Drug-Drug InteractionFLUOXETINENCT01361217
The Effects of Multiple Dose Fluoxetine and Metabolites on CYP1A2, CYP2C19, CYP2D6 and CYP3A4 Activity
A study testing Fluoxetine, Lovastatin, Omeprazole, caffeine, midazolam, dextromethorphan in people with Drug-Drug Interaction and Healthy Volunteers, run by University of Washington.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 50 yearsHealthy volunteers can take part
- Conditions the study is for
- Drug-Drug Interaction, Healthy Volunteers
- What is being tested?
- Fluoxetine, Lovastatin, Omeprazole, caffeine, midazolam, dextromethorphan
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 10 participants
- Where
- No sites listed yet
- Study dates
- Sep 2011to Jun 2012
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 50 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 12Show fewer
- 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
About this study
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.
- Conditions
- Drug-Drug Interaction, Healthy Volunteers
- Being tested
- Fluoxetine, Lovastatin, Omeprazole, caffeine, midazolam, dextromethorphan
- Keywords
- Fluoxetine, CYP3A4, CYP2D6, CYP2C19, Drug-Drug Interaction, Multi-CYP Inhibition
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Fluoxetine, Lovastatin, Omeprazole, caffeine, midazolam, dextromethorphanDrug
Also called Prozac
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.
| Study group | Role | What they receive |
|---|---|---|
| Fluoxetine DDI | Experimental | Only arm in the study. Successive Control (Study Days 1 and 3) and fluoxetine multiple-dose treatment (Study Days 16 and 18) Sessions. Receives: Drug: Fluoxetine, Lovastatin, Omeprazole, caffeine, midazolam, dextromethorphan |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Secondary outcomes (1)
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
Measured: 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.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 May 2011 (estimated)
- Study startSep 2011
- Primary completionJun 2012
- Study completionJun 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Drug-Drug InteractionStudies of the same condition, open and under way.
- More trials run by University of WashingtonThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 10 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Washington
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute of General Medical Sciences (NIGMS)
- Responsible party
- Principal investigator, Nina Isoherranen, University of Washington
- Investigators
- Nina Isoherranen, PhD., Principal investigator, University of Washington, School of Pharmacy, Department of PharmaceuticsConnie Davis, MD., Principal investigator, University of Washington, Department of Medicine
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01361217
- Sponsor's protocol ID
- 39288
- Other IDs
- P01GM032165
- Acronym
- FLUOXETINE
- Status last verified
- Jun 2018
- First submitted
- 16 May 2011
- Last updated
- 29 Jun 2018
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 29 Jun 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Effects of Multiple Dose Fluoxetine and Metabolites on CYP1A2, CYP2C19, CYP2D6 and CYP3A4 Activity
- ClinicalTrials.gov ID
- NCT01361217
- Acronym / sponsor ID
- FLUOXETINE / 39288
- Conditions
- Drug-Drug Interaction, Healthy Volunteers
- Keywords
- Fluoxetine, CYP3A4, CYP2D6, CYP2C19, Drug-Drug Interaction, Multi-CYP Inhibition
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 10 participants (actual)
- Lead sponsor
- University of WashingtonUniversity, hospital or other
- Collaborators
- National Institute of General Medical Sciences (NIGMS)
- Study start
- Sep 2011
- Primary completion
- Jun 2012 (actual)
- Study completion
- Jun 2012 (actual)
- First posted
- 26 May 2011 (estimated)
- Results
- Posted 29 Jun 2018
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Fluoxetine DDI | Experimental | Drug: Fluoxetine, Lovastatin, Omeprazole, caffeine, midazolam, dextromethorphanOnly arm in the study. Successive Control (Study Days 1 and 3) and fluoxetine multiple-dose treatment (Study Days 16 and 18) Sessions. |
Who may qualify
- Ages
- 18 to 50 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (8 listed)
- 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.
Key exclusion criteria (12 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Fluoxetine, Lovastatin, Omeprazole, caffeine, midazolam, dextromethorphanAlso: Prozac1x20mg 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. | Drug | Fluoxetine DDI |
Primary outcome
Lovastatin AUC in the Presence of Fluoxetine
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.
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.
1 secondary outcome
AUC of Dextromethorphan, Midazolam and Omeprazole in the Presence of Fluoxetine
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.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Jun 2018.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Nina Isoherranen, PhD. principal investigator
University of Washington, School of Pharmacy, Department of Pharmaceutics
Connie Davis, MD. principal investigator
University of Washington, Department of Medicine
Questions about this trial
What is this clinical trial studying?
A study testing Fluoxetine, Lovastatin, Omeprazole, caffeine, midazolam, dextromethorphan in people with Drug-Drug Interaction and Healthy Volunteers, run by University of Washington.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 29 Jun 2018. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 29 Jun 2018). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Lovastatin AUC in the Presence of Fluoxetine (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.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Jun 2018.