PMID- 24658627
OWN - NLM
STAT- MEDLINE
DCOM- 20140918
LR  - 20181202
IS  - 1432-0843 (Electronic)
IS  - 0344-5704 (Linking)
VI  - 73
IP  - 6
DP  - 2014 Jun
TI  - Effect of lenvatinib (E7080) on the QTc interval: results from a thorough QT 
      study in healthy volunteers.
PG  - 1109-17
AB  - PURPOSE: QT assessment of oncology drugs is generally challenging because they 
      are genotoxic and, of necessity,they require multisite evaluation in cancer 
      patients. Lenvatinib is not genotoxic, therefore, this thorough QT (TQT)study 
      with lenvatinib, a multityrosine kinase inhibitor, was undertaken utilizing 
      healthy volunteers and concentration effect modeling to project the TQT effect at 
      high plasma levels. METHODS: Fifty-two healthy subjects randomly received single 
      doses of lenvatinib 32 mg, placebo, or moxifloxacin 400 mg in a three-way 
      crossover study. Serial electrocardiograms were recorded, and the effect on 
      placebo corrected change-from-baseline QTcF (DeltaDeltaQTcF) was evaluated. The 
      relationship between lenvatinib plasma concentrations and QTcF was analyzed with 
      linear mixed effects modeling. RESULTS: L envatinib mildly lowered the heart rate 
      by 5-8 bpm during the first 12 h after dosing. DeltaDeltaQTcF was shortened with a peak 
      effect of -5.72 ms (90 % confidence interval (90 % CI) -7.76 to -3.69 ms) at 6 h 
      postdosing.The upper bound of mean DeltaDeltaQTcF did not exceed 2 ms at any time point 
      postdosing. A concentration-dependent effect of lenvatinib on DeltaDeltaQTcF was 
      identified with an estimated population intercept of -2.96 ms (90 % CI -4.49 
      to-1.43 ms; P = 0.0016) and a negative slope of -0.0045(90 % CI -4.49 to -1.43) 
      ms per ng/mL, respectively. The safety profile after a single dose of lenvatinib 
      was acceptable,with adverse events (AEs) of mild-to-moderate severity and no 
      serious AEs. CONCLUSIONS: L envatinib had no clinically relevant effect on the 
      QTc interval. Concentration-effect modeling supports the lack of QTc prolongation 
      at high plasma concentrations.
FAU - Shumaker, Robert C
AU  - Shumaker RC
FAU - Zhou, Meijian
AU  - Zhou M
FAU - Ren, Min
AU  - Ren M
FAU - Fan, Jean
AU  - Fan J
FAU - Martinez, Gresel
AU  - Martinez G
FAU - Aluri, Jagadeesh
AU  - Aluri J
FAU - Darpo, Borje
AU  - Darpo B
LA  - eng
PT  - Journal Article
PT  - Randomized Controlled Trial
PL  - Germany
TA  - Cancer Chemother Pharmacol
JT  - Cancer chemotherapy and pharmacology
JID - 7806519
RN  - 0 (Fluoroquinolones)
RN  - 0 (Phenylurea Compounds)
RN  - 0 (Quinolines)
RN  - EE083865G2 (lenvatinib)
RN  - U188XYD42P (Moxifloxacin)
SB  - IM
MH  - Adult
MH  - Cross-Over Studies
MH  - Electrocardiography/*drug effects
MH  - Female
MH  - Fluoroquinolones/pharmacology
MH  - Healthy Volunteers
MH  - Heart Rate/*drug effects
MH  - Humans
MH  - Long QT Syndrome/chemically induced
MH  - Male
MH  - Moxifloxacin
MH  - Phenylurea Compounds/adverse effects/*pharmacology
MH  - Quinolines/adverse effects/*pharmacology
MH  - Young Adult
EDAT- 2014/03/25 06:00
MHDA- 2014/09/19 06:00
CRDT- 2014/03/25 06:00
PHST- 2013/07/12 00:00 [received]
PHST- 2014/03/10 00:00 [accepted]
PHST- 2014/03/25 06:00 [entrez]
PHST- 2014/03/25 06:00 [pubmed]
PHST- 2014/09/19 06:00 [medline]
AID - 10.1007/s00280-014-2444-6 [doi]
PST - ppublish
SO  - Cancer Chemother Pharmacol. 2014 Jun;73(6):1109-17. doi: 
      10.1007/s00280-014-2444-6.