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.
OBJECTIVE
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.
Division of Hematology/Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University, 4100 John R, Detroit, MI 48201, USA. heathe@karmanos.org
Elisabeth I
EI
Heath
Jeffrey
J
Infante
Lionel D
LD
Lewis
Thehang
T
Luu
Joe
J
Stephenson
Antoinette R
AR
Tan
Saifuddin
S
Kasubhai
Patricia
P
LoRusso
Bo
B
Ma
A Benjamin
AB
Suttle
Joseph F
JF
Kleha
Howard A
HA
Ball
Mohammed M
MM
Dar
D000328:Adult; D000368:Aged; D000465:Algorithms; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics; D001372:Aza Compounds / Q000493:pharmacokinetics; D001794:Blood Pressure / Q000187:drug effects; D016001:Confidence Intervals; D004311:Double-Blind Method; D015716:Electrocardiography, Ambulatory; D005260:Female; D024841:Fluoroquinolones; D006329:Heart Conduction System / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007191:Indazoles; D008133:Long QT Syndrome / Q000139:chemically induced / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D009369:Neoplasms / Q000150:complications* / Q000188:drug therapy / Q000503:physiopathology; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D011804:Quinolines / Q000493:pharmacokinetics; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D055815:Young Adult
D020533:Angiogenesis Inhibitors; D000900:Anti-Bacterial Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D007191:Indazoles; D011743:Pyrimidines; D011804:Quinolines; D013449:Sulfonamides; C516667:pazopanib; D000077266:Moxifloxacin