Healthy and Renal Impairment Study of Colcrys (Colchicine, USP)

• Maximum Plasma Concentration (Cmax) [ Time Frame: Day 1 and Day 15 (for ESRD patients only) pre-dose and at 0.5, 1, 1.5 , 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 hours post dose ] [ Designated as safety issue: No ]
  The maximum or peak concentration of colchicine in the plasma.
• Time to Maximum Plasma Concentration (Tmax) [ Time Frame: Day 1 and Day 15 (for ESRD patients only) at 0.5, 1, 1.5 , 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 hours post dose ] [ Designated as safety issue: No ]
  The time to reach the maximum or peak concentration of colchicine in the plasma.
• Area Under the Concentration Time Curve From Time Zero to the Time of Last Measured Concentration (AUC 0-t) [ Time Frame: Day 1 and Day 15 (ESRD patients only), predose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, and 120 hours post dose ] [ Designated as safety issue: No ]
  The area under the plasma concentration versus time curve beginning from the first dose until the last quantifiable concentration, calculated by the linear trapezoidal method.
• Area Under the Concentration Time Curve From Time Zero to Infinity (AUC 0 - ∞) [ Time Frame: Day 1 and Day 15 (for ESRD patients only) pre-dose and at 0.5, 1, 1.5 , 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 hours post dose. ] [ Designated as safety issue: No ]
  The area under the plasma concentration versus time curve extrapolated to infinity. AUC 0 - ∞ is calculated as the sum of total AUC 0-t plus the ratio of the last measurable plasma concentration to the elimination rate constant.
• Apparent First-order Terminal Elimination Rate Constant (Kel) [ Time Frame: Day 1 and Day 15 (for ESRD patients only) pre-dose and at 0.5, 1, 1.5 , 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 hours post dose. ] [ Designated as safety issue: No ]
  Apparent first-order terminal elimination rate constant calculated from a semi-log plot of the plasma concentration versus time curve for colchicine. The parameter was calculated by linear least-squares regression analysis using the maximum number of points in the terminal log-linear phase (e.g., three or more non-zero plasma concentrations).
• Apparent First-order Terminal Elimination Half-life (t½) [ Time Frame: Day 1 and Day 15 (for ESRD patients only) pre-dose and at 0.5, 1, 1.5 , 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 hours post dose. ] [ Designated as safety issue: No ]
  The apparent first-order terminal elimination half-life was calculated as 0.693/Kel.
• The Apparent Total Volume of Distribution After Administration (V-area/F) [ Time Frame: Day 1 and Day 15 (for ESRD patients only) pre-dose and at 0.5, 1, 1.5 , 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 hours post dose. ] [ Designated as safety issue: No ]
  The apparent total volume of distribution after administration of colchicine, calculated as Dose / (AUC0-∞ × Kel).
• Weight-adjusted Apparent Total Volume of Distribution After Administration (V-area/F) [ Time Frame: Day 1 and Day 15 (for ESRD patients only) pre-dose and at 0.5, 1, 1.5 , 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 hours post dose. ] [ Designated as safety issue: No ]
  The apparent total volume of distribution after administration of colchicine, calculated as Dose / (AUC0-∞ × Kel), and normalized to body weight.
• Apparent Total Body Clearance of Colchicine [ Time Frame: Day 1 and Day 15 (for ESRD patients only) pre-dose and at 0.5, 1, 1.5 , 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 hours post dose. ] [ Designated as safety issue: No ]
  The apparent total body clearance after administration of colchicine, calculated as Dose/AUC(0-∞).
• Weight-adjusted Apparent Total Body Clearance of Colchicine [ Time Frame: Day 1 and Day 15 (for ESRD patients only) pre-dose and at 0.5, 1, 1.5 , 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 hours post dose. ] [ Designated as safety issue: No ]
  The apparent total body clearance after administration of colchicine, calculated as Dose/AUC(0-∞) and normalized to body weight (in kilograms).
• Amount of Colchicine Excreted in Urine (Ae[0-t]) [ Time Frame: Pre-dose on Day 1 and up to 120 hours post dose. ] [ Designated as safety issue: No ]
  The amount of colchicine excreted in urine during the post-dose collection, calculated as the sum of the amounts in the individual collection intervals (Ae).
• Percentage of Colchicine Dose Excreted in Urine up to the Final Collection Time [ Time Frame: Pre-dose on Day 1 and up to 120 hours post dose. ] [ Designated as safety issue: No ]
  The cumulative percentage of the colchicine dose excreted in urine up to the final collection time, calculated as Ae(0-t) × 100/dose
• Renal Clearance of Colchicine (CLR) [ Time Frame: Pre-dose on Day 1 and up to 120 hours post dose. ] [ Designated as safety issue: No ]
  Renal clearance of colchicine, calculated as Ae(0 t)/AUC 0-t.
• Dialysis Clearance of Colchicine (CLD) [ Time Frame: Day 15, post-dose during dialysis ] [ Designated as safety issue: No ]
  The dialysis clearance of colchicine, calculated as amount of colchicine recovered in dialysate / AUCt2-t1 where t1 and t2 are the times of the start and end of hemodialysis.
• Percentage of Colchicine Dose Recovered in Dialysate [ Time Frame: Day 15, post-dose during dialysis ] [ Designated as safety issue: No ]
  The cumulative percentage of the colchicine dose recovered in dialysate.

• Maximum Plasma Concentration [ Time Frame: pre-dose on Day 1 , 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, 120 hours post dose ] [ Designated as safety issue: No ]
• Urine Concentration [ Time Frame: pre dose on Day 1, 05, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96 and 120 hours post dose ] [ Designated as safety issue: No ]
• Area Under the Concentration Time Curve From Time Zero to the Time of Last Measured Concentration (AUC 0-t) [ Time Frame: pre-dose on Day 1, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, and 120 hours post dose ] [ Designated as safety issue: No ]
• Area Under the Concentration Time Curve From Zero Through Infinity (AUC 0- ∞ ) [ Time Frame: pre dosee on Day 1, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 72, 96, and 120 hours post dose ] [ Designated as safety issue: No ]
• Renal clearance of colchicine (CLR)R [ Time Frame: pre dose on Day 1, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 24, 36, 48, 60, 69-73 hours post dose ] [ Designated as safety issue: No ]

The primary objective of this study is to compare the pharmacokinetic profiles of colchicine and its primary metabolites in plasma and urine following a single 0.6 mg oral dose of colchicine in healthy adults with normal renal function, in patients with mild, moderate or severe renal impairment, and in patients with end-stage renal disease on hemodialysis. An additional objective of this study is to study the clearance of colchicine and its metabolites by hemodialysis. Secondary objectives include evaluation of the safety and tolerability of colchicine in the study population.

40 male and female subjects will be enrolled in the study and stratified into one of five groups based on their renal status as determined from creatinine clearance (CrCL) estimated using the serum creatinine (sCR) and the Cockcroft-Gault and Modified Diet in Renal Disease (MDRD) equations as follows: Treatment group 1 - healthy adults with normal renal function (CrCL/eGFR> 90 mL/min); Treatment groups 2, 3 and 4 - patients with mild (CrCL/eGFR 60-89 mL/min), moderate (CrCL/eGFR 30 to 59 mL/min), and severe (CrCL/eGFR 15 to 29 mL/min) renal impairment, respectively; and Treatment group 5 - subjects with end-stage renal disease requiring hemodialysis. On study day 1, participants in Treatment Groups 1 to 4 will be administered one colchicine 0.6 mg tablet at 8 a.m. under standard fasting conditions. Blood samples will be collected from all participants before dosing and both blood and urine samples will be collected for 120 hours post-dose on a confined basis at times sufficient to adequately define the pharmacokinetics of colchicine and its primary metabolites. There will be two study periods for treatment group 5; Period 1 off dialysis and Period 2 on dialysis with a 14 day washout period between the two study periods. On study day 1, participants in treatment group 5 will be administered one colchicine 0.6 mg tablet under standard fasting conditions immediately following dialysis. Blood samples will be collected from all participants before dosing and for up to 70 hours post-dose at times sufficient to adequately determine the pharmacokinetics of colchicine and its primary metabolites. All adverse events will be evaluated by the investigator and reported in the participant's case report form.

• Experimental: Healthy
  Healthy participants with normal renal function (Creatinine Clearance [CrCl] ≥90 mL/min) received one colchicine 0.6 mg tablet on study day 1.
  Intervention: Drug: Colchicine
• Experimental: Mild renal impairment
  Participants with mild renal impairment (estimated Glomerular Filtration Rate [eGFR] 60 to 89 mL/min) received one colchicine 0.6 mg tablet on study day 1.
  Intervention: Drug: Colchicine
• Experimental: Moderate renal impairment
  Participants with moderate renal impairment (CrCl/eGFR 30 to 59 mL/min) received one colchicine 0.6 mg tablet on study day 1.
  Intervention: Drug: Colchicine
• Experimental: Severe renal impairment
  Participants with severe renal impairment (eGFR 15 to 29 mL/min) received one colchicine 0.6 mg tablet on study day 1.
  Intervention: Drug: Colchicine
• Experimental: End stage renal disease (ESRD)
  Participants with end stage renal disease (ESRD) received one colchicine 0.6 mg tablet on study day 1 immediately following dialysis. After a 14-day washout, participants received one colchicine 0.6 mg tablet on Day 15 prior to dialysis.
  Intervention: Drug: Colchicine

Inclusion Criteria:

• Adult males and females 18-70 years old with a body mass index of <39 kg/m^2.
• Patients with normal renal function or mild renal impairment should be generally healthy on the basis of medical history and physical exam.
• Patients with moderate to end stage renal impairment should be generally medically healthy other than with respect to the morbidities associated with impaired renal function.
• Non-pregnant (post-menopausal, surgically sterile or using effective contraceptive measures).

Exclusion Criteria:

• Known hypersensitivity to colchicine or any component of the formulation of the study drug.
• Patients with a history or presence of a significant medical condition that would interfere with interpretation of the study results.
• Patients who have used any drugs or substances known to inhibit or induce cytochrome P450 (CYP) enzymes and/or P-glycoprotein within 28 days prior to the first dose and throughout the study.
• Patients with recent (2 year) history or evidence of alcoholism or drug abuse or significant psychiatric disease.
• Patients with chronic hepatic dysfunction.