The Effects of Multiple Dose Fluoxetine and Metabolites on CYP1A2, CYP2C19, CYP2D6 and CYP3A4 Activity (FLUOXETINE)
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:||Endpoint Classification: Pharmacokinetics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Basic Science
|Official Title:||The Effects of Multiple Dose Fluoxetine and Metabolites on CYP1A2, CYP2C19, CYP2D6 and CYP3A4 Activity|
- Fluoxetine-CYP3A4 DDI [ 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. ] [ Designated as safety issue: No ]Our primary outcome measure will be the interaction of fluoxetine with CYP3A4. A 50% increase in the AUC for lovastatin plus hydroxylovastatin acid (the active form of lovastatin) between treatment and control days is considered clinically significant.
- Fluoxetine-Cocktail DDI [ 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. ] [ Designated as safety issue: No ]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.
|Study Start Date:||September 2011|
|Study Completion Date:||June 2012|
|Primary Completion Date:||June 2012 (Final data collection date for primary outcome measure)|
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.
1x20mg oral fluoxetine capsules by mouth daily on Study Day 5, then 3x20mg fluoxetine capsules by mouth daily on Study Days 6 through 18.
Other Name: Prozac
Please refer to this study by its ClinicalTrials.gov identifier: NCT01361217
|United States, Washington|
|University of Washington, Institute of Translational Health Sciences, Clinical Research Center|
|Seattle, Washington, United States, 98195|
|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|