PMID- 26501204
OWN - NLM
STAT- MEDLINE
DCOM- 20151224
LR  - 20181113
IS  - 0946-1965 (Print)
IS  - 0946-1965 (Linking)
VI  - 53
IP  - 11
DP  - 2015 Nov
TI  - A randomized, placebo-controlled repeat-dose thorough QT study of inhaled 
      loxapine in healthy volunteers.
PG  - 963-71
AB  - OBJECTIVE: This randomized, double-blind, active- and placebo-controlled, 
      crossover, thorough QT study assessed the effect of two inhaled loxapine doses on 
      cardiac repolarization as measured by corrected QT (QTc) interval in healthy 
      subjects (ClinicalTrials.gov NCT01854710). METHODS: Subjects received two doses 
      of inhaled loxapine (10 mg) 2 hours apart+oral placebo, two doses of inhaled 
      placebo+oral placebo, or two doses of inhaled placebo+oral moxifloxacin (400 mg; 
      positive control), with >/=3 days washout between treatments. Two-sided 90% 
      confidence intervals (CIs) were calculated around least-squares mean predose 
      placebo-subtracted individually corrected QT durations (DeltaDeltaTcIs) at 12 time points 
      throughout 24 hours after dosing. A DeltaDeltaTcI 95% upper CI exceeding 10 msec was the 
      threshold indicating QTc prolongation (primary endpoint). Secondary endpoints 
      included Fridericia- and Bazett-corrected QT duration and QTcI outliers. 
      Pharmacokinetics and adverse events (AEs) were also assessed. RESULTS: Of 60 
      subjects enrolled (mean age, 33.8 years; 52% male), 44 completed the study. Post 
      loxapine dosing, no DeltaDeltaTcI 95% upper CI exceeded 10 msec; the largest was 6.31 
      msec 5 minutes post dose 2. Methodology was validated by DeltaDeltaTcI 95% lower CIs 
      exceeding 5 msec at 9 of 12 time points after moxifloxacin dosing. Loxapine 
      plasma concentrations increased rapidly (mean Cmax, 177 ng/mL; median tmax 2 
      minutes after dose 2, 2.03 hours after dose 1). There were no deaths, serious 
      AEs, or AEs leading to discontinuation, and one severe AE. CONCLUSIONS: Primary 
      and secondary endpoints indicated two therapeutic doses of inhaled loxapine did 
      not cause threshold QTc prolongation in this study.
FAU - Cassella, James V
AU  - Cassella JV
AD  - Alexza Pharmaceuticals, Inc., Mountain View, CA and Teva Pharmaceuticals, Frazer, 
      PA, USA.
FAU - Spyker, Daniel A
AU  - Spyker DA
FAU - Yeung, Paul P
AU  - Yeung PP
LA  - eng
SI  - ClinicalTrials.gov/NCT01854710
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
PL  - Germany
TA  - Int J Clin Pharmacol Ther
JT  - International journal of clinical pharmacology and therapeutics
JID - 9423309
RN  - 0 (Antipsychotic Agents)
RN  - 61443-77-4 (8-hydroxyloxapine)
RN  - LER583670J (Loxapine)
SB  - IM
MH  - Action Potentials
MH  - Administration, Inhalation
MH  - Adult
MH  - Antipsychotic Agents/*administration & dosage/adverse 
      effects/blood/pharmacokinetics
MH  - Biotransformation
MH  - Cross-Over Studies
MH  - Double-Blind Method
MH  - Drug Administration Schedule
MH  - Female
MH  - Healthy Volunteers
MH  - Heart Conduction System/*drug effects/physiology
MH  - Humans
MH  - Least-Squares Analysis
MH  - Loxapine/*administration & dosage/adverse effects/analogs & 
      derivatives/blood/pharmacokinetics
MH  - Male
MH  - Middle Aged
MH  - Risk Assessment
MH  - Treatment Outcome
MH  - Young Adult
PMC - PMC4611162
EDAT- 2015/10/27 06:00
MHDA- 2015/12/25 06:00
PMCR- 2015/11/01
CRDT- 2015/10/27 06:00
PHST- 2015/10/27 06:00 [entrez]
PHST- 2015/10/27 06:00 [pubmed]
PHST- 2015/12/25 06:00 [medline]
PHST- 2015/11/01 00:00 [pmc-release]
AID - 13814 [pii]
AID - 10.5414/CP202457 [doi]
PST - ppublish
SO  - Int J Clin Pharmacol Ther. 2015 Nov;53(11):963-71. doi: 10.5414/CP202457.