Therapeutic Equivalency, Healthy
Conditions
Brief summary
The purpose of this study is to evaluate and compare the relative bioavailability of a test formulation of cilostazol tablets to an equivalent dose of Pletal® (cilostazol) tablets after a single oral dose administered under fasting conditions.
Detailed description
The purpose of this study is to evaluate and compare the relative bioavailability of a test formulation of cilostazol tablets to an equivalent dose of Pletal® (cilostazol) tablets after a single oral dose administered under fasting conditions. Thirty-two non-smoking, non-obese, healthy male and female volunteers between the ages of 18 and 55 will be randomly assigned in a crossover fashion to receive each of two cilostazol 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 the test formulation, cilostazol (2 x 50 mg tablets), or a single oral dose of the reference formulation, Pletal® (2 x 50 mg tablets). 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 cilostazol. 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 pulse will be measured before dosing and at 3 and 24 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
Cilostazol (2 x 50 mg tablets) administered after an overnight fast of at least 10 hours
DRUGCilostazol (Pletal®) 50 mg Tablets
Cilostazol (Pletal® Tablets, 2 x 50mg) administered after an overnight fast of at least 10 hours.
Sponsors
Mutual Pharmaceutical Company, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy adults 18-55 years of age * Non-smoking * Non-pregnant (post-menopausal, surgically sterile or using effective contraceptive measures) * No more than 15% plus or minus from ideal weight for subject's height and elbow breadth as defined by the Metropolitan Life Insurance Company Statistical Bulletin. Extrapolations, if required, to be conducted according to BASi Standard Operating Procedures * Medically healthy on the basis of medical history and physical examination within 30 days prior to the start of the study * Test results from blood chemistry, hematology, and urinalysis performed within 30days prior to the start of the study within clinically acceptable limits * At screening, subjects must have blood pressure and pulse rate within the following ranges: Systolic blood pressure 90-140mmHg; Diastolic blood pressure 50-90mmHg; Pulse 45-100 bpm * An acceptable electrocardiogram (EKG): sinus rhythm with no evidence of AV block or ischemic changes
Exclusion criteria
* Prescription drug use (excluding hormonal contraceptives) within 14 days prior to drug administration, each period * Aspirin ingestion within 7 days prior to drug administration, each period * Use of any over-the-counter preparations, herbal remedies, and/or nutritional supplements within 7 days prior to drug administration, each period * Consumption of grapefruit juice or grapefruit-containing products within 72 hours prior to drug administration , each period * Consumption of alcohol within 24 hours prior to drug administration, each period * Consumption of caffeine within 10 hours prior to drug administration, each period * Female subjects must not be pregnant or nursing; and must be surgically sterile; one year post-menopausal; or on hormonal contraceptive agent(s), a diaphragm or condom with spermicidal foam or jelly, or IUD for at least three months prior to drug administration and agree to use the same method of contraception for at least 1 month after the last drug administration * Subjects with a history or presence of significant organ system (cardiovascular, neurological, hepatic, hematopoietic, renal, pulmonary, endocrine, or gastrointestinal) disorders, or ongoing infectious diseases * History of hypersensitivity or adverse reactions to cilostazol (Pletal®), or other related drugs * Recent (12 month) history or evidence of alcoholism or drug abuse * Positive urine screening of drugs of abuse * Positive results to Human Immunodeficiency Virus (HIV) or Hepatitis B surface Antigen (HBsAg) tests * Participation in another clinical trial in the previous 30 days before day 1 of this study * Donation of blood in the previous 30 days before day 1 of this study
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, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 16, 24, 36 and 48 hours after drug administration. | The maximum or peak concentration that cilostazol (test and reference product) 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, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 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, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 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
Recruitment details
Thirty-two healthy adult male and female volunteers from the community-at-large were enrolled.
Participants by arm
| Arm | Count |
|---|---|
| Cilostazol 50 mg Tablets and Pletal® 50 mg Tablets 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 two tablets of either Cilostazol 50 mg or Pletal® 50 mg following an overnight fast of at least 10 hours. | 32 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Washout Period of 7 Days | Protocol Violation | 2 | 0 |
| Washout Period of 7 Days | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Cilostazol 50 mg Tablets and Pletal® 50 mg Tablets |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 32 Participants |
| Age Continuous | 32.25 years STANDARD_DEVIATION 11.98 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 26 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 | 5 Participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 10 / 31 | 12 / 30 |
| serious Total, serious adverse events | 0 / 31 | 0 / 30 |
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, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 16, 24, 36 and 48 hours after drug administration.
Population: Pharmacokinetic analyses of cilostazol and Pletal® are based on 28 and 27 subjects, respectively. Reliable estimates could not be obtained for one subject administered Cilostazol and two subjects administered Pletal® because there was not a smooth decline in concentrations in the terminal phase of elimination.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cilostazol 50 mg Tablets | Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] | 8,641.26 ng-hr/mL |
| Pletal® 50 mg Tablets | Area Under the Concentration Versus Time Curve From Time 0 Extrapolated to Infinity [AUC(0-∞)] | 8,706.54 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, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 16, 24, 36 and 48 hours after drug administration.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cilostazol 50 mg Tablets | Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] | 7,265.38 ng-hr/mL |
| Pletal® 50 mg Tablets | Area Under the Concentration Versus Time Curve From Time 0 to Time t [AUC(0-t)] | 7,354.03 ng-hr/mL |
Primary
Maximum Plasma Concentration (Cmax)
The maximum or peak concentration that cilostazol (test and reference product) reaches in the plasma.
Time frame: serial pharmacokinetic plasma concentrations were drawn prior to dose administration (0 hour) and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 12, 16, 24, 36 and 48 hours after drug administration.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cilostazol 50 mg Tablets | Maximum Plasma Concentration (Cmax) | 565.52 ng/mL | Standard Deviation 155.67 |
| Pletal® 50 mg Tablets | Maximum Plasma Concentration (Cmax) | 570.60 ng/mL | Standard Deviation 174.72 |