Clinical trial NCT01084278: Healthy and Renal Impairment Study of Colcrys (Colchicine, USP)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Pharmacokinetics
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2010-03-10
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Maximum Plasma Concentration (Cmax)
timeFrame: 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
measure: Time to Maximum Plasma Concentration (Tmax)
timeFrame: 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
measure: Area Under the Concentration Time Curve From Time Zero to the Time of Last Measured Concentration (AUC 0-t)
timeFrame: 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
measure: Area Under the Concentration Time Curve From Time Zero to Infinity (AUC 0 - ∞)
timeFrame: 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.
measure: Apparent First-order Terminal Elimination Rate Constant (Kel)
timeFrame: 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.
measure: Apparent First-order Terminal Elimination Half-life (t½)
timeFrame: 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.
measure: The Apparent Total Volume of Distribution After Administration (V-area/F)
timeFrame: 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.
measure: Weight-adjusted Apparent Total Volume of Distribution After Administration (V-area/F)
timeFrame: 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.
measure: Apparent Total Body Clearance of Colchicine
timeFrame: 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.
measure: Weight-adjusted Apparent Total Body Clearance of Colchicine
timeFrame: 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.
measure: Amount of Colchicine Excreted in Urine (Ae[0-t])
timeFrame: Pre-dose on Day 1 and up to 120 hours post dose.
measure: Percentage of Colchicine Dose Excreted in Urine up to the Final Collection Time
timeFrame: Pre-dose on Day 1 and up to 120 hours post dose.
measure: Renal Clearance of Colchicine (CLR)
timeFrame: Pre-dose on Day 1 and up to 120 hours post dose.
measure: Dialysis Clearance of Colchicine (CLD)
timeFrame: Day 15, post-dose during dialysis
measure: Percentage of Colchicine Dose Recovered in Dialysate
timeFrame: Day 15, post-dose during dialysis
Secondary outcomes:
Other outcomes:
Locations:
city: Cypress
country: United States
facility: West Coast Clinical Trials
state: California
Study officials:
affiliation: Mutual Pharmaceutical Company, Inc.
name: Matthew Davis, MD
role: STUDY_CHAIR
affiliation: West Coast Clinical Trials, LLC
name: Javier T Quesada, DO
role: PRINCIPAL_INVESTIGATOR
References: