A Dose Proportionality Study of Quinine Sulfate Capsules Under Fasting Conditions

• Sponsor: Mutual Pharmaceutical Company, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00726895
• Collaborator: (none)
• Enrollment: 24
• Arms: 2
• Duration (Months): 1

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate and compare the dose proportionality of 324 mg Quinine Sulfate capsules following a single oral dose (1 x 324 mg capsules versus 2 x 324 mg capsules) in healthy adult volunteers when administered under fasting conditions.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Quinine Sulfate Capsules 324 mg; Drug: Quinine Sulfate Capsules 324 mg	Phase 1

Detailed Description

The purpose of this study is to evaluate and compare the dose proportionality of 324 mg Quinine Sulfate capsules following a single oral dose (1 x 324 mg capsules versus 2 x 324 mg capsules) in healthy adult volunteers when administered under fasting conditions.

Twenty-four healthy, non-smoking, non-obese, male and female volunteers at least 18 years of age will be randomly assigned in a crossover fashion to receive each of two Quinine Sulfate dosing regimens in sequence with a 7 day washout period between dosing periods. On the morning of Day 1, after an overnight fast of at least 10 hours, subjects will receive either a single oral dose of treatment A, Quinine Sulfate 1 x 324 mg capsule, or a single oral dose of treatment B, Quinine Sulfate 2 x 324 mg capsules. After a 7 day washout period,on the morning of Day 8 following an overnight fast of at least 10 hours, subjects will receive the alternate regimen. Blood samples will be drawn from all participants before dosing and for 24 hours post-dose on a confined basis at times sufficient to adequately define the pharmacokinetics of Quinine Sulfate. Blood sampling will then continue on a non-confined basis at 36 and 48 hours post-dose. A further goal of this study is to evaluate the safety and tolerability of this regimen in healthy volunteers. Subjects will be monitored throughout the confinement portion of the study for adverse reactions to the study drug and/or procedures. Blood pressure and heart rate will be obtained prior to dosing and as scheduled following each 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

• Study Type: Interventional
• Actual Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Single (Participant)
• Primary Purpose: Basic Science
• Official Title: A Randomized, Two-way Crossover Design Used to Compare the Dose Proportionality of Quinine Sulfate Capsules, 324 mg Following a Single Oral Dose of 1 x 324 mg Capsule Versus 2 x 324 mg Capsules in Healthy Adult Volunteers
• Study Start Date: May 1, 2004
• Actual Primary Completion Date: Jun 1, 2004
• Actual Study Completion Date: Jun 1, 2004

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Quinine Sulfate Capsules 1 x 324 mg Dose Quinine Sulfate 1 x 324 mg capsule dose.	Drug: Quinine Sulfate Capsules 324 mg; 1 x 324 mg capsule
Experimental: Quinine Sulfate Capsules 2 x 324 mg Dose Quinine Sulfate 2 x 324 mg capsules dose.	Drug: Quinine Sulfate Capsules 324 mg; 2 x 324 mg capsules

Outcome Measures

Primary Outcome Measures

1. Maximum Plasma Concentration (Cmax) [serial pharmacokinetic plasma concentrations were drawn prior to dose administration (0 hour) and at 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 16, 24, 36 and 48 hours after drug administration.]

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

2. Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] [serial pharmacokinetic plasma concentrations were drawn prior to dose administration (0 hour) and at 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 16, 24, 36 and 48 hours after drug 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.

3. Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] [serial pharmacokinetic plasma concentrations were drawn prior to dose administration (0 hour) and at 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 16, 24, 36 and 48 hours after drug 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Screening Demographics: All volunteers will be healthy men or women 18 years of age or older at the time of dosing. The weight range will not exceed ±20% for height and body frame as per Desirable Weights for Adults - 1983 Metropolitan Height and Weight Table

• Screening procedures: Each volunteer will complete the screening process within 28 days prior to Period I dosing. Consent documents for both screening evaluation and human immunodeficiency virus (HIV) antibody determination will be reviewed, discussed, and signed by each potential participant before full implementation of screening procedures

• Screening will include general observations, physical examination, demographics, medical and medication history, an electrocardiogram, sitting blood pressure and heart rate, respiratory rate and temperature. The physical examination will include, but may not be limited to, an evaluation of the cardiovascular, gastrointestinal, respiratory and central nervous systems.

• The screening clinical laboratory procedures will include:

• HEMATOLOGY: hematocrit, hemoglobin, white blood cell (WBC) count with differential, red blood cell (RBC) count, platelet count;

• CLINICAL CHEMISTRY: serum creatinine, blood urea nitrogen (BUN), glucose, AST(SGOT - Serum glutamic-oxaloacetic transaminase), ALT(SGPT - Serum glutamic-pyruvic transaminase), albumin, total bilirubin, total protein, and alkaline phosphatase;

• HIV antibody and hepatitis B surface antigen screens;

• URINALYSIS: by dipstick; full microscopic examination if dipstick positive; and

• URINE DRUG SCREEN: ethyl alcohol, amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine metabolites, opiates and phencyclidine

• SERUM PREGNANCY SCREEN (female volunteers only)

If female and:

• of childbearing potential, is practicing an acceptable method of birth control for the duration of the study as judged by the investigator(s), such as condom with spermicide, diaphragm, intrauterine device (IUD), or abstinence; or

• is postmenopausal for at least 1 year; or is surgically sterile (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy)

Exclusion Criteria:

• Volunteers with a recent history of drug or alcohol addiction or abuse

• Volunteers with the presence of a clinically significant disorder involving the cardiovascular, respiratory, renal, gastrointestinal, immunologic, hematologic, endocrine, or neurologic system(s) or psychiatric disease (as determined by the clinical investigators)

• Volunteers whose clinical laboratory test values are outside the accepted reference range and when confirmed on re-examination are deemed to be clinically significant

• Volunteers demonstrating a positive hepatitis B surface antigen screen or a reactive HIV antibody screen

• Volunteers demonstrating a positive drug abuse screen when screened for this study

• Female volunteers demonstrating a positive pregnancy screen

• Female volunteers who are currently breastfeeding

• Volunteers with a history of allergic response(s) to quinine or related drugs

• Volunteers with a history of clinically significant allergies including drug allergies

• Volunteers with a clinically significant illness during the 4 weeks prior to Period I dosing (as determined by the clinical investigators)

• Volunteers who currently use tobacco products

• Volunteers who have taken any drug known to induce or inhibit hepatic drug metabolism in the 28 days prior to Period I dosing

• Volunteers who report donating greater than 150 mL of blood within 28 days prior to Period I dosing. All subjects will be advised not to donate blood for four weeks after completing the study

• Volunteers who have donated plasma (e.g.plasmapheresis) within 14 days prior to Period I dosing. All subjects will be advised not to donate plasma for four weeks after completing the study

• Volunteers who report receiving any investigational drug within 28 days prior to Period I dosing

• Volunteers who report taking any systemic prescription medication in the 14 days prior to Period I dosing

• Volunteers with a QTc (corrected QT interval) > 480 msec on the screening electrocardiogram (ECG) or with clinically significant findings

• Volunteers who have a glucose-6-phosphate dehydrogenese deficiency (G6PD)

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Mutual Pharmaceutical Company, Inc.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00726895
• Other Study ID Numbers: R04-0376
• First Posted: Aug 1, 2008
• Last Update Posted: Jan 20, 2010
• Last Verified: Jan 1, 2010

• Keywords provided by , ,: Bioavailability
• Additional relevant MeSH terms: Quinine

Study Results

Participant Flow

Arm/Group Title	Quinine Sulfate Capsules 1 x 324 mg Dose Then 2 x 324 mg Dose	Quinine Sulfate Capsules 2 x 324 mg Dose Then 1 x 324 mg Dose
Arm/Group Description	All subjects received each of the two study regimens (Treatment A - Quinine Sulfate 1 x 324 mg capsule, Treatment B - Quinine Sulfate 2 x 324 mg capsules) in a randomly assigned sequence of dosing periods, each followed by a washout period of 7 days.	All subjects received each of the two study regimens (Treatment A - Quinine Sulfate 1 x 324 mg capsule, Treatment B - Quinine Sulfate 2 x 324 mg capsules) in a randomly assigned sequence of dosing periods, each followed by a washout period of 7 days.
Period Title: First Intervention
STARTED	12	12
COMPLETED	12	12
NOT COMPLETED	0	0
Period Title: First Intervention
STARTED	12	12
COMPLETED	12	11
NOT COMPLETED	0	1
Period Title: First Intervention
STARTED	12	11
COMPLETED	12	11
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Entire Study Population
Arm/Group Description	All subjects received each of the two study regimens in a randomly assigned sequence of dosing periods. On the mornings of Day 1 and Day 8, each subject received either one Quinine Sulfate 324 mg capsule or two Quinine Sulfate 324 mg capsules following an overnight fast of at least 10 hours.
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]	33 (13.9)
Sex: Female, Male (Count of Participants)
Female	11 45.8%
Male	13 54.2%
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	0 0%
White	23 95.8%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Maximum Plasma Concentration (Cmax)
Description	The maximum or peak concentration that the drug reaches in the plasma.
Time Frame	serial pharmacokinetic plasma concentrations were drawn prior to dose administration (0 hour) and at 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 16, 24, 36 and 48 hours after drug administration.

Outcome Measure Data

Analysis Population Description

Plasma concentration data for 23 of the 24 enrolled subjects were used in the statistical analysis. Subject number 12 dropped from the study prior to period II (Treatment A) dosing. Treatment A, Dose Adjusted to 2 x 324 mg was a statistical adjustment only used to evaluate for dose proportionality.

Arm/Group Title	Treatment A - Quinine Sulfate Capsules (1 x 324 mg Dose)	Treatment A, Dose Adjusted to 2 x 324 mg	Treatment B - Quinine Sulfate Capsules (2 x 324 mg Dose)
Arm/Group Description	Each subject received one capsule of Quinine Sulfate 324 mg after an overnight fast of at least 10 hours.	This group was a statistical adjustment only. Treatment A (Quinine Sulfate 1 x 324 mg Capsule) Dose Adjusted to 2 x 324 mg was used to evaluate for dose proportionality.	Each subject received two capsules of Quinine Sulfate 324 mg after an overnight fast of at least 10 hours.
Measure Participants	23	23	23
Mean (Standard Deviation) [ng/mL]	2,118.35 (517.79)	4,236.70 (1,035.58)	3,242.92 (685.80)

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.
Time Frame	serial pharmacokinetic plasma concentrations were drawn prior to dose administration (0 hour) and at 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 16, 24, 36 and 48 hours after drug administration.

Outcome Measure Data

Analysis Population Description

Plasma concentration data for 23 of the 24 enrolled subjects were used in the statistical analysis. Subject number 12 dropped from the study prior to period II (Treatment A) dosing. Treatment A, Dose Adjusted to 2 x 324 mg was a statistical adjustment only used to evaluate for dose proportionality.

Arm/Group Title	Treatment A - Quinine Sulfate Capsules (1 x 324 mg Dose)	Treatment A, Dose Adjusted to 2 x 324 mg	Treatment B - Quinine Sulfate Capsules (2 x 324 mg Dose)
Arm/Group Description	Each subject received one capsule of Quinine Sulfate 324 mg after an overnight fast of at least 10 hours.	This group was a statistical adjustment only. Treatment A (Quinine Sulfate 1 x 324 mg Capsule) Dose Adjusted to 2 x 324 mg was used to evaluate for dose proportionality.	Each subject received two capsules of Quinine Sulfate 324 mg after an overnight fast of at least 10 hours.
Measure Participants	23	23	23
Mean (Standard Deviation) [ng-hr/mL]	31,951.03 (10,428.59)	63,902.06 (20,857.17)	56,198.20 (15,683.25)

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.
Time Frame	serial pharmacokinetic plasma concentrations were drawn prior to dose administration (0 hour) and at 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 16, 24, 36 and 48 hours after drug administration.

Outcome Measure Data

Analysis Population Description

Plasma concentration data for 23 of the 24 enrolled subjects were used in the statistical analysis. Subject number 12 dropped from the study prior to period II (Treatment A) dosing. Treatment A, Dose Adjusted to 2 x 324 mg was a statistical adjustment only used to evaluate for dose proportionality.

Arm/Group Title	Treatment A - Quinine Sulfate Capsules (1 x 324 mg Dose)	Treatment A, Dose Adjusted to 2 x 324 mg	Treatment B - Quinine Sulfate Capsules (2 x 324 mg Dose)
Arm/Group Description	Each subject received one capsule of Quinine Sulfate 324 mg after an overnight fast of at least 10 hours.	This group was a statistical adjustment only. Treatment A (Quinine Sulfate 1 x 324 mg Capsule) Dose Adjusted to 2 x 324 mg was used to evaluate for dose proportionality.	Each subject received two capsules of Quinine Sulfate 324 mg after an overnight fast of at least 10 hours.
Measure Participants	23	23	23
Mean (Standard Deviation) [ng-hr/mL]	35,199.28 (12,678.60)	70,398.56 (25,357.19)	61,570.10 (19,295.34)

Adverse Events

Adverse Event Reporting Description	24 subjects were enrolled in this study. One subject dropped out of the study prior to receiving both interventions. 23 subjects were administered the Quinine Sulfate 1 x 324 mg capsule dose and 24 subjects were admistered the Quinine Sulfate 2 x 324 mg capusle dose.
Arm/Group Title	Treatment A - Quinine Sulfate Capsules 1 x 324 mg Dose		Treatment B - Quinine Sulfate Capsules 2 x 324 mg Dose
Arm/Group Description	All subjects received each of the two study regimens (Treatment A - Quinine Sulfate 1 x 324 mg capsule, Treatment B - Quinine Sulfate 2 x 324 mg capsules) in a randomly assigned sequence of dosing periods, each followed by a washout period of 7 days.		All subjects received each of the two study regimens (Treatment A - Quinine Sulfate 1 x 324 mg capsule, Treatment B - Quinine Sulfate 2 x 324 mg capsules) in a randomly assigned sequence of dosing periods, each followed by a washout period of 7 days.
All Cause Mortality
	Treatment A - Quinine Sulfate Capsules 1 x 324 mg Dose		Treatment B - Quinine Sulfate Capsules 2 x 324 mg Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Treatment A - Quinine Sulfate Capsules 1 x 324 mg Dose		Treatment B - Quinine Sulfate Capsules 2 x 324 mg Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/23 (0%)		0/24 (0%)
Other (Not Including Serious) Adverse Events
	Treatment A - Quinine Sulfate Capsules 1 x 324 mg Dose		Treatment B - Quinine Sulfate Capsules 2 x 324 mg Dose
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/23 (26.1%)		10/24 (41.7%)
Gastrointestinal disorders
Diarrhea	0/23 (0%)	0	1/24 (4.2%)	1
Nausea	0/23 (0%)	0	3/24 (12.5%)	3
Stomach discomfort	0/23 (0%)	0	1/24 (4.2%)	1
General disorders
Generalized pain	0/23 (0%)	0	1/24 (4.2%)	1
Pain in extremity	0/23 (0%)	0	1/24 (4.2%)	1
Pallor	1/23 (4.3%)	1	1/24 (4.2%)	1
Rigors	0/23 (0%)	0	1/24 (4.2%)	1
Injury, poisoning and procedural complications
Skin laceration	0/23 (0%)	0	1/24 (4.2%)	1
Metabolism and nutrition disorders
Loss of appetite	0/23 (0%)	0	1/24 (4.2%)	1
Musculoskeletal and connective tissue disorders
Joint injury	1/23 (4.3%)	1	0/24 (0%)	0
Myalgia in extremities	1/23 (4.3%)	1	0/24 (0%)	0
Nervous system disorders
Dizziness	0/23 (0%)	0	3/24 (12.5%)	3
Headache	2/23 (8.7%)	2	2/24 (8.3%)	2
Syncope	2/23 (8.7%)	2	0/24 (0%)	0
Tinnitus	0/23 (0%)	0	1/24 (4.2%)	1
Reproductive system and breast disorders
Dysmenorrhea	0/23 (0%)	0	1/24 (4.2%)	1
Respiratory, thoracic and mediastinal disorders
Pharyngolaryngeal - Sore throat	0/23 (0%)	0	1/24 (4.2%)	1
Tonsillitis	0/23 (0%)	0	1/24 (4.2%)	1
Upper respiratory tract infection	1/23 (4.3%)	1	0/24 (0%)	0
Skin and subcutaneous tissue disorders
Night Sweats	1/23 (4.3%)	1	0/24 (0%)	0
Sweating increased	0/23 (0%)	0	1/24 (4.2%)	1

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.