Bioequivalence
Conditions
Brief summary
Generate human PK data by collecting data following the application of metronidazole formulations.
Detailed description
This research study is intended to develop models for in vitro/in vivo correlation (IVIVC) of drug absorption from dermal products. This study will use metronidazole products that have already been approved by the Food and Drug Administration (FDA) and are already sold to customers in the United States; will not include any placebos.
Interventions
DRUGMetronidazole gel 1
RLD gel
DRUGMetronidazole gel 2
generic gel
generic cream
Sponsors
Food and Drug Administration (FDA)
University of Maryland, Baltimore
Study design
Allocation
NON_RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
1. Men or non-pregnant, women who are of any ethnic background between the age of 18 to 45 years old 2. Subjects must be non-smokers/tobacco users (must have refrained from the use of nicotine-containing substances, including tobacco products (e.g., cigarettes, cigars, chewing tobacco, snuff, gum, patches or electronic cigarettes) over the previous 2 months and are not currently using tobacco products 3. Provide written informed consent before initiation of any of the study procedures 4. Agree not to participate in another clinical trial/study during the study period or to participate in an investigational drug study for at least 1 month after the last study session 5. Able to adhere to the study protocol and study restrictions 6. Able to participate in all study sessions 7. Subjects have upper arms large enough to allow for placement of 200 cm2 \[31 in2\] area for applications of gel or cream. The arm distance from the greater tubercle to the olecranon process should be a minimum of 30 cm. The circumference of the upper arms should be a minimum of 30 cm. 8. Subjects deemed to be healthy as judged by the Medically Accountable Investigator (MAI) and determined by medical history, physical examination and medication history 9. Negative urine drug screening test (cannabinoids, amphetamines, barbiturates, benzodiazepine, cocaine, methadone, opiates, PCP) 10. Have normal screening laboratories for white blood cells (WBC), hemoglobin (Hgb), platelets, sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN), creatinine, alanine transaminase (ALT) and aspartate aminotransferase (AST) 11. Have normal screening laboratories for urine protein and urine glucose 12. Female subjects must be of non-childbearing potential (as defined as surgically sterile \[i.e. history of hysterectomy or tubal ligation\] or postmenopausal for more than 1 year), or if of childbearing potential must be non-pregnant at the time of enrollment and on the morning of each study session, and must agree to use reliable hormonal or barrier birth control such as implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence, or a vasectomized partner 13. Agrees not to donate blood to a blood bank throughout participation in the study and for at least 3 months after last study session 14. Have a normal ECG; must not have the following to be acceptable: pathologic Q wave abnormalities, significant ST-T wave changes, left ventricular hypertrophy, right bundle branch block, left bundle branch block. (sinus rhythm is between 55-100 beats per minute) 15. Have normal vital signs: * Temperature 35-37.9°C (95-100.3°F) * Systolic blood pressure 90-165 mmHg * Diastolic blood pressure 60-100 mmHg * Heart rate 55-100 beats per minute * Respiration rate 12-20 breaths per minute
Exclusion criteria
1. Women who are pregnant, lactating, breast feeding or have a positive serum pregnancy test at enrollment or positive urine pregnancy test on the morning of the first day of any study session 2. Smokers/tobacco users (current use or use over the previous 2 months of nicotine-containing substances (e.g., cigarettes, cigars, chewing tobacco, gum, snuff, patch or electronic cigarettes) 3. Current participation in any ongoing investigational drug trial/study or clinical drug trial/study 4. History as either reported by the subject or evident to the investigator of infectious disease or skin infection or of chronic skin disease (e.g., psoriasis, atopic dermatitis) 5. History of diabetes 6. History of significant skin cancers (e.g., melanoma, squamous cell carcinoma) except basal cell carcinomas that were superficial and did not involve the investigative sites 7. Body Mass Index (BMI) ≥30 kg/m2 8. History of chronic obstructive pulmonary disease or cor pulmonale, or substantially decreased respiratory reserve, hypoxia, hypercapnia or pre-existing respiratory depression 9. Active positive Hepatitis B, C and/or HIV test results 10. Positive urine drug screening test 11. Use of chronic prescription medications during the period 0 to 30 days; or over-the-counter medications (e.g. antihistamines, topical corticosteroids) and short term (\<30 days) prescription medications during the period 0-3 days before a study session (vitamins, herbal supplements and birth control medications not included) 12. Currently taking daily anticoagulants (warfarin, heparin, rivaroxaban, dabigatran, etc…) within the past month prior to entry into the study 13. History of blood dyscrasia (abnormal in structure, function and quality) 14. History of Crohn's disease 15. Donation or loss of greater than one pint of blood within 60 days of entry to the study 16. Any prior adverse reaction or hypersensitivity to metronidazole, parabens, other inactive ingredients in the topical gel or cream formulations 17. Received an experimental agent (vaccine, drug, biologic, device, blood product or medication) within 1 month before enrollment in this study or expects to receive an experimental agent during the study 18. Consumption (food or drink) of alcohol within 48 h prior to dose administration 19. Any condition that would, in the opinion of the Medically Accountable Investigator (MAI), place the subject at an unacceptable risk of injury or render the subject unable to meet the requirements of the protocol 20. Subject has an obvious difference in skin color between arms or the presence of a skin condition, excessive hair at the application site (upper arms), sunburn, raised moles or scars, open sores at application site (upper arms), scar tissue, tattoo, or coloration that would interfere with placement of metronidazole products, skin assessment, or reactions to metronidazole
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PK Parameters | 3 study sessions/subject; each session was 25 h; blood samples obtained at the following time points: -60 min, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 23, 24, 25 h; at least one week washout period between each study session | Area under the concentration-time curve from 0 to 25 h |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Topical Metronidazole Study session 1: metronidazole gel (RLD); followed by at least a one week washout period.
Study session 2: metronidazole gel (generic); followed by at least a one week washout period.
Study session 3: metronidazole cream (generic) | 7 |
| Total | 7 |
Baseline characteristics
| Characteristic | Topical Metronidazole |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants |
| Body Mass Index (BMI) | 27.5 kg/m^2 STANDARD_DEVIATION 1.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 1 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 | 2 Participants |
| Region of Enrollment United States | 7 Participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 7 | 0 / 7 |
| other Total, other adverse events | 3 / 7 | 2 / 7 | 3 / 7 |
| serious Total, serious adverse events | 0 / 7 | 0 / 7 | 0 / 7 |
Outcome results
Primary
PK Parameters
Area under the concentration-time curve from 0 to 25 h
Time frame: 3 study sessions/subject; each session was 25 h; blood samples obtained at the following time points: -60 min, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 23, 24, 25 h; at least one week washout period between each study session
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Study Session 1 (RLD Gel) | PK Parameters | 283 ng*h/mL |
| Study Session 2 (Generic Gel) | PK Parameters | 341 ng*h/mL |
| Study Session 3 (Generic Cream) | PK Parameters | 189 ng*h/mL |