Pharmacokinetics of Metronidazole Dermal Products

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.

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