FLUOXETINE: The Effects of Multiple Dose Fluoxetine and Metabolites on CYP1A2, CYP2C19, CYP2D6 and CYP3A4 Activity

• Sponsor: University of Washington (Other)
• Overall Status: Completed
• CT.gov ID: NCT01361217
• Collaborator: National Institute of General Medical Sciences (NIGMS) (NIH)
• Enrollment: 10
• Arm: 1
• Duration (Months): 9

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Drug-Drug Interaction; Healthy Volunteers	Drug: Fluoxetine, Lovastatin, Omeprazole, caffeine, midazolam, dextromethorphan	N/A

Study Design

• Study Type: Interventional
• 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: Sep 1, 2011
• Actual Primary Completion Date: Jun 1, 2012
• Actual Study Completion Date: Jun 1, 2012

Arms and Interventions

Arm

Intervention/Treatment

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.

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 Names: Prozac

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• 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

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• University of Washington
• National Institute of General Medical Sciences (NIGMS)

Investigators

• 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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Nina Isoherranen, Professor, PHARM: Department of Pharmaceutics, University of Washington
• ClinicalTrials.gov Identifier: NCT01361217
• Other Study ID Numbers: 39288; P01GM032165
• First Posted: May 26, 2011
• Last Update Posted: Jun 29, 2018
• Last Verified: Jun 1, 2018

• Keywords provided by Nina Isoherranen, Professor, PHARM: Department of Pharmaceutics, University of Washington: Fluoxetine; CYP3A4; CYP2D6; CYP2C19; Drug-Drug Interaction; Multi-CYP Inhibition
• Additional relevant MeSH terms: Midazolam; Dextromethorphan; Caffeine; Fluoxetine; Omeprazole; Lovastatin; L 647318; Dihydromevinolin

Study Results

Participant Flow

Arm/Group Title	Fluoxetine DDI
Arm/Group Description	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.
Period Title: Overall Study
STARTED	10
COMPLETED	10
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Fluoxetine DDI
Arm/Group Description	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.
Overall Participants	10
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	10 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	30 (10)
Sex: Female, Male (Count of Participants)
Female	5 50%
Male	5 50%
Race/Ethnicity, Customized (participants) [Number]
caucasian	8 80%
hispanic	1 10%
chicano	1 10%
Region of Enrollment (participants) [Number]
United States	10 100%
weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	72 (14)

Outcome Measures

1. Primary Outcome

Title	Lovastatin AUC in the Presence of Fluoxetine
Description	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Lovastatin AUC After Fluoxetine Dosing	Lovastatin Before Fluoxetine
Arm/Group Description	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.	control
Measure Participants	10	10
Mean (Standard Deviation) [nmol*hr/L]	170 (70)	180 (90)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lovastatin AUC After Fluoxetine Dosing, Lovastatin Before Fluoxetine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Lovastatin AUC After Fluoxetine Dosing
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	t-test, 2 sided
	Comments

2. Secondary Outcome

Title	AUC of Dextromethorphan, Midazolam and Omeprazole in the Presence of Fluoxetine
Description	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.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Midazolam, Caffeine, Omeprazole, Caffeine AUC After Fluoxetine
Arm/Group Description	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.
Measure Participants	10
caffeine control AUC	43000 (22000)
Caffeine treatment AUC	43000 (15000)
dextromethophan control AUC	68 (100)
Dextromethorphan treatment AUC	1850 (800)
Omeprazole control AUC	1200 (600)
omeprazole treatment AUC	8500 (3600)
midazolam control AUC	30 (27)
midazolam treatment AUC	24 (17)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Lovastatin AUC After Fluoxetine Dosing
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	t-test, 2 sided
	Comments

Adverse Events

Arm/Group Title	Fluoxetine DDI
Arm/Group Description	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.
All Cause Mortality
	Fluoxetine DDI
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Fluoxetine DDI
	Affected / at Risk (%)	# Events
Total	0/10 (0%)
Other (Not Including Serious) Adverse Events
	Fluoxetine DDI
	Affected / at Risk (%)	# Events
Total	1/10 (10%)
Psychiatric disorders
anxiety	1/10 (10%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.