Drug-Drug Interaction, Healthy Volunteers
Conditions
Keywords
Fluoxetine, CYP3A4, CYP2D6, CYP2C19, Drug-Drug Interaction, Multi-CYP Inhibition
Brief summary
Inhibitory drug-drug interactions (DDIs) are a considerable concern as inhibition of drug's clearance can lead to increased plasma concentrations and subsequent adverse events and toxicities. Fluoxetine (Prozac®) is a widely prescribed antidepressant, but is also a potent inhibitor of cytochrome P450 (CYP) enzymes. Fluoxetine was chosen as the model inhibitor for this study because it is a clinically important inhibitor of multiple CYP enzymes with varying potencies for each isoform. From in vitro data, fluoxetine is predicted to be a moderate inhibitor of CYP2D6, but a strong inhibitor of CYP2C19 and CYP3A4. However, in vivo fluoxetine causes a potent interaction with CYP2D6 and a weak-to-no interaction with CYP3A4. The magnitude of the in vivo interaction of fluoxetine with CYP2C19 is not known. This in vitro-to-in vivo discrepancy is of concern for two reasons: 1) In clinical drug development, in vivo drug-drug interactions are tested only when in vitro experiments predict a risk for in vivo DDIs and 2) Because in vivo DDI's are tested using a rank order approach of going from the most potent in vitro interaction to the least potent until no interaction in vivo is observed. In this study the interaction between fluoxetine and CYP3A4, CYP2C19 and CYP2D6 will be quantified simultaneously and the quantitative in vitro-to-in vivo predictions tested. Fluoxetine will be orally administered daily for 14 days and CYP1A2, CYP3A4, CYP2C19 and CYP2D6 activity will be tested in the end of fluoxetine dosing using a cocktail of CYP probes including caffeine, midazolam, omeprazole and dextromethorphan. Lovastatin will be administered on a separate day and used as a second CYP3A4 probe to test whether CYP3A4 inhibition by fluoxetine depends on the contribution of intestinal CYP3A4 to the probe clearance. Plasma and urine samples will be collected for 12 and 24 hrs, respectively, during the control sessions (before fluoxetine administration) and for 24 hrs during the treatment sessions (fluoxetine multiple dose). The concentrations of each of the probe drugs and their metabolites (when applicable) as well as fluoxetine and its metabolites will be measured in the collected samples and pharmacokinetic analysis will be performed. The primary outcome measures for CYP inhibition will be the increase in the area under plasma concentrations time curve (AUC) of each of the probes.The null hypothesis of this study is that the area under plasma concentrations time curves (AUCs) of caffeine, dextromethorphan, omeprazole, midazolam or lovastatin are the same between the control session and the fluoxetine session. Because lovastatin has the greatest variability in its baseline pharmacokinetics the study was powered based on the specific null hypothesis for lovastatin. The alternative hypothesis is that fluoxetine decreases the clearance of the probe drugs resulting in a significant increase in the AUCs between the control and study sessions.
Interventions
DRUGFluoxetine, Lovastatin, Omeprazole, caffeine, midazolam, dextromethorphan
1x20mg oral fluoxetine capsules by mouth daily on Study Day 5, then 3x20mg fluoxetine capsules by mouth daily on Study Days 6 through 18. On study day 1 and study day 18, 100mg caffeine, 2mg midazolam, 30mg dextromethorphan and 20mg omeprazole (enteric coated formulation) orally with 250mL of water. On study day 3 and study day 20 20mg of lovastatin with 250mL of water.
Sponsors
National Institute of General Medical Sciences (NIGMS)
University of Washington
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
* Subjects must be 18-50 years old. * Subjects must be currently in good health with normal gastrointestinal and heart function (as determined by medical history) * Laboratory values indicating normal liver (Serum Albumin 3.9 - 5.0 g/dL, Total Bilirubin \< 1.4mg/dL, Alanine Transaminase 9 - 60 IU/L and Aspartate Transaminase 10 - 40 IU/L) and kidney (Serum Creatinine \< 1.5 mg/dL and Blood Urea Nitrogen 7 - 20 mg/dL) function as well as normal blood glucose values (Fasting Blood Glucose \< 100 mg/dL). * Subjects must have no known allergies to fluoxetine or other selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), benzodiazepine drugs, caffeine, omeprazole, dextromethorphan, lovastatin or any chemically related drug. * Women of childbearing age must be willing to use measures to avoid conception during the study period and willing to have a pregnancy test on Study Days 1 and 16. * Subjects must agree not to take any known substrates, inhibitors, inducers or activators of cytochrome P450 (CYP) CYP1A2, CYP3A4, CYP2C19 and CYP2D6 for two weeks before the start of each study through three weeks after the last day of study. This list includes but is not restricted to antidepressant and antipsychotic agents, azole antifungal agents, macrolide antibiotics, anti-epileptic medications, antihypertensive agents and cholesterol lowering agents. They must also be willing to avoid ingesting grapefruit, grapefruit juice or other grapefruit containing products, and any herbal-based nutrient supplement or medication for the same period of time. Use of oral contraceptives will be permitted. * Subjects must be willing to avoid caffeine-containing foods, beverages, or dietary supplements for 24 hrs prior to and throughout each study session and avoid alcohol for 48 hrs prior to and throughout each study session. * Subjects must be willing to avoid heavy exercise during the study
Exclusion criteria
* Current cigarette smoker * History of liver, kidney, gastrointestinal or heart disease * Lab test results indicative of abnormal liver or kidney function, or diabetes (see above inclusion criteria). * Allergy to any monoamine oxidase inhibitors (MAOIs) or any other chemically related drug or to benzodiazepine drug * Prior experience of side effects to fluoxetine or other selective serotonin reuptake inhibitors (SSRIs) * CYP2D6 or CYP2C19 poor metabolizer genotype or CYP3A5 expressor genotype * Recent ingestion (\< 2 weeks) of any medication known to be metabolized by or alter CYP1A2, CYP3A4, CYP2C19 or CYP2D6 activity * A positive pregnancy test or breastfeeding * History of diabetes, peptic ulcer or inflammatory bowel disease * Overweight; a body mass index ≥ 30 or underweight; a body mass index of ≤ 18 * Use of chronic prescription or over-the-counter medications (except oral contraceptives) * Use of antidepressants during the last two weeks preceding the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Lovastatin AUC in the Presence of Fluoxetine | The primary outcome will be assessed within 2 months after the last subject is enrolled or at 2 years from the start of study enrollment, which ever is sooner. | Our primary outcome measure will be the interaction of fluoxetine with CYP3A4. A 50% increase in the AUC for lovastatin plus hydroxy-lovastatin acid (the active form of lovastatin) between treatment day 14 (study day 20) and control days (study day 2) is considered clinically significant. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC of Dextromethorphan, Midazolam and Omeprazole in the Presence of Fluoxetine | The secondary outcome will be assessed within 2 months after the last subject is enrolled or at 2 years from the start of study enrollment, which ever is sooner. | Our secondary outcome measure will be the interaction between fluoxetine and each CYP evaluated in the cocktail. A 50% increase in the AUC of caffeine (CYP1A2), dextromethorphan (CYP2D6), omeprazole (CYP2C19) or midazolam (CYP3A4) between treatment and control days is considered clinically significant. The interaction of fluoxetine with caffeine (CYP1A2) will be considered as a negative control for the study. These AUCs will be measured on study day 1 (control day) and study day 18 |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Fluoxetine DDI Only arm in the study. Successive Control (Study Days 1 and 3) and fluoxetine multiple-dose treatment (Study Days 16 and 18) Sessions.
Fluoxetine: 1x20mg oral fluoxetine capsules by mouth daily on Study Day 5, then 3x20mg fluoxetine capsules by mouth daily on Study Days 6 through 18. | 10 |
| Total | 10 |
Baseline characteristics
| Characteristic | Fluoxetine DDI |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants |
| Age, Continuous | 30 years STANDARD_DEVIATION 10 |
| Race/Ethnicity, Customized caucasian | 8 participants |
| Race/Ethnicity, Customized chicano | 1 participants |
| Race/Ethnicity, Customized hispanic | 1 participants |
| Region of Enrollment United States | 10 participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 5 Participants |
| weight | 72 kg STANDARD_DEVIATION 14 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 1 / 10 |
| serious Total, serious adverse events | 0 / 10 |
Outcome results
Primary
Lovastatin AUC in the Presence of Fluoxetine
Our primary outcome measure will be the interaction of fluoxetine with CYP3A4. A 50% increase in the AUC for lovastatin plus hydroxy-lovastatin acid (the active form of lovastatin) between treatment day 14 (study day 20) and control days (study day 2) is considered clinically significant.
Time frame: The primary outcome will be assessed within 2 months after the last subject is enrolled or at 2 years from the start of study enrollment, which ever is sooner.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Lovastatin AUC After Fluoxetine Dosing | Lovastatin AUC in the Presence of Fluoxetine | 170 nmol*hr/L | Standard Deviation 70 |
| Lovastatin Before Fluoxetine | Lovastatin AUC in the Presence of Fluoxetine | 180 nmol*hr/L | Standard Deviation 90 |
p-value: >0.05t-test, 2 sided
p-value: <0.05t-test, 2 sided
Secondary
AUC of Dextromethorphan, Midazolam and Omeprazole in the Presence of Fluoxetine
Our secondary outcome measure will be the interaction between fluoxetine and each CYP evaluated in the cocktail. A 50% increase in the AUC of caffeine (CYP1A2), dextromethorphan (CYP2D6), omeprazole (CYP2C19) or midazolam (CYP3A4) between treatment and control days is considered clinically significant. The interaction of fluoxetine with caffeine (CYP1A2) will be considered as a negative control for the study. These AUCs will be measured on study day 1 (control day) and study day 18
Time frame: The secondary outcome will be assessed within 2 months after the last subject is enrolled or at 2 years from the start of study enrollment, which ever is sooner.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Lovastatin AUC After Fluoxetine Dosing | AUC of Dextromethorphan, Midazolam and Omeprazole in the Presence of Fluoxetine | dextromethophan control AUC | 68 nmol*hr/L | Standard Deviation 100 |
| Lovastatin AUC After Fluoxetine Dosing | AUC of Dextromethorphan, Midazolam and Omeprazole in the Presence of Fluoxetine | Dextromethorphan treatment AUC | 1850 nmol*hr/L | Standard Deviation 800 |
| Lovastatin AUC After Fluoxetine Dosing | AUC of Dextromethorphan, Midazolam and Omeprazole in the Presence of Fluoxetine | Omeprazole control AUC | 1200 nmol*hr/L | Standard Deviation 600 |
| Lovastatin AUC After Fluoxetine Dosing | AUC of Dextromethorphan, Midazolam and Omeprazole in the Presence of Fluoxetine | omeprazole treatment AUC | 8500 nmol*hr/L | Standard Deviation 3600 |
| Lovastatin AUC After Fluoxetine Dosing | AUC of Dextromethorphan, Midazolam and Omeprazole in the Presence of Fluoxetine | midazolam control AUC | 30 nmol*hr/L | Standard Deviation 27 |
| Lovastatin AUC After Fluoxetine Dosing | AUC of Dextromethorphan, Midazolam and Omeprazole in the Presence of Fluoxetine | caffeine control AUC | 43000 nmol*hr/L | Standard Deviation 22000 |
| Lovastatin AUC After Fluoxetine Dosing | AUC of Dextromethorphan, Midazolam and Omeprazole in the Presence of Fluoxetine | Caffeine treatment AUC | 43000 nmol*hr/L | Standard Deviation 15000 |
| Lovastatin AUC After Fluoxetine Dosing | AUC of Dextromethorphan, Midazolam and Omeprazole in the Presence of Fluoxetine | midazolam treatment AUC | 24 nmol*hr/L | Standard Deviation 17 |
p-value: <0.001t-test, 2 sided