Drug-Drug Interaction Study Between Colchicine and Atorvastatin

• Sponsor: Mutual Pharmaceutical Company, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00960323
• Collaborator: (none)
• Enrollment: 24
• Location: 1
• Arms: 2
• Duration (Days): 28
• Patients Per Site Per Month: 26.1

Study Details

Study Description

Brief Summary

Colchicine is a substrate for cytochrome P450 3A4 (CYP3A4). In-vitro studies have indicated that the ortho-and para-hydroxylated metabolites of atorvastatin may be CYP3A4/5 competitive and mechanism-based inhibitors (MBI). This study will evaluate the effect of multiple doses of atorvastatin on the pharmacokinetic profile of a single 0.6 mg dose of colchicine. A secondary objective is to evaluate the safety and tolerability of this regimen in healthy volunteers. All study subjects will be monitored for adverse events throughout the study period.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Colchicine; Drug: Atorvastatin; Drug: Colchicine	Phase 1

Detailed Description

Colchicine is a substrate for cytochrome P450 3A4 (CYP3A4). In-vitro studies have indicated that the ortho-and para-hydroxylated metabolites of atorvastatin may be CYP3A4 /5 competitive and mechanism-based inhibitors (MBI). This study will evaluate the effect of multiple doses of atorvastatin on the pharmacokinetic profile of a single 0.6 mg dose of colchicine. Twenty-four healthy, non-smoking, non-obese, non-pregnant adult volunteers between the ages of 18 and 45 will be given one oral dose of colchicine (1 x 0.6 mg tablet) on Day 1 after an overnight fast. Blood samples will be drawn from all participants before dosing and for 24 hours post-dose at times sufficient to adequately define the pharmacokinetics of colchicine. After a 14 day washout period, starting on the morning of Day 15 and continuing through Day 27, subjects will return to the clinic for once daily administration of atorvastatin (1 x 40 mg tablet) after an overnight fast. After taking the first dose of atorvastatin on Day 15, subjects will remain in the clinic for 1 hour post-dose administration for observation. On the morning of Day 28 after an overnight fast, all study participants will receive a co-administered single oral dose of colchicine (1 x 0.6 mg tablet) and atorvastatin (1 x 40 mg tablet). Blood samples will be drawn from all participants before dosing and for twenty-four hours post-dose at times sufficient to adequately define the pharmacokinetics of colchicine in the presence of atorvastatin at steady state. A further goal of this study is to evaluate the safety and tolerability of this regimen in healthy volunteers. Subjects will be monitored throughout participation in the study for adverse reactions to the study drug and/or procedures. Seated blood pressure and pulse, respiratory rate and temperature will be measured at screening, baseline and upon study discharge. Blood pressure and pulse will also be measured pre-dose and at 1 and 2 hours post-dose on Days 1 and 28 to coincide with peak plasma concentrations of colchicine and atorvastatin. All adverse events whether elicited by query, spontaneously reported, or observed by clinic staff will be evaluated by the investigator and reported in the subject's case report form.

Study Design

• Study Type: Interventional
• Actual Enrollment: 24 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: A One-Directional, Open-Label Drug Interaction Study to Investigate the Effects of Multiple-Dose Atorvastatin on the Single-Dose Pharmacokinetics of Colchicine in Healthy Volunteers
• Study Start Date: Feb 1, 2009
• Actual Primary Completion Date: Mar 1, 2009
• Actual Study Completion Date: Mar 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Colchicine Alone baseline colchicine pharmacokinetics	Drug: Colchicine; A single dose of 0.6 mg colchicine administered alone in the morning on Day 1.
Experimental: Colchicine with Atorvastatin Colchicine pharmacokinetics in the presence of atorvastatin at steady state.	Drug: Atorvastatin; Atorvastatin (1 x 40 mg tablet) administered once daily on Days 15-28.; Drug: Colchicine; A single dose of 0.6 mg colchicine administered with a single dose of 40 mg atorvastatin in the morning on Day 28 after an overnight fast.

Outcome Measures

Primary Outcome Measures

1. Maximum Plasma Concentration (Cmax) of Colchicine [serial pharmacokinetic blood samples drawn prior to dosing on Days 1 and 28 and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 and 24 hours after dose administration.]

   The maximum or peak concentration that colchicine reaches in the plasma.

2. Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] [Serial pharmacokinetic blood samples drawn prior to dosing on Days 1 and 28 and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 and 24 hours after dose administration.]

   The area under the plasma concentration versus time curve from time 0 to the time of the last measurable concentration (t), as calculated by the linear trapezoidal rule for colchicine.

3. Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] [Serial pharmacokinetic blood samples drawn prior to dosing on Days 1 and 28 and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 and 24 hours after dose administration.]

   The area under the plasma concentration versus time curve from time 0 to infinity. [AUC(0-∞)] was calculated as the sum of AUC(0-t) plus the ratio of the last measurable plasma concentration to the elimination rate constant for colchicine.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Healthy adults 18-45 years of age

• Non-smoking and non-pregnant (post-menopausal, surgically sterile or using effective contraceptive measures)

• Body mass index (BMI) greater than or equal to 18 and less than or equal to 32, inclusive

• Hemoglobin greater than or equal to 11.5g/dL

Exclusion Criteria:

• Recent participation (within 28 days) in other research studies

• Recent significant blood donation or plasma donation

• Pregnant or lactating

• Test positive at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HbsAg), or hepatitis C virus (HCV)

• Recent (2-year) history or evidence of alcoholism or drug abuse

• History or presence of significant cardiovascular, pulmonary, hepatic, gallbladder or biliary tract, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, or psychiatric disease

• Subjects who have used any drugs or substances known to inhibit or induce cytochrome (CYP) P450 enzymes and/or P-glycoprotein (P-gp) within 28 days prior to the first dose and throughout the study

• Drug allergies to colchicine or atorvastatin or any other HMG-CoA reductase inhibitor agents (i.e. simvastatin, lovastatin, rosuvastatin, fluvastatin, and pravastatin)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	PRACS Institute, Ltd. - Cetero Research	Fargo	North Dakota	United States	58104

Sponsors and Collaborators

• Mutual Pharmaceutical Company, Inc.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00960323
• Other Study ID Numbers: MPC-004-08-1019
• First Posted: Aug 17, 2009
• Last Update Posted: Mar 30, 2010
• Last Verified: Mar 1, 2010

• Keywords provided by , ,: pharmacokinetics
• Additional relevant MeSH terms: Colchicine; Atorvastatin

Study Results

Participant Flow

Recruitment Details	Forty-two volunteers were screened for participation in this study. Eight were screen failures, four were not needed, four withdrew consent and two had a schedule conflict.

Arm/Group Title	Colchicine, Atorvastatin, Colchicine and Atorvastatin
Arm/Group Description	On the morning of Day 1, subjects received a single dose of colchicine 0.6 mg after an overnight fast, followed by a 14 day washout period. On the mornings of Days 15-27, subjects received a daily dose of atorvastatin 40 mg after an overnight fast. On the morning of Day 28, subjects received a co-administered single oral dose of colchicine 0.6 mg and atorvastatin 40 mg following an overnight fast.
Period Title: Colchicine Alone
STARTED	24
COMPLETED	24
NOT COMPLETED	0
Period Title: Colchicine Alone
STARTED	24
COMPLETED	24
NOT COMPLETED	0
Period Title: Colchicine Alone
STARTED	24
COMPLETED	23
NOT COMPLETED	1
Period Title: Colchicine Alone
STARTED	23
COMPLETED	23
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Colchicine, Atorvastatin, Colchicine and Atorvastatin
Arm/Group Description	On the morning of Day 1, subjects received a single dose of colchicine 0.6 mg after an overnight fast, followed by a 14 day washout period. On the mornings of Days 15-27, subjects received a daily dose of atorvastatin 40 mg after an overnight fast. On the morning of Day 28, subjects received a co-administered single oral dose of colchicine 0.6 mg and atorvastatin 40 mg following an overnight fast.
Overall Participants	24
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	24 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	26.29 (6.46)
Sex: Female, Male (Count of Participants)
Female	2 8.3%
Male	22 91.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	24 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 4.2%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 4.2%
White	22 91.7%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (participants) [Number]
United States	24 100%

Outcome Measures

1. Primary Outcome

Title	Maximum Plasma Concentration (Cmax) of Colchicine
Description	The maximum or peak concentration that colchicine reaches in the plasma.
Time Frame	serial pharmacokinetic blood samples drawn prior to dosing on Days 1 and 28 and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 and 24 hours after dose administration.

Outcome Measure Data

Analysis Population Description

24 subjects were enrolled in this study. One subject withdrew from the study prior to Period II check in due to a schedule conflict.

Arm/Group Title	Colchicine Alone	Colchicine With Atorvastatin
Arm/Group Description	On the morning of Day 1, subjects received a single dose of colchicine 0.6 mg after an overnight fast followed by a 14 day washout period.	On the morning of Day 28, subjects received a co-administered single oral dose of colchicine 0.6 mg and atorvastatin 40 mg after an overnight fast.
Measure Participants	23	23
Mean (Standard Deviation) [pg/mL]	2,023.29 (903.14)	2,487.96 (646.99)

2. Primary Outcome

Title	Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)]
Description	The area under the plasma concentration versus time curve from time 0 to the time of the last measurable concentration (t), as calculated by the linear trapezoidal rule for colchicine.
Time Frame	Serial pharmacokinetic blood samples drawn prior to dosing on Days 1 and 28 and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 and 24 hours after dose administration.

Outcome Measure Data

Analysis Population Description

24 subjects were enrolled in this study. One subject withdrew from the study prior to Period II check in due to a schedule conflict.

Arm/Group Title	Colchicine Alone	Colchicine With Atorvastatin
Arm/Group Description	On the morning of Day 1, subjects received a single dose of colchicine 0.6 mg after an overnight fast, followed by a 14 day washout period.	On the morning of Day 28, subjects received a co-administered single oral dose of colchicine 0.6 mg and atorvastatin 40 mg after an overnight fast.
Measure Participants	23	23
Mean (Standard Deviation) [pg*hr/mL]	8,717.33 (4,208.19)	10,714.92 (4,060.71)

3. Primary Outcome

Title	Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)]
Description	The area under the plasma concentration versus time curve from time 0 to infinity. [AUC(0-∞)] was calculated as the sum of AUC(0-t) plus the ratio of the last measurable plasma concentration to the elimination rate constant for colchicine.
Time Frame	Serial pharmacokinetic blood samples drawn prior to dosing on Days 1 and 28 and then 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 and 24 hours after dose administration.

Outcome Measure Data

Analysis Population Description

24 subjects were enrolled in this study. One subject withdrew prior to Period II check-in. The pharmacokinetic parameter, AUC(0-∞), could not be determined for 1 subject in the Colchicine Alone group and for 4 subjects in the Colchicine with Atorvastatin group.

Arm/Group Title	Colchicine Alone	Colchicine With Atorvastatin
Arm/Group Description	On the morning of Day 1, subjects received a single dose of colchicine 0.6 mg after an overnight fast, followed by a 14 day washout period.	On the morning of Day 28, subjects received a co-administered single oral dose of colchicine 0.6 mg and atorvastatin 40 mg after an overnight fast.
Measure Participants	22	19
Mean (Standard Deviation) [pg*hr/mL]	9,592.53 (3,349.19)	11,043.58 (3,867.03)

Adverse Events

Adverse Event Reporting Description	24 subjects were enrolled in this study. One subject withdrew consent prior to Period II check-in.
Arm/Group Title	Colchicine Alone		Atorvastatin Alone		Colchicine and Atorvastatin
Arm/Group Description	On the morning of Day 1, subjects received a single dose of colchicine 0.6 mg after an overnight fast, followed by a 14 day washout period.		On the mornings of Days 15-27, subjects received a daily dose of atorvastatin 40 mg after an overnight fast.		On the morning of Day 28, subjects received a co-administered single oral dose of colchicine 0.6 mg and atorvastatin 40 mg after an overnight fast.
All Cause Mortality
	Colchicine Alone		Atorvastatin Alone		Colchicine and Atorvastatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Colchicine Alone		Atorvastatin Alone		Colchicine and Atorvastatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/24 (0%)		0/24 (0%)		0/23 (0%)
Other (Not Including Serious) Adverse Events
	Colchicine Alone		Atorvastatin Alone		Colchicine and Atorvastatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/24 (16.7%)		6/24 (25%)		1/23 (4.3%)
Eye disorders
Ocular hyperaemia	1/24 (4.2%)	1	1/24 (4.2%)	1	0/23 (0%)	0
Gastrointestinal disorders
Nausea	0/24 (0%)	0	1/24 (4.2%)	1	0/23 (0%)	0
General disorders
Fatigue	0/24 (0%)	0	1/24 (4.2%)	1	0/23 (0%)	0
Nervous system disorders
Dizziness	2/24 (8.3%)	2	1/24 (4.2%)	1	1/23 (4.3%)	1
Headache	1/24 (4.2%)	1	2/24 (8.3%)	2	0/23 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pharyngolaryngeal pain	0/24 (0%)	0	2/24 (8.3%)	2	0/23 (0%)	0
Skin and subcutaneous tissue disorders
Cold sweat	0/24 (0%)	0	1/24 (4.2%)	1	0/23 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.