The Effects of Multiple Dose Fluoxetine and Metabolites on CYP1A2, CYP2C19, CYP2D6 and CYP3A4 Activity
Condition: Drug-Drug Interaction; Healthy Volunteers
Study type: Interventional

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.
    


Intervention name(s): Fluoxetine, Lovastatin, Omeprazole, caffeine, midazolam, dextromethorphan
Intervention type(s): Drug
Intervention description(s): 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 intervention name(s): Prozac
Intervention MeSH terms: Midazolam; Dextromethorphan; Caffeine; Fluoxetine; Omeprazole; Lovastatin; L 647318; Dihydromevinolin
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Fluoxetine; CYP3A4; CYP2D6; CYP2C19; Drug-Drug Interaction; Multi-CYP Inhibition