Healthy
Conditions
Keywords
rosiglitazone, quinine sulfate, drug interactions, cytochrome p450
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.
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.
Interventions
DRUGRosiglitazone 4 mg Tablets
Rosiglitazone 4 mg tablet administered as a single oral dose on the morning of Day 1.
DRUGQuinine 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.
Sponsors
Cetero Research, San Antonio
Mutual Pharmaceutical Company, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Recruitment details
Twenty-three (23) healthy, non-smoking, adult male and female volunteers from the community at large were enrolled.
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| Rosiglitazone Alone, Quinine Alone, Rosiglitazone With Quinine 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). | 23 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Quinine Sulfate Alone | Adverse Event | 4 |
| Rosiglitazone With Quinine Sulfate | Adverse Event | 1 |
Baseline characteristics
| Characteristic | Rosiglitazone Alone, Quinine Alone, Rosiglitazone With Quinine |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 23 Participants |
| Age Continuous | 25.61 years STANDARD_DEVIATION 7.07 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 22 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 20 Participants |
| Region of Enrollment United States | 23 participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 23 | 18 / 23 | 3 / 19 |
| serious Total, serious adverse events | 0 / 23 | 0 / 23 | 0 / 19 |
Outcome results
Primary
Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)]
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.
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rosiglitazone Alone | Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] | 1.99 ug-hr/mL | Standard Deviation 0.43 |
| Rosiglitazone With Quinine Sulfate | Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] | 2.10 ug-hr/mL | Standard Deviation 0.46 |
Primary
Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)]
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.
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rosiglitazone Alone | Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] | 1.96 ug-hr/mL | Standard Deviation 0.41 |
| Rosiglitazone With Quinine Sulfate | Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] | 2.07 ug-hr/mL | Standard Deviation 0.45 |
Primary
Maximum Plasma Concentration (Cmax) of Rosiglitazone
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.
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Rosiglitazone Alone | Maximum Plasma Concentration (Cmax) of Rosiglitazone | 0.41 ug/mL | Standard Deviation 0.08 |
| Rosiglitazone With Quinine Sulfate | Maximum Plasma Concentration (Cmax) of Rosiglitazone | 0.43 ug/mL | Standard Deviation 0.08 |