PMID- 22283559
OWN - NLM
STAT- MEDLINE
DCOM- 20120615
LR  - 20211021
IS  - 1179-1918 (Electronic)
IS  - 1173-2563 (Linking)
VI  - 32
IP  - 3
DP  - 2012 Mar 1
TI  - Randomized open-label drug-drug interaction trial of dextromethorphan/quinidine 
      and paroxetine in healthy volunteers.
PG  - 157-69
LID - 10.2165/11599870-000000000-00000 [doi]
AB  - BACKGROUND AND 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. CONCLUSION: 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.
FAU - Schoedel, Kerri A
AU  - Schoedel KA
AD  - INC Research-Toronto, Toronto, Canada.
FAU - Pope, Laura E
AU  - Pope LE
FAU - Sellers, Edward M
AU  - Sellers EM
LA  - eng
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
PL  - New Zealand
TA  - Clin Drug Investig
JT  - Clinical drug investigation
JID - 9504817
RN  - 41VRH5220H (Paroxetine)
RN  - 7355X3ROTS (Dextromethorphan)
RN  - ITX08688JL (Quinidine)
SB  - IM
MH  - Adult
MH  - Affective Symptoms/*drug therapy
MH  - Dextromethorphan/adverse effects/*pharmacokinetics
MH  - Drug Interactions
MH  - Drug Therapy, Combination
MH  - Electrocardiography/drug effects
MH  - Female
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Paroxetine/adverse effects/*pharmacokinetics
MH  - Quinidine/adverse effects/*pharmacokinetics
EDAT- 2012/01/31 06:00
MHDA- 2012/06/16 06:00
CRDT- 2012/01/31 06:00
PHST- 2012/01/31 06:00 [entrez]
PHST- 2012/01/31 06:00 [pubmed]
PHST- 2012/06/16 06:00 [medline]
AID - 10.2165/11599870-000000000-00000 [doi]
PST - ppublish
SO  - Clin Drug Investig. 2012 Mar 1;32(3):157-69. doi: 
      10.2165/11599870-000000000-00000.