Ignite Creation Date:
2024-05-06 @ 6:48 PM
Last Modification Date:
2024-10-26 @ 2:55 PM
Study NCT ID:
NCT05796362
Status:
NOT_YET_RECRUITING
Last Update Posted:
2023-04-03
First Post:
2022-09-16
Brief Title:
A Single-Dose Three-Way Three-Sequence Crossover BA Study of Azithromycin Oleogel
Sponsor:
Brigham and Womens Hospital
Organization:
Brigham and Womens Hospital
Study Overview
Official Title:
A Randomized Balanced Single Dose Three-treatment Three-period Crossover Bioavailability Study of Azithromycin Oleogel in Healthy Adult Human Subjects Under Fasting Condition
Status:
NOT_YET_RECRUITING
Status Verified Date:
2023-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
This is an exploratory study to describe the pharmacokinetics of the azithromycin oral and rectal oleogel in humans compared to the reference oral drug to Zithromax assess the impact of the novel formulation on bioavailability The investigators will perform a randomized balanced single dose three-treatment three-period crossover oral bioavailability study under fasted conditions to evaluate the safety and tolerability of azithromycin oleogel and compare the bioavailability of the azithromycin oleogel to the reference drug
Detailed Description:
Children have difficulties swallowing tablets including azithromycin AZT tablets In low socioeconomic countries tablets are typically crushed dispersed in water and administered as a suspension to the child This practice introduces several points of failure including unpalatability leading to refusal of the drug and lack of clean water for resuspension Thus there remains a critical need to develop dosage forms that do not require crushing and suspension The investigators have developed a formulation inspired by techniques recently described in the field of molecular gastronomy that transform oils into gels also known as oleogels Oils have a prolonged history of use in the food industry and a very well-established safety profile Plant-derived oils represent an attractive vehicle for drug delivery Many drugs have hydrophobic properties and therefore have a greater wettability and solubility in oil in comparison to water Ingestion of fats stimulates secretion of bile salts and enzymes that enhance drug dissolution in the physiological fluids and drug absorption Furthermore converting oils into gels allows for altering the mouth-feel and texture of the dosage form which affects patient acceptance
The aim of this exploratory study is to determine azithromycin bioavailability of oral and rectal oleogels in healthy volunteers as well as to make an initial safety evaluation of the oleogels The reference azithromycin tablet has a bioavailability of 38 with an AUC of 43 mcghrml Cmax 05 mcgml and Tmax of 22 hours The half-life is approximately 68 hours The safety profile of azithromycin has been well characterized and single doses of azithromycin are well tolerated with common reactions including diarrhealoose stools nausea abdominal pain vomiting dyspepsia and vaginitis all less than 10 of subjects in studies
The intersubject variability of the pharmacokinetics PK parameter estimates for the azithromycin oleogel are derived from our preclinical studies of the azithromycin oleogel in swine the coefficient of variation for both the oral tablets oral oleogels and rectal oleogels are between 30-40 These estimates of intersubject variability informed our number of subjects N21 for this crossover study Additional coefficient of variability estimates for oral tablets were found in the literature and were approximately 30
Azithromycin is not approved for rectal administration However our own studies of the rectal azithromycin oleogel in female Yorkshire swine at doses of 5 mgkg 40-70 kg weight range found the following pharmacokinetic parameters Cmax 0224 mcgml CV 35 n4 AUC 1680 mcghml CV 30 n4 The animals were treated with azithromycin oleogel rectally After 24 h tissue mucosal biopsies were collected from the rectum endoscopically under anesthesia Samples were fixed and stained with Hematoxylin and Eosin and analyzed by a clinical pathologist Overall there was no evidence of activity chronicity or rectal tissue toxicity in the colorectal mucosa of the rectum in our preclinical swine models either by gross observation or histologic examination Table 2 This is in keeping with two exploratory clinical trials of an azithromycin suppository which did not report any clinically observed or patient-reported safety concerns besides diarrhea at doses of 125-500mg or 1g of azithromycin suppository
This is an exploratory study to describe the pharmacokinetics of the azithromycin oral and rectal oleogel in humans compared to the reference oral drug to assess the impact of the novel formulation on bioavailability The investigators will perform a randomized balanced single dose three-treatment three-period crossover oral bioavailability study under fasted conditions to evaluate the safety and tolerability of azithromycin oleogel and compare the bioavailability of the azithromycin oleogel to the reference drug The cross-over design will minimize intersubject variability Given azithromycins coefficient of variability which is estimated to be 30 in humans for the reference drug and 30-40 for the oleogel in swine experiments the investigators estimate that 21 subjects will be sufficient This number also accounts for any potential subject dropouts Due to the half-life of azithromycin being 68 hours the investigators will give 17 days between drug administrations to allow for sufficient wash-out of at least 5 half-lives of azithromycin Subjects in the study will be closely monitored for any signs of adverse reactions
Subjects will be given 250mg of azithromycin in each formulation The maximum recommended dose of azithromycin in humans is 2g in the oral formulation bioavailability 38 effective dose 760 mg or 500mg in the IV formulation The maximum dose administered to humans is 4g intravenously with the following pharmacokinetic measurements Cmax 991 mcgml AUC 82 mcghml At this high dose side effects seen were most commonly nausea vomiting and tinnitus which were mild In subjects administered 2g intravenous azithromycin 4 out of 6 developed neutropenia however this was not seen at 4g Based on our non-clinical data in swine with a dosage of 5 mgkg and a weight range of 40-70 kg the equivalent human dose would be 406-489 mgkg approximately 305-367 mg for a 75 kg person The maximum azithromycin a subject would absorb is 250 mg which is still lower than the 2g dose with 38 bioavailability 760mg
Subjects will be screened for up to 28 days prior to first dose Treatment Period 1 begins with baseline when subjects are admitted to the study center the night before for a 10-hour overnight fast prior to the first dose After admission subjects will undergo pre-study evaluations The subjects will be assigned a subject number before the first study-specific procedure during baseline eg blood sample A randomization number will be assigned just prior to dosing after baseline evaluation results have established their continued study eligibility
After a 10-hour overnight fast subject will receive a single dose of rectal oleogel test X 250mg drug in about 15 ml of oleogel with continued fast oral oleogel test T 250mg drug in about 15 ml of oleogel or oral reference tablet R with 240 mL of water For four hours thereafter subjects should remain in the fasting state and seated in the upright or semi-recumbent position Brief periods of ambulation are allowed for study-related activities and use of the toilet Blood samples will be obtained predose and over the next 72 hours Water will be permitted ad libitum except for one hour before and one hour after dosing Subjects will be served standardized meals according to a predefined schedule throughout the study
After approximately a 17-day period away from the study subjects will return to the study site for Treatment Period 2 and undergo assessments and blood collection similar to Treatment Period 1 The treatment administered will be defined in the randomization schedule
After approximately a 17-day period away from the study subjects will return to the study site for Treatment Period 3 and undergo assessments and blood collection similar to Treatment Periods 1 and 2 The treatment administered will be defined in the randomization schedule
The end-of-study EOS evaluation will be performed after completion of the final PK sample following Treatment Period 3 or up to 7 days thereafter
The aim of this exploratory study is to determine azithromycin bioavailability of oral and rectal oleogels in healthy volunteers as well as to make an initial safety evaluation of the oleogels The reference azithromycin tablet has a bioavailability of 38 with an AUC of 43 mcghrml Cmax 05 mcgml and Tmax of 22 hours The half-life is approximately 68 hours The safety profile of azithromycin has been well characterized and single doses of azithromycin are well tolerated with common reactions including diarrhealoose stools nausea abdominal pain vomiting dyspepsia and vaginitis all less than 10 of subjects in studies
The intersubject variability of the pharmacokinetics PK parameter estimates for the azithromycin oleogel are derived from our preclinical studies of the azithromycin oleogel in swine the coefficient of variation for both the oral tablets oral oleogels and rectal oleogels are between 30-40 These estimates of intersubject variability informed our number of subjects N21 for this crossover study Additional coefficient of variability estimates for oral tablets were found in the literature and were approximately 30
Azithromycin is not approved for rectal administration However our own studies of the rectal azithromycin oleogel in female Yorkshire swine at doses of 5 mgkg 40-70 kg weight range found the following pharmacokinetic parameters Cmax 0224 mcgml CV 35 n4 AUC 1680 mcghml CV 30 n4 The animals were treated with azithromycin oleogel rectally After 24 h tissue mucosal biopsies were collected from the rectum endoscopically under anesthesia Samples were fixed and stained with Hematoxylin and Eosin and analyzed by a clinical pathologist Overall there was no evidence of activity chronicity or rectal tissue toxicity in the colorectal mucosa of the rectum in our preclinical swine models either by gross observation or histologic examination Table 2 This is in keeping with two exploratory clinical trials of an azithromycin suppository which did not report any clinically observed or patient-reported safety concerns besides diarrhea at doses of 125-500mg or 1g of azithromycin suppository
This is an exploratory study to describe the pharmacokinetics of the azithromycin oral and rectal oleogel in humans compared to the reference oral drug to assess the impact of the novel formulation on bioavailability The investigators will perform a randomized balanced single dose three-treatment three-period crossover oral bioavailability study under fasted conditions to evaluate the safety and tolerability of azithromycin oleogel and compare the bioavailability of the azithromycin oleogel to the reference drug The cross-over design will minimize intersubject variability Given azithromycins coefficient of variability which is estimated to be 30 in humans for the reference drug and 30-40 for the oleogel in swine experiments the investigators estimate that 21 subjects will be sufficient This number also accounts for any potential subject dropouts Due to the half-life of azithromycin being 68 hours the investigators will give 17 days between drug administrations to allow for sufficient wash-out of at least 5 half-lives of azithromycin Subjects in the study will be closely monitored for any signs of adverse reactions
Subjects will be given 250mg of azithromycin in each formulation The maximum recommended dose of azithromycin in humans is 2g in the oral formulation bioavailability 38 effective dose 760 mg or 500mg in the IV formulation The maximum dose administered to humans is 4g intravenously with the following pharmacokinetic measurements Cmax 991 mcgml AUC 82 mcghml At this high dose side effects seen were most commonly nausea vomiting and tinnitus which were mild In subjects administered 2g intravenous azithromycin 4 out of 6 developed neutropenia however this was not seen at 4g Based on our non-clinical data in swine with a dosage of 5 mgkg and a weight range of 40-70 kg the equivalent human dose would be 406-489 mgkg approximately 305-367 mg for a 75 kg person The maximum azithromycin a subject would absorb is 250 mg which is still lower than the 2g dose with 38 bioavailability 760mg
Subjects will be screened for up to 28 days prior to first dose Treatment Period 1 begins with baseline when subjects are admitted to the study center the night before for a 10-hour overnight fast prior to the first dose After admission subjects will undergo pre-study evaluations The subjects will be assigned a subject number before the first study-specific procedure during baseline eg blood sample A randomization number will be assigned just prior to dosing after baseline evaluation results have established their continued study eligibility
After a 10-hour overnight fast subject will receive a single dose of rectal oleogel test X 250mg drug in about 15 ml of oleogel with continued fast oral oleogel test T 250mg drug in about 15 ml of oleogel or oral reference tablet R with 240 mL of water For four hours thereafter subjects should remain in the fasting state and seated in the upright or semi-recumbent position Brief periods of ambulation are allowed for study-related activities and use of the toilet Blood samples will be obtained predose and over the next 72 hours Water will be permitted ad libitum except for one hour before and one hour after dosing Subjects will be served standardized meals according to a predefined schedule throughout the study
After approximately a 17-day period away from the study subjects will return to the study site for Treatment Period 2 and undergo assessments and blood collection similar to Treatment Period 1 The treatment administered will be defined in the randomization schedule
After approximately a 17-day period away from the study subjects will return to the study site for Treatment Period 3 and undergo assessments and blood collection similar to Treatment Periods 1 and 2 The treatment administered will be defined in the randomization schedule
The end-of-study EOS evaluation will be performed after completion of the final PK sample following Treatment Period 3 or up to 7 days thereafter
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None