The Effects of Multiple Dose Fluoxetine and Metabolites on CYP1A2, CYP2C19, CYP2D6 and CYP3A4 Activity (FLUOXETINE)
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ClinicalTrials.gov Identifier: NCT01361217 |
Recruitment Status :
Completed
First Posted : May 26, 2011
Results First Posted : June 29, 2018
Last Update Posted : June 29, 2018
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Condition or disease | Intervention/treatment | Phase |
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Drug-Drug Interaction Healthy Volunteers | Drug: Fluoxetine, Lovastatin, Omeprazole, caffeine, midazolam, dextromethorphan | Not Applicable |
Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 10 participants |
Allocation: | N/A |
Intervention Model: | Single Group Assignment |
Masking: | None (Open Label) |
Primary Purpose: | Basic Science |
Official Title: | The Effects of Multiple Dose Fluoxetine and Metabolites on CYP1A2, CYP2C19, CYP2D6 and CYP3A4 Activity |
Study Start Date : | September 2011 |
Actual Primary Completion Date : | June 2012 |
Actual Study Completion Date : | June 2012 |

Arm | Intervention/treatment |
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Experimental: 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.
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Drug: Fluoxetine, 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. Other Name: Prozac |
- 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.
- 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. ]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

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Ages Eligible for Study: | 18 Years to 50 Years (Adult) |
Sexes Eligible for Study: | All |
Accepts 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

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01361217
Principal Investigator: | Nina Isoherranen, PhD. | University of Washington, School of Pharmacy, Department of Pharmaceutics | |
Principal Investigator: | Connie Davis, MD. | University of Washington, Department of Medicine |
Responsible Party: | Nina Isoherranen, Professor, PHARM: Department of Pharmaceutics, University of Washington |
ClinicalTrials.gov Identifier: | NCT01361217 |
Other Study ID Numbers: |
39288 P01GM032165 ( U.S. NIH Grant/Contract ) |
First Posted: | May 26, 2011 Key Record Dates |
Results First Posted: | June 29, 2018 |
Last Update Posted: | June 29, 2018 |
Last Verified: | June 2018 |
Fluoxetine CYP3A4 CYP2D6 |
CYP2C19 Drug-Drug Interaction Multi-CYP Inhibition |
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