Electrocardiographic characterization of the QTc interval in patients with advanced solid tumors: pharmacokinetic- pharmacodynamic evaluation of sunitinib.
OBJECTIVE
To evaluate the effects of sunitinib, a multitargeted tyrosine kinase inhibitor, on the QT interval in patients with cancer.


METHODS
Patients received sunitinib loading doses (150-200 mg) on days 3 and 9 and maintenance doses (50 mg/d) on days 4 to 8. Moxifloxacin (day 1), placebo (day 2), and granisetron [with placebo (day 2) or sunitinib (days 3 and 9)] were also administered. Treatment effects were evaluated by time-matched, serial electrocardiograms, and manually overread.


RESULTS
Twenty-four of 48 patients were QT/PK evaluable. Moxifloxacin produced a time-matched, maximum mean placebo-adjusted corrected QT interval (QT(c)F) of 5.6 ms [90% confidence interval (CI), 1.9-9.3]. Sunitinib QT(c)F changes correlated with exposure, but not T(max). Maximum mean time-matched, placebo-adjusted QT(c)F was 9.6 ms (90% CI, 4.1-15.1) at steady state/therapeutic concentrations (day 3) and 15.4 ms (90% CI, 8.4-22.4) at supratherapeutic concentrations (day 9). No patient had a QT(c)F >500 ms. Concomitant granisetron produced no significant QT(c)F prolongation. Sunitinib-related adverse events were as previously described.


CONCLUSIONS
Sunitinib has a dose-dependent effect on QT interval. The increased risk of ventricular arrhythmias must be weighed against the therapeutic benefit sunitinib provides to patients with advanced cancer.
Bello
Carlo L
CL
Pfizer Global Research and Development, New York, New York, USA. Carlo.bello@pfizer.com
Mulay
Marilyn
M
Huang
Xin
X
Patyna
Shem
S
Dinolfo
Melissa
M
Levine
Steven
S
Van Vugt
Andrew
A
Toh
Melvin
M
Baum
Charles
C
Rosen
Lee
L
D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000150:complications*; D001372:Aza Compounds / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000379:methods*; D024841:Fluoroquinolones; D017829:Granisetron / Q000627:therapeutic use; D006352:Heart Ventricles / Q000473:pathology; D006801:Humans; D007211:Indoles / Q000493:pharmacokinetics* / Q000494:pharmacology; D000077266:Moxifloxacin; D009369:Neoplasms / Q000150:complications* / Q000188:drug therapy*; D010919:Placebos; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000493:pharmacokinetics* / Q000494:pharmacology; D011804:Quinolines / Q000627:therapeutic use; D012306:Risk; D000077210:Sunitinib; D013997:Time Factors
D000970:Antineoplastic Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D017829:Granisetron; D007211:Indoles; D000077266:Moxifloxacin; D010919:Placebos; D011505:Protein-Tyrosine Kinases; D011758:Pyrroles; D011804:Quinolines; D000077210:Sunitinib