Pharmacokinetics
Conditions
Brief summary
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
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.
Interventions
DRUGColchicine
Colchicine tablets
Sponsors
Takeda
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Apparent First-order Terminal Elimination Half-life (t½) | 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 first-order terminal elimination half-life was calculated as 0.693/Kel. |
| Apparent First-order Terminal Elimination Rate Constant (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. | 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). |
| Maximum Plasma Concentration (Cmax) | 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 maximum or peak concentration of colchicine in the plasma. |
| Time to Maximum Plasma Concentration (Tmax) | 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 | 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) | 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 | 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 - ∞) | 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 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. |
| The Apparent Total Volume of Distribution After Administration (V-area/F) | 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 of colchicine, calculated as Dose / (AUC0-∞ × Kel). |
| Weight-adjusted Apparent Total Volume of Distribution After Administration (V-area/F) | 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 of colchicine, calculated as Dose / (AUC0-∞ × Kel), and normalized to body weight. |
| Apparent Total Body Clearance of Colchicine | 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 body clearance after administration of colchicine, calculated as Dose/AUC(0-∞). |
| Weight-adjusted Apparent Total Body Clearance of Colchicine | 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 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]) | Pre-dose on Day 1 and up to 120 hours post dose. | 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 | Pre-dose on Day 1 and up to 120 hours post dose. | 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) | Pre-dose on Day 1 and up to 120 hours post dose. | Renal clearance of colchicine, calculated as Ae(0 t)/AUC 0-t. |
| Dialysis Clearance of Colchicine (CLD) | Day 15, post-dose during dialysis | 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 | Day 15, post-dose during dialysis | The cumulative percentage of the colchicine dose recovered in dialysate. |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at three investigative sites in the United States from 25 May 2010 to 28 February 2011.
Pre-assignment details
Healthy participants, participants with mild, moderate or severe renal impairment and participants with end stage renal disease (requiring hemodialysis) were stratified to one of five treatment groups based on their renal status. All participants received 0.6 mg colchicine.
Participants by arm
| Arm | Count |
|---|---|
| Healthy Healthy participants with normal renal function (Creatinine Clearance \[CrCl\] ≥90 mL/min) received one colchicine 0.6 mg tablet on study day 1. | 8 |
| Mild 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. | 8 |
| Moderate Participants with moderate renal impairment CrCl/eGFR 30 to 59 mL/min) received one colchicine 0.6 mg tablet on study day 1. | 8 |
| Severe Participants with severe renal impairment (eGFR 15 to 29 mL/min) received one colchicine 0.6 mg tablet on study day 1. | 8 |
| 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. | 8 |
| Total | 40 |
Baseline characteristics
| Characteristic | Total | ESRD | Severe | Healthy | Moderate | Mild |
|---|---|---|---|---|---|---|
| Age Continuous | 55.85 years STANDARD_DEVIATION 10.96 | 42.2 years STANDARD_DEVIATION 12.85 | 57.6 years STANDARD_DEVIATION 8.48 | 52.5 years STANDARD_DEVIATION 5.29 | 63.0 years STANDARD_DEVIATION 5.4 | 63.9 years STANDARD_DEVIATION 3.94 |
| Body Mass Index (BMI) | 27.60 kg/m^2 STANDARD_DEVIATION 5.28 | 25.66 kg/m^2 STANDARD_DEVIATION 5.018 | 33.96 kg/m^2 STANDARD_DEVIATION 4.489 | 26.54 kg/m^2 STANDARD_DEVIATION 2.113 | 28.64 kg/m^2 STANDARD_DEVIATION 4.823 | 23.18 kg/m^2 STANDARD_DEVIATION 2.56 |
| Child Bearing Potential No | 17 participants | 2 participants | 4 participants | 4 participants | 3 participants | 4 participants |
| Child Bearing Potential Yes | 3 participants | 2 participants | 0 participants | 0 participants | 1 participants | 0 participants |
| Creatinine Clearance/estimated Glomerular Filtration Rate | 55.70 mL/min STANDARD_DEVIATION 36.61 | 10.9 mL/min STANDARD_DEVIATION 2.97 | 22 mL/min STANDARD_DEVIATION 4.17 | 111.49 mL/min STANDARD_DEVIATION 22.651 | 40.0 mL/min STANDARD_DEVIATION 6.78 | 73.3 mL/min STANDARD_DEVIATION 8.1 |
| Height | 169.09 cm STANDARD_DEVIATION 9.27 | 168.05 cm STANDARD_DEVIATION 11.991 | 172.06 cm STANDARD_DEVIATION 8.643 | 170.33 cm STANDARD_DEVIATION 7.722 | 164.83 cm STANDARD_DEVIATION 9.054 | 167.94 cm STANDARD_DEVIATION 8.865 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 participants | 0 participants | 0 participants | 0 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized Asian | 2 participants | 0 participants | 0 participants | 0 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized Black or African American | 12 participants | 6 participants | 3 participants | 0 participants | 3 participants | 0 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 12 participants | 0 participants | 1 participants | 5 participants | 3 participants | 3 participants |
| Race/Ethnicity, Customized Native Hawaiian or other pacific islander | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 28 participants | 8 participants | 7 participants | 3 participants | 5 participants | 5 participants |
| Race/Ethnicity, Customized Other | 1 participants | 0 participants | 1 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized White | 24 participants | 2 participants | 4 participants | 8 participants | 4 participants | 6 participants |
| Region of Enrollment United States | 40 participants | 8 participants | 8 participants | 8 participants | 8 participants | 8 participants |
| Sex: Female, Male Female | 20 Participants | 4 Participants | 4 Participants | 4 Participants | 4 Participants | 4 Participants |
| Sex: Female, Male Male | 20 Participants | 4 Participants | 4 Participants | 4 Participants | 4 Participants | 4 Participants |
| Weight | 78.95 kg STANDARD_DEVIATION 18.47 | 73.86 kg STANDARD_DEVIATION 22.287 | 100.81 kg STANDARD_DEVIATION 16.856 | 77.09 kg STANDARD_DEVIATION 8.494 | 77.55 kg STANDARD_DEVIATION 10.667 | 65.55 kg STANDARD_DEVIATION 9.904 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 8 | 2 / 8 | 4 / 8 | 4 / 8 | 4 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 |
Outcome results
Primary
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).
Time frame: Pre-dose on Day 1 and up to 120 hours post dose.
Population: Per Protocol Analysis Population - Participants renal function was characterized by CrCl using the Cockcroft-Gault equation as healthy (≥90 mL/min), and characterized by Modified Diet in Renal Disease (MDRD) equations as mild (60 - 89 mL/min), moderate (30 - 59 mL/min), severe (15 - 29 mL/min), and ESRD patients requiring dialysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy | Amount of Colchicine Excreted in Urine (Ae[0-t]) | 0.110 mg | Standard Deviation 0.032 |
| Mild | Amount of Colchicine Excreted in Urine (Ae[0-t]) | 0.100 mg | Standard Deviation 0.026 |
| Moderate | Amount of Colchicine Excreted in Urine (Ae[0-t]) | 0.094 mg | Standard Deviation 0.053 |
| Severe | Amount of Colchicine Excreted in Urine (Ae[0-t]) | 0.058 mg | Standard Deviation 0.012 |
Primary
Apparent First-order Terminal Elimination Half-life (t½)
The apparent first-order terminal elimination half-life was calculated as 0.693/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.
Population: Per Protocol Analysis Population - Participants renal function was characterized by CrCl using the Cockcroft-Gault equation as healthy (≥90 mL/min), and characterized by Modified Diet in Renal Disease (MDRD) equations as mild (60 - 89 mL/min), moderate (30 - 59 mL/min), severe (15 - 29 mL/min), and ESRD patients requiring dialysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy | Apparent First-order Terminal Elimination Half-life (t½) | 30.63 hr | Standard Deviation 5.43 |
| Mild | Apparent First-order Terminal Elimination Half-life (t½) | 30.92 hr | Standard Deviation 3.54 |
| Moderate | Apparent First-order Terminal Elimination Half-life (t½) | 39.90 hr | Standard Deviation 3.93 |
| Severe | Apparent First-order Terminal Elimination Half-life (t½) | 49.53 hr | Standard Deviation 6.01 |
| ESRD - Off Dialysis | Apparent First-order Terminal Elimination Half-life (t½) | 29.38 hr | Standard Deviation 7.51 |
| ESRD - on Dialysis | Apparent First-order Terminal Elimination Half-life (t½) | 40.80 hr | Standard Deviation 21.71 |
Primary
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).
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.
Population: Per Protocol Analysis Population - Participants renal function was characterized by CrCl using the Cockcroft-Gault equation as healthy (≥90 mL/min), and characterized by Modified Diet in Renal Disease (MDRD) equations as mild (60 - 89 mL/min), moderate (30 - 59 mL/min), severe (15 - 29 mL/min), and ESRD patients requiring dialysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy | Apparent First-order Terminal Elimination Rate Constant (Kel) | 0.023 1/hr | Standard Deviation 0.004 |
| Mild | Apparent First-order Terminal Elimination Rate Constant (Kel) | 0.023 1/hr | Standard Deviation 0.003 |
| Moderate | Apparent First-order Terminal Elimination Rate Constant (Kel) | 0.018 1/hr | Standard Deviation 0.002 |
| Severe | Apparent First-order Terminal Elimination Rate Constant (Kel) | 0.014 1/hr | Standard Deviation 0.002 |
| ESRD - Off Dialysis | Apparent First-order Terminal Elimination Rate Constant (Kel) | 0.025 1/hr | Standard Deviation 0.006 |
| ESRD - on Dialysis | Apparent First-order Terminal Elimination Rate Constant (Kel) | 0.020 1/hr | Standard Deviation 0.007 |
Primary
Apparent Total Body Clearance of Colchicine
The apparent total body clearance after administration of colchicine, calculated as Dose/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.
Population: Per Protocol Analysis Population - Participants renal function was characterized by CrCl using the Cockcroft-Gault equation as healthy (≥90 mL/min), and characterized by Modified Diet in Renal Disease (MDRD) equations as mild (60 - 89 mL/min), moderate (30 - 59 mL/min), severe (15 - 29 mL/min), and ESRD patients requiring dialysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy | Apparent Total Body Clearance of Colchicine | 26.34 L/hr | Standard Deviation 7.57 |
| Mild | Apparent Total Body Clearance of Colchicine | 23.04 L/hr | Standard Deviation 5.6 |
| Moderate | Apparent Total Body Clearance of Colchicine | 13.63 L/hr | Standard Deviation 5.8 |
| Severe | Apparent Total Body Clearance of Colchicine | 14.59 L/hr | Standard Deviation 7.37 |
| ESRD - Off Dialysis | Apparent Total Body Clearance of Colchicine | 22.07 L/hr | Standard Deviation 9.87 |
| ESRD - on Dialysis | Apparent Total Body Clearance of Colchicine | 25.78 L/hr | Standard Deviation 15.08 |
Primary
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.
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.
Population: Per Protocol Analysis Population - Participants renal function was characterized by CrCl using the Cockcroft-Gault equation as healthy (≥90 mL/min), and characterized by Modified Diet in Renal Disease (MDRD) equations as mild (60 - 89 mL/min), moderate (30 - 59 mL/min), severe (15 - 29 mL/min), and ESRD patients requiring dialysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy | Area Under the Concentration Time Curve From Time Zero to Infinity (AUC 0 - ∞) | 24.73 ng*h/mL | Standard Deviation 8.1 |
| Mild | Area Under the Concentration Time Curve From Time Zero to Infinity (AUC 0 - ∞) | 27.21 ng*h/mL | Standard Deviation 5.56 |
| Moderate | Area Under the Concentration Time Curve From Time Zero to Infinity (AUC 0 - ∞) | 48.94 ng*h/mL | Standard Deviation 13.45 |
| Severe | Area Under the Concentration Time Curve From Time Zero to Infinity (AUC 0 - ∞) | 48.00 ng*h/mL | Standard Deviation 17.36 |
| ESRD - Off Dialysis | Area Under the Concentration Time Curve From Time Zero to Infinity (AUC 0 - ∞) | 31.68 ng*h/mL | Standard Deviation 12.28 |
| ESRD - on Dialysis | Area Under the Concentration Time Curve From Time Zero to Infinity (AUC 0 - ∞) | 30.61 ng*h/mL | Standard Deviation 17.29 |
Primary
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.
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
Population: Per Protocol Analysis Population - Participants renal function was characterized by CrCl using the Cockcroft-Gault equation as healthy (≥90 mL/min), and characterized by Modified Diet in Renal Disease (MDRD) equations as mild (60 - 89 mL/min), moderate (30 - 59 mL/min), severe (15 - 29 mL/min), and ESRD patients requiring dialysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy | Area Under the Concentration Time Curve From Time Zero to the Time of Last Measured Concentration (AUC 0-t) | 23.37 ng*h/mL | Standard Deviation 7.75 |
| Mild | Area Under the Concentration Time Curve From Time Zero to the Time of Last Measured Concentration (AUC 0-t) | 25.83 ng*h/mL | Standard Deviation 5.43 |
| Moderate | Area Under the Concentration Time Curve From Time Zero to the Time of Last Measured Concentration (AUC 0-t) | 43.94 ng*h/mL | Standard Deviation 11.68 |
| Severe | Area Under the Concentration Time Curve From Time Zero to the Time of Last Measured Concentration (AUC 0-t) | 40.44 ng*h/mL | Standard Deviation 13.58 |
| ESRD - Off Dialysis | Area Under the Concentration Time Curve From Time Zero to the Time of Last Measured Concentration (AUC 0-t) | 26.09 ng*h/mL | Standard Deviation 8.73 |
| ESRD - on Dialysis | Area Under the Concentration Time Curve From Time Zero to the Time of Last Measured Concentration (AUC 0-t) | 22.65 ng*h/mL | Standard Deviation 8.54 |
Primary
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.
Time frame: Day 15, post-dose during dialysis
Population: ESRD participants on dialysis, where data were available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy | Dialysis Clearance of Colchicine (CLD) | 7.4 L/h | Standard Deviation 0.7 |
Primary
Maximum Plasma Concentration (Cmax)
The maximum or peak concentration of colchicine in the plasma.
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
Population: Per Protocol Analysis Population - Participants renal function was characterized by CrCl using the Cockcroft-Gault equation as healthy (≥90 mL/min), and characterized by Modified Diet in Renal Disease (MDRD) equations as mild (60 - 89 mL/min), moderate (30 - 59 mL/min), severe (15 - 29 mL/min), and ESRD patients requiring dialysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy | Maximum Plasma Concentration (Cmax) | 2.43 ng/mL | Standard Deviation 0.68 |
| Mild | Maximum Plasma Concentration (Cmax) | 2.73 ng/mL | Standard Deviation 0.78 |
| Moderate | Maximum Plasma Concentration (Cmax) | 3.69 ng/mL | Standard Deviation 1.42 |
| Severe | Maximum Plasma Concentration (Cmax) | 2.53 ng/mL | Standard Deviation 0.73 |
| ESRD - Off Dialysis | Maximum Plasma Concentration (Cmax) | 2.67 ng/mL | Standard Deviation 0.94 |
| ESRD - on Dialysis | Maximum Plasma Concentration (Cmax) | 2.27 ng/mL | Standard Deviation 0.71 |
Primary
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
Time frame: Pre-dose on Day 1 and up to 120 hours post dose.
Population: Per Protocol Analysis Population - Participants renal function was characterized by CrCl using the Cockcroft-Gault equation as healthy (≥90 mL/min), and characterized by Modified Diet in Renal Disease (MDRD) equations as mild (60 - 89 mL/min), moderate (30 - 59 mL/min), severe (15 - 29 mL/min), and ESRD patients requiring dialysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy | Percentage of Colchicine Dose Excreted in Urine up to the Final Collection Time | 18.34 percent of dose | Standard Deviation 5.39 |
| Mild | Percentage of Colchicine Dose Excreted in Urine up to the Final Collection Time | 16.69 percent of dose | Standard Deviation 4.3 |
| Moderate | Percentage of Colchicine Dose Excreted in Urine up to the Final Collection Time | 15.67 percent of dose | Standard Deviation 8.77 |
| Severe | Percentage of Colchicine Dose Excreted in Urine up to the Final Collection Time | 9.63 percent of dose | Standard Deviation 2.05 |
Primary
Percentage of Colchicine Dose Recovered in Dialysate
The cumulative percentage of the colchicine dose recovered in dialysate.
Time frame: Day 15, post-dose during dialysis
Population: ESRD participants on dialysis, where data were available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy | Percentage of Colchicine Dose Recovered in Dialysate | 5.2 percent dose | Standard Deviation 2.3 |
Primary
Renal Clearance of Colchicine (CLR)
Renal clearance of colchicine, calculated as Ae(0 t)/AUC 0-t.
Time frame: Pre-dose on Day 1 and up to 120 hours post dose.
Population: Per Protocol Analysis Population - Participants renal function was characterized by CrCl using the Cockcroft-Gault equation as healthy (≥90 mL/min), and characterized by Modified Diet in Renal Disease (MDRD) equations as mild (60 - 89 mL/min), moderate (30 - 59 mL/min), severe (15 - 29 mL/min), and ESRD patients requiring dialysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy | Renal Clearance of Colchicine (CLR) | 4.78 L/hr | Standard Deviation 0.51 |
| Mild | Renal Clearance of Colchicine (CLR) | 3.90 L/hr | Standard Deviation 0.74 |
| Moderate | Renal Clearance of Colchicine (CLR) | 2.12 L/hr | Standard Deviation 0.86 |
| Severe | Renal Clearance of Colchicine (CLR) | 1.69 L/hr | Standard Deviation 1.13 |
Primary
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).
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.
Population: Per Protocol Analysis Population - Participants renal function was characterized by CrCl using the Cockcroft-Gault equation as healthy (≥90 mL/min), and characterized by Modified Diet in Renal Disease (MDRD) equations as mild (60 - 89 mL/min), moderate (30 - 59 mL/min), severe (15 - 29 mL/min), and ESRD patients requiring dialysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy | The Apparent Total Volume of Distribution After Administration (V-area/F) | 1131.68 L | Standard Deviation 247.32 |
| Mild | The Apparent Total Volume of Distribution After Administration (V-area/F) | 1024.22 L | Standard Deviation 266.47 |
| Moderate | The Apparent Total Volume of Distribution After Administration (V-area/F) | 761.81 L | Standard Deviation 237.07 |
| Severe | The Apparent Total Volume of Distribution After Administration (V-area/F) | 1009.02 L | Standard Deviation 419.88 |
| ESRD - Off Dialysis | The Apparent Total Volume of Distribution After Administration (V-area/F) | 870.46 L | Standard Deviation 230.68 |
| ESRD - on Dialysis | The Apparent Total Volume of Distribution After Administration (V-area/F) | 1263.0 L | Standard Deviation 462.4 |
Primary
Time to Maximum Plasma Concentration (Tmax)
The time to reach the maximum or peak concentration of colchicine in the plasma.
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
Population: Per Protocol Analysis Population - Participants renal function was characterized by CrCl using the Cockcroft-Gault equation as healthy (≥90 mL/min), and characterized by Modified Diet in Renal Disease (MDRD) equations as mild (60 - 89 mL/min), moderate (30 - 59 mL/min), severe (15 - 29 mL/min), and ESRD patients requiring dialysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy | Time to Maximum Plasma Concentration (Tmax) | 1.31 hours | Standard Deviation 0.37 |
| Mild | Time to Maximum Plasma Concentration (Tmax) | 1.01 hours | Standard Deviation 0.04 |
| Moderate | Time to Maximum Plasma Concentration (Tmax) | 1.31 hours | Standard Deviation 0.37 |
| Severe | Time to Maximum Plasma Concentration (Tmax) | 1.58 hours | Standard Deviation 0.68 |
| ESRD - Off Dialysis | Time to Maximum Plasma Concentration (Tmax) | 1.31 hours | Standard Deviation 0.46 |
| ESRD - on Dialysis | Time to Maximum Plasma Concentration (Tmax) | 1.29 hours | Standard Deviation 1.01 |
Primary
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).
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.
Population: Per Protocol Analysis Population - Participants renal function was characterized by CrCl using the Cockcroft-Gault equation as healthy (≥90 mL/min), and characterized by Modified Diet in Renal Disease (MDRD) equations as mild (60 - 89 mL/min), moderate (30 - 59 mL/min), severe (15 - 29 mL/min), and ESRD patients requiring dialysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy | Weight-adjusted Apparent Total Body Clearance of Colchicine | 0.34 L/hr/kg | Standard Deviation 0.08 |
| Mild | Weight-adjusted Apparent Total Body Clearance of Colchicine | 0.36 L/hr/kg | Standard Deviation 0.12 |
| Moderate | Weight-adjusted Apparent Total Body Clearance of Colchicine | 0.18 L/hr/kg | Standard Deviation 0.09 |
| Severe | Weight-adjusted Apparent Total Body Clearance of Colchicine | 0.14 L/hr/kg | Standard Deviation 0.06 |
| ESRD - Off Dialysis | Weight-adjusted Apparent Total Body Clearance of Colchicine | 0.35 L/hr/kg | Standard Deviation 0.26 |
| ESRD - on Dialysis | Weight-adjusted Apparent Total Body Clearance of Colchicine | 0.41 L/hr/kg | Standard Deviation 0.36 |
Primary
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.
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.
Population: Per Protocol Analysis Population - Participants renal function was characterized by CrCl using the Cockcroft-Gault equation as healthy (≥90 mL/min), and characterized by Modified Diet in Renal Disease (MDRD) equations as mild (60 - 89 mL/min), moderate (30 - 59 mL/min), severe (15 - 29 mL/min), and ESRD patients requiring dialysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Healthy | Weight-adjusted Apparent Total Volume of Distribution After Administration (V-area/F) | 14.84 L/kg | Standard Deviation 3.36 |
| Mild | Weight-adjusted Apparent Total Volume of Distribution After Administration (V-area/F) | 15.80 L/kg | Standard Deviation 3.94 |
| Moderate | Weight-adjusted Apparent Total Volume of Distribution After Administration (V-area/F) | 10.06 L/kg | Standard Deviation 3.65 |
| Severe | Weight-adjusted Apparent Total Volume of Distribution After Administration (V-area/F) | 9.91 L/kg | Standard Deviation 3.1 |
| ESRD - Off Dialysis | Weight-adjusted Apparent Total Volume of Distribution After Administration (V-area/F) | 13.35 L/kg | Standard Deviation 6.94 |
| ESRD - on Dialysis | Weight-adjusted Apparent Total Volume of Distribution After Administration (V-area/F) | 18.91 L/kg | Standard Deviation 11.91 |