PMID- 25546001
OWN - NLM
STAT- MEDLINE
DCOM- 20160222
LR  - 20240323
IS  - 1365-2125 (Electronic)
IS  - 0306-5251 (Print)
IS  - 0306-5251 (Linking)
VI  - 79
IP  - 6
DP  - 2015 Jun
TI  - The effect of tafamidis on the QTc interval in healthy subjects.
PG  - 918-25
LID - 10.1111/bcp.12561 [doi]
AB  - AIMS: The transthyretin (TTR) stabilizer, tafamidis, has demonstrated efficacy 
      and safety in the treatment of TTR familial amyloid polyneuropathy (20 mg day(-1) 
      ). Tafamidis use in TTR cardiomyopathy led to the study of the potential effect 
      of tafamidis on the QTc interval in healthy subjects. METHODS: This randomized, 
      three treatment, three period, six sequence crossover study with placebo, a 
      positive control (moxifloxacin 400 mg) and tafamidis (400 mg, to achieve a 
      supra-therapeutic Cmax of ~20 microg ml(-1) ) was conducted in healthy volunteers at 
      three clinical research units. Oral dosing in each of the three treatment periods 
      was separated by a washout period of  >/= 14 days. Serial triplicate 12-lead 
      electrocardiograms were performed. QTc intervals were derived using the 
      Fridericia correction method. Safety and tolerability were assessed by physical 
      examination, vital signs measurement, laboratory analyses and monitoring of 
      adverse events (AEs). RESULTS: A total of 42 subjects completed the study. The 
      upper limit of the two-sided 90% confidence intervals (CIs) for the difference in 
      baseline-adjusted QTc F between tafamidis 400 mg and placebo was <10 ms 
      (non-inferiority criterion) for all time points. The lower limit of the two-sided 
      90% CI between moxifloxacin 400 mg and placebo exceeded 5 ms at the pre-specified 
      moxifloxacin tmax of 3 h post-dose, confirming assay sensitivity. Cmax and 
      AUC(0,24 h) for tafamidis were 20.36 microg ml(-1) and 305.4 microg ml(-1) h, 
      respectively. There were no serious/severe AEs or treatment discontinuations due 
      to AEs. CONCLUSIONS: This thorough QTc study suggests that a supra-therapeutic 
      single 400 mg oral dose of tafamidis does not prolong the QTc interval and is 
      well-tolerated in healthy volunteers.
CI  - (c) 2015 The British Pharmacological Society.
FAU - Klamerus, Karen J
AU  - Klamerus KJ
AD  - Pfizer, Inc., San Diego, CA and.
FAU - Watsky, Eric
AU  - Watsky E
AD  - Pfizer, Inc., Groton, CT, USA.
FAU - Moller, Robert
AU  - Moller R
AD  - Pfizer, Inc., Groton, CT, USA.
FAU - Wang, Ronnie
AU  - Wang R
AD  - Pfizer, Inc., Groton, CT, USA.
FAU - Riley, Steve
AU  - Riley S
AD  - Pfizer, Inc., Groton, CT, USA.
LA  - eng
SI  - ClinicalTrials.gov/NCT01775761
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Br J Clin Pharmacol
JT  - British journal of clinical pharmacology
JID - 7503323
RN  - 0 (Benzoxazoles)
RN  - 8FG9H9D31J (tafamidis)
SB  - IM
MH  - Action Potentials
MH  - Administration, Oral
MH  - Adult
MH  - Belgium
MH  - Benzoxazoles/*administration & dosage/*adverse effects/pharmacokinetics
MH  - Cross-Over Studies
MH  - Drug Administration Schedule
MH  - Electrocardiography
MH  - Female
MH  - Healthy Volunteers
MH  - Heart Conduction System/*drug effects/physiopathology
MH  - Heart Rate/*drug effects
MH  - Humans
MH  - Long QT Syndrome/*chemically induced/diagnosis/physiopathology
MH  - Male
MH  - Middle Aged
MH  - Risk Assessment
MH  - Singapore
MH  - United States
MH  - Young Adult
PMC - PMC4456124
OTO - NOTNLM
OT  - QTc prolongation
OT  - cardiomyopathy
OT  - familial amyloid polyneuropathy
OT  - tafamidis
OT  - transthyretin amyloidosis
EDAT- 2014/12/30 06:00
MHDA- 2016/02/24 06:00
PMCR- 2016/06/01
CRDT- 2014/12/30 06:00
PHST- 2014/08/07 00:00 [received]
PHST- 2014/11/13 00:00 [revised]
PHST- 2014/11/24 00:00 [accepted]
PHST- 2014/12/30 06:00 [entrez]
PHST- 2014/12/30 06:00 [pubmed]
PHST- 2016/02/24 06:00 [medline]
PHST- 2016/06/01 00:00 [pmc-release]
AID - 10.1111/bcp.12561 [doi]
PST - ppublish
SO  - Br J Clin Pharmacol. 2015 Jun;79(6):918-25. doi: 10.1111/bcp.12561.