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. 2021 Jun;51(6):643-656.
doi: 10.1080/00498254.2021.1909782. Epub 2021 Apr 12.

Colchicine for the treatment of COVID-19 patients: efficacy, safety, and model informed dosage regimens

Eleni Karatza  1 , George Ismailos  2 , Vangelis Karalis  1
Affiliations
Free PMC article

Colchicine for the treatment of COVID-19 patients: efficacy, safety, and model informed dosage regimens

Eleni Karatza et al. Xenobiotica. 2021 Jun.
Free PMC article

Abstract

Colchicine is widely investigated for cardioprotection of COVID-19 patients since it can prevent the phenomenon of 'cytokine storm' and may reduce the complications arising from COVID-19. Despite the potentially beneficial effects of colchicine, there is no consensus on the appropriate dosage regimen and numerous schemes are currently used.In this study, simulations were performed to identify the ability of dosage regimens to attain plasma levels in CVOID-19 patients, known to be generally safe and efficacious. Since renal and hepatic impairment, as well as, drug-drug interactions have been identified to be the most significant factors increasing colchicine toxicity, the impact of these interactions was assessed in the simulations.Some dosage regimens lead to high colchicine concentrations, while others result in sub-therapeutic levels. Additional dosage schemes were proposed in this study aiming to be applied in patients with clearance insufficiency. Colchicine administration of 0.5 mg twice daily, can be considered safe and effective. In cases of clearance impairment, doses as low as 0.25 mg thrice or twice daily should be applied.Colchicine is a narrow therapeutic index drug and dosage regimens tailored to patients' needs should be designed.

Keywords: COVID-19; Colchicine; cardioprotection; dosage regimens; pharmacokinetics; simulations.

Conflict of interest statement

The authors report no declarations of interest.

Figures

Figure 1.
Figure 1.
A schematic representation of the pharmacokinetic model used for the simulations. This model was obtained from the study of Thomas et al. (1989). Colchicine is distributed in two compartments, the central and the peripheral compartment. Key: Vc, volume of distribution of the central compartment; Clr, first-order renal clearance from the central compartment; Clnr, first-order non-renal clearance from the central compartment; k12, first-order inter-compartmental transfer constant from the central to the peripheral compartment; k21, first-order inter-compartmental transfer constant from the peripheral to the central compartment.
Figure 2.
Figure 2.
Simulated plasma colchicine concentrations (μg/l) versus time (h) according to dosing schemes (Table 4) currently used in clinical practice or in clinical trials. (A) 1 mg once daily, (B) 0.5 mg once daily, (C) 0.5 mg twice daily, (D) Loading dose of 1.5 mg, followed by 0.5 mg after 2 h and then 0.5 twice daily for 14 days, (E) COLCORONA trial: 0.5 mg twice daily for the first 3 days and then 0.5 once daily for 27 days, (F) GRECCO-19 trial: Loading dose 1.5 mg, followed by 0.5 mg after 1 h and then 0.5 twice daily. (G) RECOVERY trial: Loading dose of 1 mg, followed by 0.5 mg 12 h later, then maintenance dose 0.5 mg twice daily for a further of nine days (10 days in total) or until hospital discharge, (H) 0.5 mg thrice daily for 5 days, then 0.5 mg twice daily for 5 days. Upper line: 3 μg/l, plasma concentration that elicits toxic effects. Lower line: 0.5 μg/l, minimum effective plasma concentration. The inter-individual variability values, considered for all pharmacokinetic parameters, were those reported in the study of Thomas et al. (1989). Dashed lines indicate the average peak and trough concentration values at steady state.
Figure 3.
Figure 3.
Simulated plasma colchicine concentrations (μg/l) versus time (h) in case of its co-administration with other medicines. (A) Co-administration with azithromycin (thus colchicine clearance would be reduced by 30%): Loading dose of 1 mg, followed then 0.5 twice daily, (B) Co-administration with lopinavir/ritonavir (thus colchicine clearance would be reduced by 70%): Loading dose of 0.5 mg and then after 72 h 0.5 mg every 72 h for 14 days or until discharge, (C) Co-administration with CYP3A4 inhibitors (e.g. diltiazem, imatinib, letermovir) [RECOVERY trial]: Loading dose of 1 mg, followed by 0.5 mg 12 h later, then maintenance dose 0.5 mg once daily. Upper line: 3 μg/l, plasma concentration that elicits toxic effects. Lower line: 0.5 μg/l, minimum effective plasma concentration. The inter-individual variability values, considered for all pharmacokinetic parameters, were those reported in the study of Thomas et al. (1989). Dashed lines indicate the average peak and trough concentration values at steady state.
Figure 4.
Figure 4.
Simulated mean plasma colchicine concentrations (μg/l) versus time (h) of patients with normal clearance, 30% impaired total clearance, 50% impaired total clearance, and 70% impaired total clearance. Eight different dosage regimens (Table 4) are simulated as following: (A) 1 mg once daily, (B) 0.5 mg once daily, (C) 0.5 mg twice daily, (D) Loading dose of 1.5 mg, followed by 0.5 mg after 2 h and then 0.5 twice daily for 14 days, (E) 0.5 mg twice daily for the first 3 days and then 0.5 once daily for 27 days, (F) Loading dose of 1.5 mg, followed by 0.5 mg after 1 h and then 0.5 mg twice daily, (G) 0.5 mg thrice daily for 5 days, then 0.5 mg twice daily for 5 days, (H) 0.25 mg thrice daily for 5 days, then 0.25 mg twice daily for 5 days. Upper line: 3 μg/l, plasma concentration that elicits toxic effects. Lower line: 0.5 μg/l, minimum effective plasma concentration.
Figure 5.
Figure 5.
Simulated mean plasma colchicine concentrations (μg/l) versus time (h) of patients with normal clearance, 30% impaired total clearance, 50% impaired total clearance, and 70% impaired total clearance. The two dosing regimens of the RECOVERY trial are simulated (Table 4). (A) Loading dose of 1 mg, followed by 0.5 mg 12 h later, then maintenance dose 0.5 mg twice daily for a further of 9 days (10 days in total) or until hospital discharge, (B) Loading dose of 1 mg, followed by 0.5 mg 12 h later, then maintenance dose 0.5 mg once daily. Upper line: 3 μg/l, plasma concentration that elicits toxic effects. Lower line: 0.5 μg/l, minimum effective plasma concentration.
Figure 6.
Figure 6.
Simulated plasma colchicine concentrations (μg/l) versus time (h) for three levels (30%, 50%, and 70%) of clearance impairment. For each level of impairment, a newly proposed dosage regimen is utilised. (A) 30% impairment: 0.25 mg thrice daily, (B) 50% impairment: 0.25 mg twice daily, (C) 70% impairment: 0.25 mg twice daily for the first two days and then 0.25 mg once daily. Upper line: 3 μg/l, plasma concentration that elicits toxic effects. Lower line: 0.5 μg/l, minimum effective plasma concentration. The inter-individual variability values, considered for all pharmacokinetic parameters, were those reported in the study of Thomas et al. (1989). Dashed lines indicate the average peak and trough concentration values at steady state.
Figure A1.
Figure A1.
Mean simulated plasma colchicine concentrations (μg/l) versus time (h) of patients with normal clearance, mild renal impairment, moderate renal impairment, severe renal impairment, 30% impaired total clearance, 50% impaired total clearance, 70% impaired total clearance receiving dosing schemes A: 1 mg once daily, B: 0.5 mg once daily, C: 0.5 mg twice daily, D: Loading dose of 1.5 mg, followed by 0.5 mg after 2 h and then 0.5 twice daily for 14 days, E: 0.5 mg twice daily for the first 3 days and then 0.5 once daily for 27 days, F : Loading dose of 1.5 mg, followed by 0.5 mg after 1 h and then 0.5 twice daily. Upper line: 3 μg/l, plasma concentration that elicits toxic effects. Lower line: 0.5 μg/l, minimum effective plasma concentration.
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