Drug - Drug Interaction Study of Quinine Sulfate and Ciprofloxacin
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: Quinine Sulfate Baseline quinine sulfate pharmacokinetics |
Drug: Quinine Sulfate Capsules 324 mg
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.
Other Names:
|
| Experimental: Quinine Sulfate with Ciprofloxacin Quinine sulfate pharmacokinetics in the presence of steady state ciprofloxacin |
Drug: Ciprofloxacin 500 mg
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.
Other Names:
Drug: Quinine Sulfate Capsules 324 mg
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.
Other Names:
|
Outcome Measures
Primary Outcome Measures
- 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.
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)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
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Mutual Pharmaceutical Company, Inc.
Investigators
- Principal Investigator: Anthony R Godfrey, PharmD, PRACS Institute, Ltd.
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-001-08-1027
Study Results
Participant Flow
| Recruitment Details | Twenty-four (24) healthy, non-smoking, adult male and female volunteers from the community at large were enrolled. |
|---|---|
| Pre-assignment Detail | 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. |
| Arm/Group Title | Quinine Alone, Ciprofloxacin Alone, Quinine With Ciprofloxacin |
|---|---|
| Arm/Group Description | 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. |
| Period Title: Quinine Sulfate Alone | |
| STARTED | 24 |
| COMPLETED | 24 |
| NOT COMPLETED | 0 |
| Period Title: Quinine Sulfate Alone | |
| STARTED | 24 |
| COMPLETED | 21 |
| NOT COMPLETED | 3 |
| Period Title: Quinine Sulfate Alone | |
| STARTED | 21 |
| COMPLETED | 21 |
| NOT COMPLETED | 0 |
| Period Title: Quinine Sulfate Alone | |
| STARTED | 21 |
| COMPLETED | 21 |
| NOT COMPLETED | 0 |
Baseline Characteristics
| Arm/Group Title | Quinine Alone, Ciprofloxacin Alone, Quinine With Ciprofloxacin |
|---|---|
| Arm/Group Description | 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. |
| 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] |
25.9
(7.44)
|
| Sex: Female, Male (Count of Participants) | |
| Female |
15
62.5%
|
| Male |
9
37.5%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |
| Hispanic or Latino |
4
16.7%
|
| Not Hispanic or Latino |
20
83.3%
|
| Unknown or Not Reported |
0
0%
|
| Race (NIH/OMB) (Count of Participants) | |
| American Indian or Alaska Native |
1
4.2%
|
| Asian |
0
0%
|
| 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%
|
Outcome Measures
| Title | Maximum Plasma Concentration(Cmax) |
|---|---|
| Description | 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Quinine Sulfate Alone | Quinine Sulfate With Ciprofloxacin |
|---|---|---|
| Arm/Group Description | On Day 1 in the morning, after a fast of at least 10 hours, all subjects received a single dose of quinine sulfate (2 x 324 mg capsules) followed by a 7-day washout period. | On Day 11 in the morning, after a fast of at least 10 hours, all 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). |
| Measure Participants | 21 | 21 |
| Mean (Standard Deviation) [ng/mL] |
4,240.65
(1,162.25)
|
4,521.20
(1,122.28)
|
| 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 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Quinine Sulfate Alone | Quinine Sulfate With Ciprofloxacin |
|---|---|---|
| Arm/Group Description | On Day 1 in the morning, after a fast of at least 10 hours, all subjects received a single dose of quinine sulfate (2 x 324 mg capsules) followed by a 7-day washout period. | On Day 11 in the morning, after a fast of at least 10 hours, all 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). |
| Measure Participants | 21 | 21 |
| Mean (Standard Deviation) [ng-hr/mL] |
63,415.67
(16,009.17)
|
68,572.17
(18,922.82)
|
| Title | Area Under the Concentration 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 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. |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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/Group Title | Quinine Sulfate Alone | Quinine Sulfate With Ciprofloxacin |
|---|---|---|
| Arm/Group Description | On Day 1 in the morning, after a fast of at least 10 hours, all subjects received a single dose of quinine sulfate (2 x 324 mg capsules) followed by a 7-day washout period. | On Day 11 in the morning, after a fast of at least 10 hours, all 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). |
| Measure Participants | 20 | 20 |
| Mean (Standard Deviation) [ng-hr/mL] |
67,694.99
(15,644.74)
|
77,439.24
(26,083.49)
|
Adverse Events
| Time Frame | ||||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | 24 subjects were enrolled in this study. Several subjects dropped out of the study prior to receiving all interventions. 24 subjects were administered Quinine sulfate, 21 subjects were administered Ciprofloxacin and 18 subjects were co-administered Quinine Sulfate and Ciprofloxacin. | |||||
| Arm/Group Title | Quinine Sulfate Alone | Ciprofloxacin Alone | Quinine Sulfate With Ciprofloxacin | |||
| Arm/Group Description | On Day 1 in the morning, after a fast of at least 10 hours, all subjects received a single dose of quinine sulfate (2 x 324 mg capsules) followed by a 7-day washout period. On Day 11 in the morning, all 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) following an overnight fast of 10 hours. | Beginning on Day 8 in the morning and continuing through Day 11 in the evening, all subjects received a dose of ciprofloxacin (1 x 500 mg tablet) twice daily for a total of 8 doses. | On Day 11 in the morning, all subjects received a dose of quinine sulfate (2 x 324 mg capsules) co-administered with a dose of ciprofloxacin (1 x 500 mg tablet) after an overnight fast of at least 10 hours. | |||
All Cause Mortality |
||||||
| Quinine Sulfate Alone | Ciprofloxacin Alone | Quinine Sulfate With Ciprofloxacin | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | / (NaN) | / (NaN) | / (NaN) | |||
Serious Adverse Events |
||||||
| Quinine Sulfate Alone | Ciprofloxacin Alone | Quinine Sulfate With Ciprofloxacin | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/24 (0%) | 0/21 (0%) | 0/18 (0%) | |||
Other (Not Including Serious) Adverse Events |
||||||
| Quinine Sulfate Alone | Ciprofloxacin Alone | Quinine Sulfate With Ciprofloxacin | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 9/24 (37.5%) | 1/21 (4.8%) | 3/18 (16.7%) | |||
| Ear and labyrinth disorders | ||||||
| Ear discomfort | 2/24 (8.3%) | 2 | 0/21 (0%) | 0 | 0/18 (0%) | 0 |
| Tinnitus | 3/24 (12.5%) | 3 | 0/21 (0%) | 0 | 1/18 (5.6%) | 1 |
| Gastrointestinal disorders | ||||||
| Nausea | 1/24 (4.2%) | 1 | 0/21 (0%) | 0 | 1/18 (5.6%) | 1 |
| General disorders | ||||||
| Pain | 0/24 (0%) | 0 | 0/21 (0%) | 0 | 1/18 (5.6%) | 1 |
| Injury, poisoning and procedural complications | ||||||
| Arthropod sting | 1/24 (4.2%) | 1 | 0/21 (0%) | 0 | 0/18 (0%) | 0 |
| Musculoskeletal and connective tissue disorders | ||||||
| Back pain | 1/24 (4.2%) | 1 | 0/21 (0%) | 0 | 0/18 (0%) | 0 |
| Nervous system disorders | ||||||
| Dizziness | 2/24 (8.3%) | 2 | 0/21 (0%) | 0 | 0/18 (0%) | 0 |
| Dysgeusia | 1/24 (4.2%) | 1 | 0/21 (0%) | 0 | 1/18 (5.6%) | 1 |
| Headache | 1/24 (4.2%) | 1 | 1/21 (4.8%) | 1 | 1/18 (5.6%) | 1 |
| Tremor | 0/24 (0%) | 0 | 0/21 (0%) | 0 | 1/18 (5.6%) | 1 |
| Respiratory, thoracic and mediastinal disorders | ||||||
| Epistaxis | 1/24 (4.2%) | 1 | 0/21 (0%) | 0 | 0/18 (0%) | 0 |
| Respiratory tract congestion | 1/24 (4.2%) | 1 | 0/21 (0%) | 0 | 0/18 (0%) | 0 |
| Sinus congestion | 0/24 (0%) | 0 | 1/21 (4.8%) | 1 | 0/18 (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-001-08-1027