Prophylaxis of Gout Flares in Patients with Renal Impairment: Dosing Adjustments with Colchicine Oral Solution Informed by a Pharmacokinetic Model.

Background: Patients receiving the standard prophylaxis dose of colchicine for gout flares are at increased risk for developing toxicity if there are pre-existing renal impairment or drug-drug interactions. Guidelines recommend exercising caution, deferring dose adjustment to the clinician's discretion.

Methods: Pharmacokinetic study data for colchicine oral solution in healthy subjects was used to build a pharmacokinetic model. Using the derived pharmacokinetic disposition parameters from the best fit model and the derived parameters of clearance in patients with renal impairment, simulation of colchicine plasma levels to target 0.5-3 ng/mL with colchicine oral solution was undertaken for various dose levels in different degrees of renal impairment.

Results: With the standard colchicine 0.6 mg daily dose, plasma levels are expected to be therapeutic in patients with mild renal impairment (estimated glomerular filtration rate [eGFR] 60-89 mL/min/1.73 m2). However, with this same 0.6 mg daily dose, patients with moderate renal impairment (eGFR 30-59 mL/min/1.73 m2) and severe renal impairment (eGFR of 15-29 mL/min/1.73 m2) would have excursions up to 10% and 36%, respectively, above the maximum tolerated level. Administering a lower dose such as 0.3 mg daily by splitting the conventional 0.6 mg tablet or by administering 0.6 mg once every-other-day (QOD) in moderate renal impairment would result in plasma colchicine levels in subtherapeutic range (< 0.5 ng/mL) for 20-70% of the dosing interval.

Conclusions: Analysis of pharmacokinetic model data confirms that the majority of patients with renal impairment taking colchicine solid dosage formulations will be above or below therapeutic levels, exposing them to potential side effects. However, more precise dosing with colchicine oral solution of 0.48 mg (4 mL) or 0.5 mg tablet available in certain countries for moderate renal impairment and 0.3 mg (2.5 mL) for severe renal impairment are associated with optimal levels and safer for patients with renal impairment. No dosage adjustment is needed for patients with mild renal impairment.