Document Detail


A randomized, double-blind, placebo-controlled study to evaluate the effect of repeated oral doses of pazopanib on cardiac conduction in patients with solid tumors.
MedLine Citation:
PMID:  23344712     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: As tyrosine kinase inhibitors have been associated with cardiotoxicity, we evaluated the effect of pazopanib, an inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit, on electrocardiographic parameters in patients with cancer.
METHODS: This double-blind, placebo-controlled, parallel-group study randomized patients (N = 96) to moxifloxacin (positive control) or placebo on Day 1 followed by pazopanib or placebo 800 mg/day (fasted) on Days 2-8 and 1,600 mg (with food) on Day 9. Treatment effects were evaluated by baseline-adjusted, time-matched, serial Holter electrocardiograms.
RESULTS: Sixty-five patients were evaluable for preplanned analyses. On Day 1, the maximum mean difference in baseline-adjusted, time-matched Fridericia-corrected QT (QTcF) interval in moxifloxacin-treated patients versus placebo was 10.6 ms (90% confidence interval [CI]: 4.2, 17.0). The administration scheme increased plasma pazopanib concentrations approximately 1.3- to 1.4-fold versus the recommended 800 mg once-daily dose. Pazopanib caused clinically significant increases from baseline in blood pressure, an anticipated class effect, and an unexpected reduction in heart rate from baseline that correlated with pazopanib exposure. On Day 9, the maximum mean difference in baseline-adjusted, time-matched QTcF interval in pazopanib-treated patients versus placebo was 4.4 ms (90% CI: -2.4, 11.2). Mixed-effects modeling indicated no significant concentration-dependent effect of pazopanib or its metabolites on QTcF interval.
CONCLUSIONS: Pazopanib as administered in this study achieved supratherapeutic concentrations, produced a concentration-dependent decrease in heart rate, and caused a small, concentration-independent prolongation of the QTcF interval.
Authors:
Elisabeth I Heath; Jeffrey Infante; Lionel D Lewis; Thehang Luu; Joe Stephenson; Antoinette R Tan; Saifuddin Kasubhai; Patricia LoRusso; Bo Ma; A Benjamin Suttle; Joseph F Kleha; Howard A Ball; Mohammed M Dar
Publication Detail:
Type:  Journal Article; Multicenter Study; Randomized Controlled Trial; Research Support, Non-U.S. Gov't     Date:  2013-01-24
Journal Detail:
Title:  Cancer chemotherapy and pharmacology     Volume:  71     ISSN:  1432-0843     ISO Abbreviation:  Cancer Chemother. Pharmacol.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-02-25     Completed Date:  2013-04-08     Revised Date:  2014-03-06    
Medline Journal Info:
Nlm Unique ID:  7806519     Medline TA:  Cancer Chemother Pharmacol     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  565-73     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adult
Aged
Algorithms
Angiogenesis Inhibitors / administration & dosage,  adverse effects*,  pharmacokinetics
Anti-Bacterial Agents / pharmacokinetics
Aza Compounds / pharmacokinetics
Blood Pressure / drug effects
Confidence Intervals
Double-Blind Method
Electrocardiography, Ambulatory
Female
Heart Conduction System / drug effects*
Heart Rate / drug effects
Humans
Long QT Syndrome / chemically induced,  physiopathology
Male
Middle Aged
Neoplasms / complications*,  drug therapy,  physiopathology
Pyrimidines / administration & dosage,  adverse effects*,  pharmacokinetics
Quinolines / pharmacokinetics
Sulfonamides / administration & dosage,  adverse effects*,  pharmacokinetics
Young Adult
Grant Support
ID/Acronym/Agency:
P30 CA023108/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Angiogenesis Inhibitors; 0/Anti-Bacterial Agents; 0/Aza Compounds; 0/Pyrimidines; 0/Quinolines; 0/Sulfonamides; 7RN5DR86CK/pazopanib; U188XYD42P/moxifloxacin
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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