title: Randomized open-label drug-drug interaction trial of dextromethorphan/quinidine and paroxetine in healthy volunteers.
abstract: OBJECTIVE
  The novel combination of dextromethorphan (DM) and quinidine (Q) [DMQ] has been extensively studied in well controlled clinical trials as treatment for pseudobulbar affect (PBA), and is the first US Food and Drug Administration (FDA)-approved treatment for this indication. The approved dosage of DMQ is DM 20 mg and Q 10 mg twice daily. DM is metabolized via cytochrome P450 2D6 (CYP2D6); Q is a CYP2D6 inhibitor used to increase DM plasma concentrations. Paroxetine is both a substrate and inhibitor of CYP2D6. This trial evaluated the effect of DMQ at a dose of DM 30 mg and Q 30 mg twice daily on the steady-state pharmacokinetics of paroxetine 20 mg daily and the effects of paroxetine on the steady-state pharmacokinetics of DMQ in healthy volunteers.
  
  
  METHODS
  This was an open-label, randomized, parallel-group, 20-day trial. Drug plasma concentrations were analysed following monotherapy and concomitant (DMQ + paroxetine) therapy. Participants were 27 healthy adults who were randomized in a 1 : 1 fashion to one of two groups. Group 1 received paroxetine 20 mg once daily for 12 days to attain steady state, at which point DMQ 30 mg/30 mg twice daily was added for 8 days. Group 2 received DMQ 30 mg/30 mg twice daily for 8 days to attain steady state, at which point paroxetine 20 mg once daily was added for 12 days. The primary endpoints were the 90% confidence intervals (CIs) for the ratio of the area under the plasma concentration-time curve (AUC) during concomitant therapy versus monotherapy. Safety and tolerability measures including adverse events (AEs) were also assessed.
  
  
  RESULTS
  The 90% CIs of the AUCs were outside of the predefined range [0.80, 1.25] for all analytes, indicating a drug-drug interaction. In group 1 (n = 14), addition of DMQ to paroxetine resulted in a 30% increase in mean plasma exposure of paroxetine (AUC up to 24 hours). In group 2 (n = 13), addition of paroxetine to DMQ resulted in increases in mean plasma exposure (AUC up to 12 hours) of 50% for DM and 40% for Q, and a decrease of 12.3% for dextrorphan, the metabolite of DM. The incidence of AEs was higher with paroxetine monotherapy and combination therapy, compared with DMQ given alone (30.8% with DMQ alone vs 83.3% following addition of paroxetine, and 78.6% with paroxetine alone vs 64.3% following addition of DMQ). Three subjects discontinued due to AEs, and no serious AEs were reported.
  
  
  CONCLUSIONS
  The addition of DMQ 30 mg/30 mg twice daily to paroxetine increased steady-state paroxetine plasma concentrations and addition of paroxetine to DMQ 30 mg/30 mg twice daily increased steady-state plasma concentrations of DM and Q, indicating a potential interaction. Thus, patients should be monitored for AEs and dosage adjustment considered when combining these two agents.
authors.affiliation: INC Research-Toronto, Toronto, Canada.
authors.forename: Kerri A
authors.initials: KA
authors.lastname: Schoedel
authors.forename: Laura E
authors.initials: LE
authors.lastname: Pope
authors.forename: Edward M
authors.initials: EM
authors.lastname: Sellers
mesh_terms: D000328:Adult; D000342:Affective Symptoms / Q000188:drug therapy*; D003915:Dextromethorphan / Q000009:adverse effects / Q000493:pharmacokinetics*; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D017374:Paroxetine / Q000009:adverse effects / Q000493:pharmacokinetics*; D011802:Quinidine / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D017374:Paroxetine; D003915:Dextromethorphan; D011802:Quinidine