Healthy
Conditions
Keywords
quinine sulfate, ciprofloxacin, drug interactions, cytochrome p450, male, female, adult, pharmacokinetics
Brief summary
Ciprofloxacin is moderate inhibitor of cytochrome P450 1A2 (CYP1A2), one of the enzymes responsible for the metabolism of quinine. This study will evaluate the effect of ciprofloxacin-related inhibition of CYP1A2 on the pharmacokinetics of quinine sulfate.
Detailed description
Ciprofloxacin is moderate inhibitor of cytochrome P450 1A2 (CYP1A2), one of the enzymes responsible for the metabolism of quinine. This study will evaluate the effect of ciprofloxacin-related inhibition of CYP1A2 on the pharmacokinetics of quinine sulfate. In the morning 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 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 36 hours post-dose at times sufficient to adequately define the pharmacokinetics of quinine sulfate. A 7-day washout period will be completed after the first dose of quinine sulfate on Day 1. Beginning at 07:45 am on Day 8 and continuing through Day 10, all subjects will return to the clinic for non-confined dosing of ciprofloxacin (1 x 500 mg tablet) every 12 hours. Administered ciprofloxacin doses on these days will not be in a fasted state. At 07:45 am on Day 11 after a fast of at least 10 hours, all study participants will receive a co-administered single oral dose of quinine sulfate (2 x 324 mg capsules) and ciprofloxacin (1 x 500 mg tablet). A final dose of ciprofloxacin (1 x 500 mg tablet) will be administered 12 hours later. Blood samples will be drawn from all participants before dosing and for 36 hours post-dose at times sufficient to adequately define the pharmacokinetics of quinine sulfate. Fasting will continue for 4 hours following the co-administered dose of quinine sulfate and ciprofloxacin. 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 will be measured pre-dose and at 1, 2 and 3 hours post-dose on Days 1 and 11. An electrocardiogram (ECG) will be done pre-dose and at 1, 2 and 4 hours post-dose on Days 1 and 11. 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
A single dose of quinine sulfate (2 x 324 mg capsules) administered on the morning of Day 1 after an overnight fast of at least 10 hours.
A single dose of quinine sulfate (2 x 324 mg capsules) co-administered with a single dose of ciprofloxacin (1 x 500 mg tablet) in the morning on Day 11 after an overnight fast of at least 10 hours.
Sponsors
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)between 18 and 32 * Medically healthy on the basis of medical history and physical examination * Hemoglobin \> or = to 11.5 g/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 mefloquine or quinidine
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration(Cmax) | Serial pharmacokinetic blood samples for quinine sulfate collected on Days 1 and 11 before dosing and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24 and 36 hours post-dose. | The maximum or peak concentration that the drug reaches in the plasma. |
| Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] | Serial pharmacokinetic blood samples for quinine sulfate collected on Days 1 and 11 before dosing and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24 and 36 hours post-dose. | The area under the plasma concentration versus time curve beginning from the first dose (time 0) to the last measurable concentration (time t), as calculated by the linear trapezoidal method. |
| Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)]. | Serial pharmacokinetic blood samples for quinine sulfate collected on Days 1 and 11 before dosing and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24 and 36 hours post-dose. | The area under the plasma concentration versus time curve from time 0 to infinity. AUC(0-∞)was calculated as the sum of the AUC(0-t) plus the ratio of the last measurable plasma concentration to the elimination rate constant. |
Participant flow
Recruitment details
Twenty-four (24) healthy, non-smoking, adult male and female volunteers from the community at large were enrolled.
Pre-assignment details
Thirty-nine (39) subjects were screened. Four (4) did not meet eligibility criteria, nine (9) had a schedule conflict prior to Period I check-in, and two (2) transferred to another study.
Participants by arm
| Arm | Count |
|---|---|
| Quinine Alone, Ciprofloxacin Alone, Quinine With Ciprofloxacin All subjects received a single dose of quinine sulfate (2 x 324 mg capsules) on Day 1 following an overnight fast of at least 10 hours. After a 7-day washout period, beginning on the morning of Day 8 subjects received a dose of ciprofloxacin (1 x 500 mg tablet) twice a day for 4 days. On Day 11 in the morning, subjects received a single dose of quinine sulfate (2 x 324 mg capsules) co-administered with a single dose of ciprofloxacin (1 x 500 mg tablet). On Day 11 in the evening, the final dose of ciprofloxacin (1 x 500 mg tablet) was administered. | 24 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| 7 Day Washout Period | Protocol Violation | 3 |
Baseline characteristics
| Characteristic | Quinine Alone, Ciprofloxacin Alone, Quinine With Ciprofloxacin |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 24 Participants |
| Age Continuous | 25.9 years STANDARD_DEVIATION 7.44 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 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 | 0 Participants |
| Race (NIH/OMB) White | 22 Participants |
| Sex: Female, Male Female | 15 Participants |
| Sex: Female, Male Male | 9 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 | 9 / 24 | 1 / 21 | 3 / 18 |
| serious Total, serious adverse events | 0 / 24 | 0 / 21 | 0 / 18 |
Outcome results
Primary
Area Under the Concentration 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 the AUC(0-t) plus the ratio of the last measurable plasma concentration to the elimination rate constant.
Time frame: Serial pharmacokinetic blood samples for quinine sulfate collected on Days 1 and 11 before dosing and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24 and 36 hours post-dose.
Population: Pharmacokinetic analyses are based on 20 subjects out of the 21 subjects who completed the study. One value was determined to be unreliable and was not used.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Quinine Sulfate Alone | Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)]. | 67,694.99 ng-hr/mL |
| Quinine Sulfate With Ciprofloxacin | Area Under the Concentration Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)]. | 77,439.24 ng-hr/mL |
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 beginning from the first dose (time 0) to the last measurable concentration (time t), as calculated by the linear trapezoidal method.
Time frame: Serial pharmacokinetic blood samples for quinine sulfate collected on Days 1 and 11 before dosing and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24 and 36 hours post-dose.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Quinine Sulfate Alone | Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] | 63,415.67 ng-hr/mL |
| Quinine Sulfate With Ciprofloxacin | Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] | 68,572.17 ng-hr/mL |
Primary
Maximum Plasma Concentration(Cmax)
The maximum or peak concentration that the drug reaches in the plasma.
Time frame: Serial pharmacokinetic blood samples for quinine sulfate collected on Days 1 and 11 before dosing and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 24 and 36 hours post-dose.
Population: Pharmacokinetic analyses are based on twenty-one (21) subjects who successfully completed the study. Three (#3) subjects were dropped by the sponsor due to protocol violation.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Quinine Sulfate Alone | Maximum Plasma Concentration(Cmax) | 4,240.65 ng/mL |
| Quinine Sulfate With Ciprofloxacin | Maximum Plasma Concentration(Cmax) | 4,521.20 ng/mL |