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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Single-Dose, Open-Label Study of the Pharmacokinetics, Safety, and Tolerability of Colcrys (Colchicine, USP) Tablets 0.6 mg Administered to Healthy Subjects and Subjects With Mild, Moderate, Severe Renal Impairment, and End-Stage Renal Disease

Conditions
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Pharmacokinetics

Intervention / Treatment
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* Drug: Colchicine


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Healthy<br>Healthy participants with normal renal function (Creatinine Clearance [CrCl] ≥90 mL/min) received one colchicine 0.6 mg tablet on study day 1. | Drug: Colchicine<br>* Colchicine tablets<br>* Other names: COLCRYS;|
| Experimental: Mild renal impairment<br>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. | Drug: Colchicine<br>* Colchicine tablets<br>* Other names: COLCRYS;|
| Experimental: Moderate renal impairment<br>Participants with moderate renal impairment (CrCl/eGFR 30 to 59 mL/min) received one colchicine 0.6 mg tablet on study day 1. | Drug: Colchicine<br>* Colchicine tablets<br>* Other names: COLCRYS;|
| Experimental: Severe renal impairment<br>Participants with severe renal impairment (eGFR 15 to 29 mL/min) received one colchicine 0.6 mg tablet on study day 1. | Drug: Colchicine<br>* Colchicine tablets<br>* Other names: COLCRYS;|
| Experimental: End stage renal disease (ESRD)<br>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. | Drug: Colchicine<br>* Colchicine tablets<br>* Other names: COLCRYS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Plasma Concentration (Cmax) | The maximum or peak concentration of colchicine in the plasma. | 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 | 
| Time to Maximum Plasma Concentration (Tmax) | The time to reach the maximum or peak concentration of colchicine in the plasma. | 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 | 
| Area Under the Concentration Time Curve From Time Zero to the Time of Last Measured Concentration (AUC 0-t) | 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. | 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 | 
| Area Under the Concentration Time Curve From Time Zero to Infinity (AUC 0 - ∞) | 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. | 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. | 
| Apparent First-order Terminal Elimination Rate Constant (Kel) | 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). | 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. | 
| Apparent First-order Terminal Elimination Half-life (t½) | The apparent first-order terminal elimination half-life was calculated as 0.693/Kel. | 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. | 
| The Apparent Total Volume of Distribution After Administration (V-area/F) | The apparent total volume of distribution after administration of colchicine, calculated as Dose / (AUC0-∞ × Kel). | 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. | 
| Weight-adjusted Apparent Total Volume of Distribution After Administration (V-area/F) | The apparent total volume of distribution after administration of colchicine, calculated as Dose / (AUC0-∞ × Kel), and normalized to body weight. | 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. | 
| Apparent Total Body Clearance of Colchicine | The apparent total body clearance after administration of colchicine, calculated as Dose/AUC(0-∞). | 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. | 
| Weight-adjusted Apparent Total Body Clearance of Colchicine | The apparent total body clearance after administration of colchicine, calculated as Dose/AUC(0-∞) and normalized to body weight (in kilograms). | 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. | 
| Amount of Colchicine Excreted in Urine (Ae[0-t]) | 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). | Pre-dose on Day 1 and up to 120 hours post dose. | 
| Percentage of Colchicine Dose Excreted in Urine up to the Final Collection Time | The cumulative percentage of the colchicine dose excreted in urine up to the final collection time, calculated as Ae(0-t) × 100/dose | Pre-dose on Day 1 and up to 120 hours post dose. | 
| Renal Clearance of Colchicine (CLR) | Renal clearance of colchicine, calculated as Ae(0 t)/AUC 0-t. | Pre-dose on Day 1 and up to 120 hours post dose. | 
| Dialysis Clearance of Colchicine (CLD) | 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. | Day 15, post-dose during dialysis | 
| Percentage of Colchicine Dose Recovered in Dialysate | The cumulative percentage of the colchicine dose recovered in dialysate. | Day 15, post-dose during dialysis |