Depression
Conditions
Brief summary
The objectives of this project are to determine if the bioavailability and release pattern of bupropion HCl products differ and if the genotype of the metabolic enzymes affects the saturation of intestinal enzymes with different dose strengths within one product line. Findings from this project will help the FDA Center for Drug Evaluation and Research's (CDER) Office of Generic Drugs improve policy development and review practice in the future for similar products, e.g. extended release oral drug products being metabolized in the gut wall and having multiple strengths. Aim 1: To compare the pharmacokinetics of bupropion and its metabolites in plasma in healthy individuals when they ingest different strengths of bupropion (75-300 mg) with variable release profiles (IR vs XL vs SR) in GI tract. Working hypothesis: Variation in release rate and mechanism of bupropion formulations in gastrointestinal (GI) tract will impact metabolism and saturation of bupropion in GI tract, which will generate different concentration of bupropion and its metabolites in plasma. Aim 2: To investigate pharmacogenomics of CYP 2B6 that influences metabolism, saturation, and pharmacokinetics of bupropion Working hypothesis: The gain of function of CYP2B6 variants (allele \*4 and \*22) in patients will increase the metabolism of bupropion in the GI tract and liver, reduce both local concentration and plasma concentration of bupropion, and thus cause non-bioequivalence when bupropion is released earlier in GI tract
Interventions
DRUGgeneric bupropion
We are comparing different formulations of bupropion that release this drug at different rates. The abbreviation IR75 means immediate release and the number is the dose in mg. The other abbreviations represent SR for sustained-release and XL for extended release, which release the drug slower than the IR formulation.
Sponsors
University of Michigan
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
25 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy volunteers 25 to 55 years old. * Volunteers have a Body Mass Index (BMI), calculated from the ratio of height and weight, within a range of 18.5 to 35. * Willing to be medication and supplement free 2 weeks prior to beginning study, and throughout the study. All forms of birth control are okay.
Exclusion criteria
* Individuals unwilling or unable to comply with the study protocol (e.g. unable to remain medication or supplement free during the study). * Individuals unwilling or unable to take bupropion or have an allergy to bupropion * Any medical or surgical conditions which might significantly alter bupropion absorption (e.g., history of malabsorption, liver disease, gastric bypass surgery ) * Individuals with a history of psychiatric or neurological illness, including seizure disorders * Nicotine dependence * Alcohol dependence * Pregnant or nursing women
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Comparision of the Buproprion Area Under the Concentration Time Curve (AUC) From Time 0 to 96 Hours by Type of Formulation and Dosage | 4 days | Each formulation of buproprion has a different rate of release. Some release the drug immediately while others release the drug slowly. We will compare the exposure of buproprion by formulation and dose by looking at the area under the concentration time curve. The area under the concentration time curve is a mathematical way of looking at drug exposure in the body. The reported values are AUC (0-96 hours). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Comparision of the Buproprion Maximum Concentration (Cmax) by Type of Formulation and Dosage | 4 days | Each formulation of buproprion has a different rate of release. Some release the drug immediately while others release the drug slowly. We will compare the exposure of buproprion by formulation and dose by looking at the maximum concentration. The maximum concentration depends on the rate of drug release and so looking at this value can help us compare differences between formulation. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| IR 75, IR 100, SR 100, SR 150, XL 150 and XL 300 Participants were randomized to receive one pill each of IR 75, IR 100, SR 100, SR 150, XL 150 and XL 300,in randomized order at six time points. Given the large number of possible sequence combinations, participants are reported as a single Participant Flow Arm with Milestones used to indicate how many participants received each intervention | 34 |
| Total | 34 |
Baseline characteristics
| Characteristic | IR 75, IR 100, SR 100, SR 150, XL 150 and XL 300 |
|---|---|
| Age, Customized 25-65 years | 34 Participants |
| Age, Customized <25 years | 0 Participants |
| Age, Customized >65 years | 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 | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 24 Participants |
| Region of Enrollment United States | 34 Participants |
| Sex: Female, Male Female | 18 Participants |
| Sex: Female, Male Male | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 34 |
| other Total, other adverse events | 10 / 34 |
| serious Total, serious adverse events | 0 / 34 |
Outcome results
Primary
Comparision of the Buproprion Area Under the Concentration Time Curve (AUC) From Time 0 to 96 Hours by Type of Formulation and Dosage
Each formulation of buproprion has a different rate of release. Some release the drug immediately while others release the drug slowly. We will compare the exposure of buproprion by formulation and dose by looking at the area under the concentration time curve. The area under the concentration time curve is a mathematical way of looking at drug exposure in the body. The reported values are AUC (0-96 hours).
Time frame: 4 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Generic Bupropion IR75 | Comparision of the Buproprion Area Under the Concentration Time Curve (AUC) From Time 0 to 96 Hours by Type of Formulation and Dosage | 469 h*nanogram/milliliter | Standard Deviation 177 |
| Generic Bupropion IR100 | Comparision of the Buproprion Area Under the Concentration Time Curve (AUC) From Time 0 to 96 Hours by Type of Formulation and Dosage | 667 h*nanogram/milliliter | Standard Deviation 418 |
| Generic Bupropion SR100 | Comparision of the Buproprion Area Under the Concentration Time Curve (AUC) From Time 0 to 96 Hours by Type of Formulation and Dosage | 706 h*nanogram/milliliter | Standard Deviation 304 |
| Generic Bupropion SR150 | Comparision of the Buproprion Area Under the Concentration Time Curve (AUC) From Time 0 to 96 Hours by Type of Formulation and Dosage | 1002 h*nanogram/milliliter | Standard Deviation 516 |
| Generic Bupropion XL150 | Comparision of the Buproprion Area Under the Concentration Time Curve (AUC) From Time 0 to 96 Hours by Type of Formulation and Dosage | 740 h*nanogram/milliliter | Standard Deviation 449 |
| Generic Bupropion XL300 | Comparision of the Buproprion Area Under the Concentration Time Curve (AUC) From Time 0 to 96 Hours by Type of Formulation and Dosage | 1356 h*nanogram/milliliter | Standard Deviation 637 |
Secondary
Comparision of the Buproprion Maximum Concentration (Cmax) by Type of Formulation and Dosage
Each formulation of buproprion has a different rate of release. Some release the drug immediately while others release the drug slowly. We will compare the exposure of buproprion by formulation and dose by looking at the maximum concentration. The maximum concentration depends on the rate of drug release and so looking at this value can help us compare differences between formulation.
Time frame: 4 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Generic Bupropion IR75 | Comparision of the Buproprion Maximum Concentration (Cmax) by Type of Formulation and Dosage | 93 nanogram/milliliter | Standard Error 36 |
| Generic Bupropion IR100 | Comparision of the Buproprion Maximum Concentration (Cmax) by Type of Formulation and Dosage | 136 nanogram/milliliter | Standard Error 70 |
| Generic Bupropion SR100 | Comparision of the Buproprion Maximum Concentration (Cmax) by Type of Formulation and Dosage | 61 nanogram/milliliter | Standard Error 29 |
| Generic Bupropion SR150 | Comparision of the Buproprion Maximum Concentration (Cmax) by Type of Formulation and Dosage | 78 nanogram/milliliter | Standard Error 40 |
| Generic Bupropion XL150 | Comparision of the Buproprion Maximum Concentration (Cmax) by Type of Formulation and Dosage | 61 nanogram/milliliter | Standard Error 34 |
| Generic Bupropion XL300 | Comparision of the Buproprion Maximum Concentration (Cmax) by Type of Formulation and Dosage | 111 nanogram/milliliter | Standard Error 44 |