PMID- 25236915
OWN - NLM
STAT- MEDLINE
DCOM- 20160219
LR  - 20220408
IS  - 1879-114X (Electronic)
IS  - 0149-2918 (Linking)
VI  - 36
IP  - 11
DP  - 2014 Nov 1
TI  - Influence of CYP3A4 induction/inhibition on the pharmacokinetics of vilazodone in 
      healthy subjects.
PG  - 1638-49
LID - S0149-2918(14)00534-7 [pii]
LID - 10.1016/j.clinthera.2014.08.003 [doi]
AB  - PURPOSE: Vilazodone is a serotonin reuptake inhibitor and 5-HT1A partial agonist 
      approved for the treatment of major depressive disorder in adults. Vilazodone 
      seems to be metabolized primarily by the cytochrome P-450 (CYP) 3A4 isozyme and 
      non-CYP-mediated pathways; concomitant use of drugs that affect CYP3A4 activity 
      could potentially alter systemic exposure to vilazodone. The present studies 
      evaluated whether CYP3A4 inhibition (study 1) or induction (study 2) affected the 
      pharmacokinetics of vilazodone. METHODS: Participants were healthy adult 
      volunteers. Study 1 was conducted in 2 parts and evaluated the pharmacokinetics 
      of single-dose vilazodone administered with multiple-dose (200 mg once daily) 
      ketoconazole, a CYP3A4 inhibitor. Part 1 was an open-label pharmacokinetic 
      assessment of a single 5-mg vilazodone dose with or without ketoconazole. Part 2 
      was a randomized, double-blind, placebo-controlled, crossover study comparing 
      vilazodone pharmacokinetics after a single 10-mg dose alone or co-administered 
      with ketoconazole or placebo. Study 2 was an open-label, multiple-dose, 
      single-sequence study evaluating the effect of steady-state carbamazepine, a 
      CYP3A4 substrate and inducer, on the pharmacokinetics of steady-state vilazodone 
      (40 mg once daily). Primary pharmacokinetic parameters for both studies were AUC 
      and Cmax for vilazodone. Lack of pharmacokinetic interaction was concluded if the 
      90% CIs of the ratio of vilazodone plus the CYP3A4 inhibitor/inducer relative to 
      vilazodone alone (or plus placebo) for AUC and Cmax were within the 80% to 125% 
      range. Subject-reported and investigator-identified adverse events (AEs), 
      laboratory values, vital signs, and 12-lead ECG parameters were recorded. 
      FINDINGS: In study 1/parts 1 and 2 (n = 15 and 22 enrolled, respectively), mean 
      vilazodone AUC increased 42% and 51%, respectively, in the presence of 
      ketoconazole (expected to be at steady state) versus vilazodone alone (part 1) or 
      with placebo (part 2). The upper limit of the 90% CIs for the vilazodone AUC and 
      Cmax geometric mean ratios exceeded 125%. In study 2 (n = 30 enrolled), 
      co-administration of vilazodone and the carbamazepine extended-release 
      formulation decreased mean steady-state vilazodone exposure ~45%, and the 90% CIs 
      for the vilazodone AUC and Cmax geometric mean ratios were not within the range 
      of 80% to 125%. In both studies, most AEs were of mild intensity, and 
      gastrointestinal AEs predominated. IMPLICATIONS: These results suggest that up to 
      a 50% decrease of vilazodone dosage should be considered when it is given in 
      combination with strong CYP3A4 inhibitors; conversely, increasing the vilazodone 
      dosage up to a maximum of 80 mg/d should be considered when it is given in 
      combination with strong CYP3A4 inducers. (Study registration numbers: 
      SB-659746/029; VLZ-PK-02.).
CI  - Copyright (c) 2014 Elsevier HS Journals, Inc. All rights reserved.
FAU - Boinpally, Ramesh
AU  - Boinpally R
AD  - Forest Research Institute, Inc, Harborside Financial Center, Jersey City, New 
      Jersey. Electronic address: ramesh.boinpally@frx.com.
FAU - Gad, Nayra
AU  - Gad N
AD  - Forest Research Institute, Inc, Harborside Financial Center, Jersey City, New 
      Jersey.
FAU - Gupta, Samir
AU  - Gupta S
AD  - Forest Research Institute, Inc, Harborside Financial Center, Jersey City, New 
      Jersey.
FAU - Periclou, Antonia
AU  - Periclou A
AD  - Forest Research Institute, Inc, Harborside Financial Center, Jersey City, New 
      Jersey.
LA  - eng
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20140916
PL  - United States
TA  - Clin Ther
JT  - Clinical therapeutics
JID - 7706726
RN  - 0 (Cytochrome P-450 CYP3A Inducers)
RN  - 0 (Cytochrome P-450 CYP3A Inhibitors)
RN  - 33CM23913M (Carbamazepine)
RN  - R9400W927I (Ketoconazole)
RN  - U8HTX2GK8J (Vilazodone Hydrochloride)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Carbamazepine/*pharmacology
MH  - Cross-Over Studies
MH  - Cytochrome P-450 CYP3A Inducers/*pharmacology
MH  - Cytochrome P-450 CYP3A Inhibitors/*pharmacology
MH  - Depressive Disorder, Major
MH  - Double-Blind Method
MH  - Drug Interactions
MH  - Female
MH  - Healthy Volunteers
MH  - Humans
MH  - Ketoconazole/*pharmacology
MH  - Male
MH  - Middle Aged
MH  - Vilazodone Hydrochloride/administration & dosage/*pharmacokinetics
MH  - Young Adult
OTO - NOTNLM
OT  - CYP3A4
OT  - carbamazepine
OT  - depression
OT  - ketoconazole
OT  - pharmacokinetics
OT  - vilazodone
EDAT- 2014/09/23 06:00
MHDA- 2016/02/20 06:00
CRDT- 2014/09/20 06:00
PHST- 2014/01/21 00:00 [received]
PHST- 2014/07/28 00:00 [revised]
PHST- 2014/08/11 00:00 [accepted]
PHST- 2014/09/20 06:00 [entrez]
PHST- 2014/09/23 06:00 [pubmed]
PHST- 2016/02/20 06:00 [medline]
AID - S0149-2918(14)00534-7 [pii]
AID - 10.1016/j.clinthera.2014.08.003 [doi]
PST - ppublish
SO  - Clin Ther. 2014 Nov 1;36(11):1638-49. doi: 10.1016/j.clinthera.2014.08.003. Epub 
      2014 Sep 16.