2581 - Colchicine Dosing Guidelines for Gout Patients with Varying Degrees of Renal Impairment Based on Pharmacokinetic Data

Wednesday, November 9, 2011: 9:30 AM
W474a (McCormick Place West)
Suman Wason, Robert D. Faulkner and Matthew W. Davis, URL Pharma, Philadelphia, PA
Presentation Number: 2581

Background/Purpose: Dosing of colchicine (Col) in gout patients with renal impairment is currently based on empirical data. This study obtained single-dose pharmacokinetic (PK) data in healthy subjects and subjects with varying degrees of renal impairment to allow predictions of Col steady state concentrations following 1.2mg/day Col given as 0.6 mg twice daily (the currently recommended dose of colchicine for gout flare prophylaxis). Based on these findings, dosing recommendations are made for renally impaired patients who require gout flare prophylaxis to achieve desired Col concentrations (i.e. ~2 ng/mL).

Method: In this open-label, parallel-group study, 8 subjects in each group were randomized, based on Creatinine Clearance (CrCl), to receive a single dose of oral Col 0.6 mg as follows:

Healthy normal (CrCl> 90 mL/min), mild decrease renal function (CrCl >50 – 90 mL/min), moderate decrease renal function (CrCl >30 – 50 mL/min), severe decrease renal function (CrCl >15 – 30 mL/min), and end-stage renal disease (ESRD) (on and off dialysis, separated by 14 days) CrCl not determined.

Result: Col PK parameters were similar for subjects with normal renal function, subjects with mild renal impairment, and ESRD patients on and off dialysis. However, in subjects with moderate and severe renal impairment, Col clearance was reduced, resulting in higher AUC (approximately 2-fold increase) and Cmax (up to 1.5-fold increase). The single-dose data were then used to predict steady state (10 days) concentrations of Col following the recommended colchicine 0.6 mg twice daily regimen. With twice-daily dosing to steady state, Col concentrations in normal subjects, those with mild decrease, and those in ESRD averaged ~2 ng/mL. These concentrations were greatly exceeded in patients with moderate and severe renal impairment (Col concentrations ~5-6 ng/mL), suggesting that these groups require dosage adjustment.

Metabolites

Despite the reduced clearance of Col in renally impaired subjects, there was no difference in accumulation of metabolites in patients with moderate and severe renal impairment compared to the other groups.

 ESRD and dialysis

On the day of dialysis, subjects were given Col 0.6 mg and dialyzed for 3-4 hrs beginning at one-hour post-dose. While on dialysis, the concentrations were generally lower by  approximately 0.5 ng/mL.

Conclusion: Based on these data, for the prophylaxis of gout flares, no dosing adjustments are needed for patients with normal renal function or mild impairment (CrCl >50 mL/min) or ESRD on or off hemodialysis. For patients with moderate and severe renal failure (CrCl <50 mL/min), it is recommended that Col dose be reduced 50% (i.e. for those patients requiring 0.6 mg twice daily, the dose should be decreased to 0.6 mg once a day, and for those requiring 0.6 mg once a day, the dose should be decreased to 0.3 mg per day).


Keywords: bioavailability, colchcine and gout

Disclosure: S. Wason, URL Pharma, 3 ; R. D. Faulkner, URL Pharma, 3 ; M. W. Davis, URL Pharma, 3 .