Fungal Infection
Conditions
Brief summary
For tablets to be absorbed, the drug must dissolve after being swallowed. Drugs with low solubility sometimes require the inert ingredients in tablets to help the drug dissolve after being swallowed. This study uses itraconazole as an example drug with low solubility. Itraconazole tablets with different inert ingredients and manufacturing will be administered to healthy volunteers to see if the different inert ingredients and manufacturing impact drug absorption.
Interventions
DRUGfast itraconazole tablet
100mg dose
DRUGmedium itraconazole tablet
100mg dose
DRUGslow itraconazole tablet
100mg dose
DRUGoral itraconazole solution
100mg dose
Sponsors
University of Maryland, Baltimore
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Subject is healthy, as determined by screening evaluation that is not greater than 30 days before the first drug study visit * Subject is male or female between 18 and 65 years of age inclusive. * Subject is an acceptable candidate for venipuncture. * Subject is willing to stop all non-routine OTC medications, as well as vitamins, dietary supplements, and herbals, for 24 hours prior to study drug administration and during pharmacokinetic study visits. * Subject is willing, for each of the four drug study periods, to stop consuming grapefruit, grapefruit products, star fruit, star fruit products, Seville oranges, and St. John's wort from 72-hour before study drug administration until the period's last blood sample * Subject is willing to not smoke (or use e-cigarettes) during study visits.
Exclusion criteria
* Subject has a significant medical disease (including cardiovascular, pulmonary, hematologic, endocrine, immunologic, neurologic, gastrointestinal or psychiatric). * Subject shows evidence of congestive heart failure or history of congestive heart failure. * Subject exhibits electrocardiogram (12 lead) with clinically significant abnormalities (e.g. QTcF \>450 msec). * Subject has a history of alcohol or drug abuse, which in the opinion of the investigator, could jeopardize the subject's health or would compromise the subject's ability to participate in this trial. * Subject is pregnant, breast feeding, or trying to become pregnant. * Female subject of childbearing potential is unwilling or unable to use a medically acceptable method of contraception throughout the entire study period and for one week after the study is completed. Medically acceptable methods of contraception that may be used by the subject and/or her partner are: oral birth control pill, condom with spermicide, diaphragm with spermicide, IUD, vaginal spermicidal suppository, surgical sterilization of patient or their partner(s), abstinence, or hormonal-based patches, ring, injections, and implants. * Subject routinely uses (i.e. daily or weekly) prescription medication except hormonal birth control medication, routinely uses (i.e. daily or weekly) OTC medication, or routinely uses (i.e. daily or weekly) St. John's Wort. OTC medications do not include vitamins, dietary supplements, or herbals. * Subject routinely uses (i.e. daily or weekly) acid blockers, antacids, anti-diarrhea, stimulants, appetite suppressants, or anti-nausea medication or other drugs that modulate GI functio * Subject is currently taking itraconazole or medication known to interact with itraconazole. * Subject is allergic to itraconazole. * Subject has liver impairment as assessed by alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin levels greater than the upper limit of normal (ULN). * Subject has renal impairment as assessed by creatinine clearance lower than 50mL/min/1.73m2, using the CKD-EPI formula. * Subject is not willing or able to be adherent to study protocol (e.g. study visits). * Subject has a condition in which in the opinion of the PI or medical physician would increase risk to the subject or interfere with the integrity of the study. * Subject has received an investigational product within 30 days prior to study drug administration, plans to receive an investigational product during their study participation period, or plans to donate blood to any other clinical trial during their study participation period. * Subject has provided plasma donation within 1 month of screening or any blood donation/loss more than 500 mL within 8 weeks prior to study drug administration.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC | 0-72hr | area under the curve from 0-72hr |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cmax | 0-72hr | maximum concentration during the time interval |
Countries
United States
Participant flow
Recruitment details
Recruitment was done through flyers and A/V advertisement throughout the University of Maryland Baltimore campus. Additionally, ResearchMatch.org was used. Planned initial interactions were phone calls and emails from potential subjects. Additionally, individuals who previously indicated a willingness to be contacted for future studies were contacted. Recruitment period was from September 17th 2019 to June 24th 2021.
Pre-assignment details
Enrollment number is the number of participants who signed a consent form and passed screening tests.
Participants by arm
| Arm | Count |
|---|---|
| Sequence A (Fast, Medium, Oral Solution, Then Slow) Participants first receive fast tablet, then medium tablet, then oral solution, and then slow tablet. Washout period is (at least) one week.
fast itraconazole tablet: 100mg dose
medium itraconazole tablet: 100mg dose
slow itraconazole tablet: 100mg dose
oral itraconazole solution: 100mg dose | 4 |
| Sequence B (Medium, Slow, Fast, Then Oral Solution) Participants first receive medium tablet, then slow tablet, then fast tablet, and then oral solution. Washout period is (at least) one week.
fast itraconazole tablet: 100mg dose
medium itraconazole tablet: 100mg dose
slow itraconazole tablet: 100mg dose
oral itraconazole solution: 100mg dose | 4 |
| Sequence C (Slow, Oral Solution, Medium, Then Fast) Participants first receive slow tablet, then oral solution, then medium tablet, then fast tablet. Washout period is (at least) one week.
fast itraconazole tablet: 100mg dose
medium itraconazole tablet: 100mg dose
slow itraconazole tablet: 100mg dose
oral itraconazole solution: 100mg dose | 4 |
| Sequence D (Oral Solution, Fast, Slow, Then Medium) Participants first receive oral solution, fast tablet, then slow tablet, and then medium tablet. Washout period is (at least) one week.
fast itraconazole tablet: 100mg dose
medium itraconazole tablet: 100mg dose
slow itraconazole tablet: 100mg dose
oral itraconazole solution: 100mg dose | 5 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Participant lived out of state and due to COVID-19 pandemic could not travel to study site. | 0 | 1 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Sequence A (Fast, Medium, Oral Solution, Then Slow) | Sequence B (Medium, Slow, Fast, Then Oral Solution) | Sequence C (Slow, Oral Solution, Medium, Then Fast) | Sequence D (Oral Solution, Fast, Slow, Then Medium) | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 4 Participants | 4 Participants | 5 Participants | 17 Participants |
| Age, Continuous | 26 years STANDARD_DEVIATION 4.7 | 41.3 years STANDARD_DEVIATION 12 | 28.3 years STANDARD_DEVIATION 1.7 | 41 years STANDARD_DEVIATION 15.3 | 34.5 years STANDARD_DEVIATION 11.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 4 Participants | 4 Participants | 4 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 3 Participants | 2 Participants | 4 Participants | 10 Participants |
| Region of Enrollment United States | 4 participants | 4 participants | 4 participants | 5 participants | 17 participants |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 3 Participants | 2 Participants | 10 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 1 Participants | 3 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 14 | 0 / 13 | 0 / 12 |
| other Total, other adverse events | 3 / 14 | 1 / 14 | 1 / 13 | 1 / 12 |
| serious Total, serious adverse events | 0 / 14 | 0 / 14 | 0 / 13 | 0 / 12 |
Outcome results
Primary
AUC
area under the curve from 0-72hr
Time frame: 0-72hr
Population: Seventeen participants were randomized in this cross-over study to receive all 4 itraconazole products at least one week apart. Twelve participants completed all 4 interventions. Analysis was only done of data from participants who completed all four interventions (n=12).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fast Tablet | AUC | 1624.8 ng*hr/mL | Standard Error 146.1 |
| Medium Tablet | AUC | 1365.5 ng*hr/mL | Standard Error 184 |
| Slow Tablet | AUC | 1282.2 ng*hr/mL | Standard Error 220.3 |
| Oral Solution | AUC | 1848.7 ng*hr/mL | Standard Error 139.7 |
Secondary
Cmax
maximum concentration during the time interval
Time frame: 0-72hr
Population: Seventeen participants were randomized in this cross-over study to receive all 4 itraconazole products at least one week apart. Twelve participants completed all 4 interventions. Analysis was only done of data from participants who completed all four interventions.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Fast Tablet | Cmax | 174.3 ng/mL | Standard Error 30.9 |
| Medium Tablet | Cmax | 108.5 ng/mL | Standard Error 14.9 |
| Slow Tablet | Cmax | 121.3 ng/mL | Standard Error 26.4 |
| Oral Solution | Cmax | 266.7 ng/mL | Standard Error 40.5 |