Healthy
Conditions
Keywords
Bioavailability
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.
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.
Interventions
1 x 324 mg capsule
Sponsors
Mutual Pharmaceutical Company, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population 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. | 24 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Washout Period of 7 Days | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 24 Participants |
| Age Continuous | 33 years STANDARD_DEVIATION 13.9 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 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 | 23 Participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 23 | 10 / 24 |
| serious Total, serious adverse events | 0 / 23 | 0 / 24 |
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.
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.
Population: 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 | Measure | Value (MEAN) |
|---|---|---|
| Treatment A - Quinine Sulfate Capsules (1 x 324 mg Dose) | Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] | 35,199.28 ng-hr/mL |
| Treatment A, Dose Adjusted to 2 x 324 mg | Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] | 70,398.56 ng-hr/mL |
| Treatment B - Quinine Sulfate Capsules (2 x 324 mg Dose) | Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] | 61,570.10 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, 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.
Population: 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 | Measure | Value (MEAN) |
|---|---|---|
| Treatment A - Quinine Sulfate Capsules (1 x 324 mg Dose) | Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] | 31,951.03 ng-hr/mL |
| Treatment A, Dose Adjusted to 2 x 324 mg | Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] | 63,902.06 ng-hr/mL |
| Treatment B - Quinine Sulfate Capsules (2 x 324 mg Dose) | Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] | 56,198.20 ng-hr/mL |
Primary
Maximum Plasma Concentration (Cmax)
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.
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Treatment A - Quinine Sulfate Capsules (1 x 324 mg Dose) | Maximum Plasma Concentration (Cmax) | 2,118.35 ng/mL | Standard Deviation 517.79 |
| Treatment A, Dose Adjusted to 2 x 324 mg | Maximum Plasma Concentration (Cmax) | 4,236.70 ng/mL | — |
| Treatment B - Quinine Sulfate Capsules (2 x 324 mg Dose) | Maximum Plasma Concentration (Cmax) | 3,242.92 ng/mL | Standard Deviation 685.8 |