur in those with a body weight > 80 kg. Higher colchicine dosages of > 1.5 mg daily may exceed the proposed upper limit of safety in many individuals, particularly those with low body weight who are taking statins.

Conclusion: A model for the pharmacokinetics of colchicine was developed and evaluated. Low-dose regimes (≤ 1.5 mg daily) are not predicted to achieve concentrations above the proposed safety threshold of 3 ng/mL in most people, although concentrations below the lower limit of the therapeutic range may occur in those taking 0.5-mg doses who are > 80 kg in body weight. Higher colchicine dosages of > 1.5 mg daily may exceed the proposed upper limit of safety in individuals with low body weight who are taking statins.