Pharmacokinetics of Metronidazole Dermal Products

• Sponsor: University of Maryland, Baltimore (Other)
• Overall Status: Completed
• CT.gov ID: NCT03271983
• Collaborator: Food and Drug Administration (FDA) (U.S. Fed)
• Enrollment: 7
• Location: 1
• Arms: 3
• Actual Duration (Months): 6.8
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

Generate human PK data by collecting data following the application of metronidazole formulations.

Condition or Disease	Intervention/Treatment	Phase
Bioequivalence	Drug: Metronidazole gel 1; Drug: Metronidazole gel 2; Drug: Metronidazole cream	Early Phase 1

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 7 participants
• Allocation: Non-Randomized
• Intervention Model: Crossover Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Evaluation of the Bioavailability of Metronidazole Dermal Products
• Actual Study Start Date: Apr 9, 2019
• Actual Primary Completion Date: Oct 31, 2019
• Actual Study Completion Date: Nov 3, 2019

Arms and Interventions

Arm	Intervention/Treatment
Other: metronidazole gel 1 RLD gel	Drug: Metronidazole gel 1; RLD gel; Other Names: metronidazole
Other: metronidazole gel 2 generic gel	Drug: Metronidazole gel 2; generic gel; Other Names: metronidazole
Other: metronidazole cream generic cream	Drug: Metronidazole cream; generic cream; Other Names: metronidazole

Outcome Measures

Primary Outcome Measures

1. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	General Clinical Research Center (GCRC) at the University of Maryland Medical Center	Baltimore	Maryland	United States	21201

Sponsors and Collaborators

• University of Maryland, Baltimore
• Food and Drug Administration (FDA)

Investigators

• Principal Investigator: Audra L Stinchcomb, PhD, University of Maryland, Baltimore School of Pharmacy

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 12, 2019

More Information

Publications

None provided.

• Responsible Party: Audra Stinchcomb, Professor, University of Maryland, Baltimore
• ClinicalTrials.gov Identifier: NCT03271983
• Other Study ID Numbers: HP-00071790
• First Posted: Sep 5, 2017
• Last Update Posted: May 17, 2022
• Last Verified: Mar 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Additional relevant MeSH terms: Metronidazole

Study Results

Participant Flow

Arm/Group Title	Topical Metronidazole
Arm/Group Description	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)
Period Title: Overall Study
STARTED	7
COMPLETED	7
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Topical Metronidazole
Arm/Group Description	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)
Overall Participants	7
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	7 100%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	4 57.1%
Male	3 42.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 14.3%
Not Hispanic or Latino	6 85.7%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	2 28.6%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	2 28.6%
White	2 28.6%
More than one race	1 14.3%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	7 100%
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	27.5 (1.2)

Outcome Measures

1. Primary Outcome

Title	PK Parameters
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Session 1 (RLD Gel)	Study Session 2 (Generic Gel)	Study Session 3 (Generic Cream)
Arm/Group Description	Metronidazole gel: RLD gel	Metronidazole gel: generic gel	Metronidazole cream: generic cream
Measure Participants	7	7	7
Mean (90% Confidence Interval) [ng*h/mL]	283	341	189

Adverse Events

Time Frame	For 25 h after product administration plus 72 h after product removal from the arms. Subjects received a phone call within 72 h after completion of the study session to determine there were no adverse events. A total of ~97 h for each study session.
Arm/Group Title	Study Session 1 (RLD Gel)		Study Session 2 (Generic Gel)		Study Session 3 (Generic Cream)
Arm/Group Description	Metronidazole gel: RLD gel		Metronidazole gel: generic gel		Metronidazole cream: generic cream
All Cause Mortality
	Study Session 1 (RLD Gel)		Study Session 2 (Generic Gel)		Study Session 3 (Generic Cream)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/7 (0%)		0/7 (0%)
Serious Adverse Events
	Study Session 1 (RLD Gel)		Study Session 2 (Generic Gel)		Study Session 3 (Generic Cream)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/7 (0%)		0/7 (0%)
Other (Not Including Serious) Adverse Events
	Study Session 1 (RLD Gel)		Study Session 2 (Generic Gel)		Study Session 3 (Generic Cream)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/7 (42.9%)		2/7 (28.6%)		3/7 (42.9%)
Cardiac disorders
Decreased blood pressure	1/7 (14.3%)	1	2/7 (28.6%)	2	1/7 (14.3%)	1
Decreased heart rate	1/7 (14.3%)	1	0/7 (0%)	0	0/7 (0%)	0
Skin and subcutaneous tissue disorders
PRURITUS	1/7 (14.3%)	1	0/7 (0%)	0	1/7 (14.3%)	1
ERYTHEMA (skin reddening)	1/7 (14.3%)	1	0/7 (0%)	0	0/7 (0%)	0
Pain at IV site	0/7 (0%)	0	0/7 (0%)	0	1/7 (14.3%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.