The Effects of Multiple Dose Fluoxetine and Metabolites on CYP1A2, CYP2C19, CYP2D6 and CYP3A4 Activity
| Status: | Completed |
|---|---|
| Conditions: | Healthy Studies |
| Therapuetic Areas: | Other |
| Healthy: | No |
| Age Range: | 18 - 50 |
| Updated: | 10/14/2017 |
| Start Date: | September 2011 |
| End Date: | June 2012 |
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.
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.
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 ofcyrochrome 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
We found this trial at
1
site
1959 Northeast Pacific Street
Seattle, Washington 98195
Seattle, Washington 98195
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