Drug-Drug Interaction Study Between Quinine Sulfate and Rosiglitazone
Study Details
Study Description
Brief Summary
Rosiglitazone is predominantly metabolized by cytochrome P450 (CYP) 2C8. Quinine sulfate is an inhibitor of CYP 2C8. This study will evaluate the effect of multiple doses of quinine sulfate at steady-state on the pharmacokinetics of single-dose rosiglitazone in healthy adult subjects.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Detailed Description
Rosiglitazone is predominantly metabolized by cytochrome P450 (CYP) 2C8. Quinine sulfate is an inhibitor of CYP 2C8. This study will evaluate the effect of multiple doses of quinine sulfate at steady-state on the pharmacokinetics of single-dose rosiglitazone in healthy adult subjects.
On study Day 1 after a fast of at least 10 hours, 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 rosiglitazone (1 x 4 mg tablet). Fasting will continue for 4 hours after the dose. 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 rosiglitazone. A 2 day washout period will be completed after the first dose of rosiglitazone on Day 1. On Days 4-7 all subjects will receive a dose of quinine sulfate (2 x 324 mg capsules) every 8 hours starting with the 7:15 a.m. dose on Day 4 and continuing through the 11:15 p.m. dose on Day 7. Doses of quinine sulfate on Days 4-6 will be administered without regard to meals. On the morning of Day 7 after an overnight fast of at least 10 hours, all study participants will receive co-administered doses of rosiglitazone (1 x 4 mg tablet) and quinine sulfate (2 x 324 mg capsules). Fasting will continue for 4 hours after the dose. Blood samples will be drawn from all participants before dosing and for 24 hours post-dose at times sufficient to adequately determine the pharmacokinetics of rosiglitazone. 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. Blood pressure (sitting for at least 3 minutes) and pulse will be measured prior to dosing and at 1, 2 and 3 hours after the morning dose of rosiglitazone on Days 1 and 7. Electrocardiograms (EKG) will be recorded on Day 4 before dosing of quinine sulfate and at 1, 2 and 4 hours post-dose and on Day 7 before the co-administered doses of rosiglitazone and quinine sulfate and at 1, 2 and 4 hours post-dose. 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
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: Rosiglitazone Alone Baseline rosiglitazone pharmacokinetics. |
Drug: Rosiglitazone 4 mg Tablets
Rosiglitazone 4 mg tablet administered as a single oral dose on the morning of Day 1.
Other Names:
|
| Experimental: Rosiglitazone with Steady State Quinine Sulfate Rosiglitazone pharmacokinetics in the presence of steady state quinine sulfate. |
Drug: Rosiglitazone 4 mg Tablets
Co-administered single oral doses of rosiglitazone 4 mg (1 x 4 mg tablet) and quinine sulfate 648 mg (2 x 324 mg capsules) on the morning of Day 7.
Other Names:
Drug: Quinine Sulfate 324 mg Capsules
Co-administered single oral doses of rosiglitazone 4 mg (1 x 4 mg tablet) and quinine sulfate 648 mg (2 x 324 mg capsules) on the morning of Day 7.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Maximum Plasma Concentration (Cmax) of Rosiglitazone [serial pharmacokinetic blood samples drawn prior to dosing on Days 1 and 7 and then 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 20 and 24 hours after dose administration.]
The maximum or peak concentration that rosiglitazone reaches in the plasma.
- 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 7 and then 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 20 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 rosiglitazone.
- 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 7 and then 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 20 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 rosiglitazone.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Healthy adults 18-45 years of age
-
Non-smoking
-
Non-pregnant (post-menopausal, surgically sterile or using effective contraceptive measures)
-
Body mass index (BMI) less than or equal to 32
-
Medically healthy on the basis of medical history and physical examination
-
Hemoglobin > or = to 11.5g/dL
-
Completion of the screening process within 28 days prior to dosing
-
Provision of voluntary written informed consent
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 quinine sulfate or rosiglitazone
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Cetero Research | East Grand Forks | Minnesota | United States | 56721 |
Sponsors and Collaborators
- Mutual Pharmaceutical Company, Inc.
- Cetero Research, San Antonio
Investigators
- Study Chair: Matthew Davis, MD, Mutual Pharmaceutical Company, Inc.
Study Documents (Full-Text)
None provided.More Information
Additional Information:
- Recalls, Market Withdrawals and Safety Alerts
- Daily Med - Posting of Recently Submitted Labeling to the FDA
Publications
None provided.- MPC-001-08-1028
- R08-0591
Study Results
Participant Flow
| Recruitment Details | Twenty-three (23) healthy, non-smoking, adult male and female volunteers from the community at large were enrolled. |
|---|---|
| Pre-assignment Detail | Thirty-three (33) subjects were screened. Four (4) did not qualify for the study, four (4) did not finish the screening process and two (2) were transferred to another study. |
| Arm/Group Title | Rosiglitazone Alone, Quinine Alone, Rosiglitazone With Quinine |
|---|---|
| Arm/Group Description | On the morning of Day 1, subjects received a single dose of rosiglitazone (1 x 4 mg tablet) after an overnight fast of at least 10 hours, followed by a 2 day washout period. On Days 4-7, subjects received a dose of quinine sulfate (2 x 324 mg capsules) every 8 hours beginning at 7:15 am on Day 4 and continuing through the 11:15 p.m. dose on Day 7. On the morning of Day 7, subjects received a single dose of rosiglitazone (1 x 4 mg tablet) along with the morning dose of quinine sulfate ( 2 x 324 mg capsules). |
| Period Title: Rosiglitazone Alone | |
| STARTED | 23 |
| COMPLETED | 23 |
| NOT COMPLETED | 0 |
| Period Title: Rosiglitazone Alone | |
| STARTED | 23 |
| COMPLETED | 23 |
| NOT COMPLETED | 0 |
| Period Title: Rosiglitazone Alone | |
| STARTED | 23 |
| COMPLETED | 19 |
| NOT COMPLETED | 4 |
| Period Title: Rosiglitazone Alone | |
| STARTED | 19 |
| COMPLETED | 18 |
| NOT COMPLETED | 1 |
Baseline Characteristics
| Arm/Group Title | Rosiglitazone Alone, Quinine Alone, Rosiglitazone With Quinine |
|---|---|
| Arm/Group Description | On the morning of Day 1, subjects received a single dose of rosiglitazone (1 x 4 mg tablet) after an overnight fast of at least 10 hours, followed by a 2 day washout period. On Days 4-7, subjects received a dose of quinine sulfate (2 x 324 mg capsules) every 8 hours beginning at 7:15 am on Day 4 and continuing through the 11:15 p.m. dose on Day 7. On the morning of Day 7, subjects received a single dose of rosiglitazone (1 x 4 mg tablet) along with the morning dose of quinine sulfate ( 2 x 324 mg capsules). |
| Overall Participants | 23 |
| Age (Count of Participants) | |
| <=18 years |
0
0%
|
| Between 18 and 65 years |
23
100%
|
| >=65 years |
0
0%
|
| Age (years) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [years] |
25.61
(7.07)
|
| Sex: Female, Male (Count of Participants) | |
| Female |
9
39.1%
|
| Male |
14
60.9%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |
| Hispanic or Latino |
1
4.3%
|
| Not Hispanic or Latino |
22
95.7%
|
| Unknown or Not Reported |
0
0%
|
| Race (NIH/OMB) (Count of Participants) | |
| American Indian or Alaska Native |
1
4.3%
|
| Asian |
0
0%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
| Black or African American |
1
4.3%
|
| White |
20
87%
|
| More than one race |
0
0%
|
| Unknown or Not Reported |
1
4.3%
|
| Region of Enrollment (participants) [Number] | |
| United States |
23
100%
|
Outcome Measures
| Title | Maximum Plasma Concentration (Cmax) of Rosiglitazone |
|---|---|
| Description | The maximum or peak concentration that rosiglitazone reaches in the plasma. |
| Time Frame | serial pharmacokinetic blood samples drawn prior to dosing on Days 1 and 7 and then 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 20 and 24 hours after dose administration. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Twenty Three (23) subjects were enrolled in this study. Five (5) subjects withdrew from the study. Pharmacokinetic analyses are based upon data obtained from the eighteen (18) subjects that completed the study. |
| Arm/Group Title | Rosiglitazone Alone | Rosiglitazone With Quinine Sulfate |
|---|---|---|
| Arm/Group Description | On the morning of Day 1, subjects received a single dose of rosiglitazone 4 mg after an overnight fast of at least 10 hours, followed by a 2 day washout period. | On the morning of Day 7, subjects received a co-administered single oral dose of rosiglitazone 4 mg and quinine sulfate 648 mg after an overnight fast. |
| Measure Participants | 18 | 18 |
| Mean (Standard Deviation) [ug/mL] |
0.41
(0.08)
|
0.43
(0.08)
|
| 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 rosiglitazone. |
| Time Frame | serial pharmacokinetic blood samples drawn prior to dosing on Days 1 and 7 and then 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 20 and 24 hours after dose administration. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Twenty Three (23) subjects were enrolled in this study. Five (5) subjects withdrew from the study. Pharmacokinetic analyses are based upon data obtained from the eighteen (18) subjects that completed the study. |
| Arm/Group Title | Rosiglitazone Alone | Rosiglitazone With Quinine Sulfate |
|---|---|---|
| Arm/Group Description | On the morning of Day 1, subjects received a single dose of rosiglitazone 4 mg after an overnight fast of at least 10 hours, followed by a 2 day washout period. | On the morning of Day 7, subjects received a co-administered single oral dose of rosiglitazone 4 mg and quinine sulfate 648 mg after an overnight fast. |
| Measure Participants | 18 | 18 |
| Mean (Standard Deviation) [ug-hr/mL] |
1.96
(0.41)
|
2.07
(0.45)
|
| 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 rosiglitazone. |
| Time Frame | serial pharmacokinetic blood samples drawn prior to dosing on Days 1 and 7 and then 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 20 and 24 hours after dose administration. |
Outcome Measure Data
| Analysis Population Description |
|---|
| Twenty Three (23) subjects were enrolled in this study. Five (5) subjects withdrew from the study. Pharmacokinetic analyses are based upon data obtained from the eighteen (18) subjects that completed the study. |
| Arm/Group Title | Rosiglitazone Alone | Rosiglitazone With Quinine Sulfate |
|---|---|---|
| Arm/Group Description | On the morning of Day 1, subjects received a single dose of rosiglitazone 4 mg after an overnight fast of at least 10 hours, followed by a 2 day washout period. | On the morning of Day 7, subjects received a co-administered single oral dose of rosiglitazone 4 mg and quinine sulfate 648 mg after an overnight fast. |
| Measure Participants | 18 | 18 |
| Mean (Standard Deviation) [ug-hr/mL] |
1.99
(0.43)
|
2.10
(0.46)
|
Adverse Events
| Time Frame | ||||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | ||||||
| Arm/Group Title | Rosiglitazone Alone | Quinine Sulfate Alone | Rosiglitazone With Quinine Sulfate | |||
| Arm/Group Description | On the morning of Day 1, subjects received a single dose of rosiglitazone (1 x 4 mg tablet) after an overnight fast of at least 10 hours, followed by a 2 day washout period. | On Days 4-7, subjects received a dose of quinine sulfate 648 mg (2 x 324 mg capsules) every 8 hours beginning with the 7:15 a.m. dose on Day 4 and continuing through the 11:15 p.m. dose on Day 7. | On the morning of Day 7, subjects were co-administered a dose of rosiglitazone 4mg and quinine sulfate 648 mg (2 x 324 mg capsules) following an overnight fast of at least 10 hours. | |||
All Cause Mortality |
||||||
| Rosiglitazone Alone | Quinine Sulfate Alone | Rosiglitazone With Quinine Sulfate | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | / (NaN) | |||
Serious Adverse Events |
||||||
| Rosiglitazone Alone | Quinine Sulfate Alone | Rosiglitazone With Quinine Sulfate | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/23 (0%) | 0/23 (0%) | 0/19 (0%) | |||
Other (Not Including Serious) Adverse Events |
||||||
| Rosiglitazone Alone | Quinine Sulfate Alone | Rosiglitazone With Quinine Sulfate | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 1/23 (4.3%) | 18/23 (78.3%) | 3/19 (15.8%) | |||
| Cardiac disorders | ||||||
| Cardiac flutter | 0/23 (0%) | 0 | 1/23 (4.3%) | 1 | 0/19 (0%) | 0 |
| Palpitations | 0/23 (0%) | 0 | 1/23 (4.3%) | 1 | 0/19 (0%) | 0 |
| Ear and labyrinth disorders | ||||||
| Ear congestion | 0/23 (0%) | 0 | 1/23 (4.3%) | 1 | 0/19 (0%) | 0 |
| Ear discomfort | 0/23 (0%) | 0 | 10/23 (43.5%) | 15 | 1/19 (5.3%) | 1 |
| Hypoacusis | 0/23 (0%) | 0 | 4/23 (17.4%) | 4 | 0/19 (0%) | 0 |
| Tinnitus | 0/23 (0%) | 0 | 7/23 (30.4%) | 9 | 0/19 (0%) | 0 |
| Gastrointestinal disorders | ||||||
| Abdominal pain upper | 0/23 (0%) | 0 | 2/23 (8.7%) | 2 | 0/19 (0%) | 0 |
| Diarrhea | 0/23 (0%) | 0 | 1/23 (4.3%) | 1 | 0/19 (0%) | 0 |
| Nausea | 0/23 (0%) | 0 | 5/23 (21.7%) | 6 | 2/19 (10.5%) | 4 |
| Vomiting | 0/23 (0%) | 0 | 4/23 (17.4%) | 5 | 0/19 (0%) | 0 |
| General disorders | ||||||
| Chest pain | 0/23 (0%) | 0 | 1/23 (4.3%) | 1 | 0/19 (0%) | 0 |
| Fatigue | 0/23 (0%) | 0 | 0/23 (0%) | 0 | 1/19 (5.3%) | 1 |
| Feeling hot | 0/23 (0%) | 0 | 1/23 (4.3%) | 1 | 1/19 (5.3%) | 1 |
| Pain | 0/23 (0%) | 0 | 1/23 (4.3%) | 1 | 1/19 (5.3%) | 1 |
| Vessel puncture site pain | 1/23 (4.3%) | 1 | 0/23 (0%) | 0 | 0/19 (0%) | 0 |
| Nervous system disorders | ||||||
| Dizziness | 0/23 (0%) | 0 | 7/23 (30.4%) | 9 | 2/19 (10.5%) | 2 |
| Dysgeusia | 0/23 (0%) | 0 | 3/23 (13%) | 3 | 0/19 (0%) | 0 |
| Headache | 0/23 (0%) | 0 | 3/23 (13%) | 3 | 2/19 (10.5%) | 2 |
| Hypoaesthesia | 0/23 (0%) | 0 | 0/23 (0%) | 0 | 1/19 (5.3%) | 1 |
| Tremor | 0/23 (0%) | 0 | 3/23 (13%) | 4 | 1/19 (5.3%) | 1 |
| Psychiatric disorders | ||||||
| Paranoia | 0/23 (0%) | 0 | 0/23 (0%) | 0 | 1/19 (5.3%) | 1 |
| Nervousness | 0/23 (0%) | 0 | 1/23 (4.3%) | 1 | 0/19 (0%) | 0 |
| Renal and urinary disorders | ||||||
| Dysuria | 0/23 (0%) | 0 | 1/23 (4.3%) | 1 | 0/19 (0%) | 0 |
| Respiratory, thoracic and mediastinal disorders | ||||||
| Epistaxis | 0/23 (0%) | 0 | 1/23 (4.3%) | 1 | 0/19 (0%) | 0 |
| Nasal congestion | 0/23 (0%) | 0 | 1/23 (4.3%) | 1 | 0/19 (0%) | 0 |
| Vascular disorders | ||||||
| Flushing | 0/23 (0%) | 0 | 1/23 (4.3%) | 1 | 0/19 (0%) | 0 |
Limitations/Caveats
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.
Results Point of Contact
| Name/Title | Medical Director |
|---|---|
| Organization | Mutual Pharmaceutical Company, Inc. |
| Phone | 215-697-1743 |
| clinicaltrials@urlmutual.com |
- MPC-001-08-1028
- R08-0591