Medline ® Abstract for Reference 27
of 'Prevention and treatment of chemotherapy-induced nausea and vomiting in adults'
A randomized, placebo-controlled, four-period crossover, definitive QT study of the effects of APF530 exposure, high-dose intravenous granisetron, and moxifloxacin on QTc prolongation.
Mason JW, Moon TE, O'Boyle E, Dietz A
Cancer Manag Res. 2014;6:181. Epub 2014 Mar 26.
BACKGROUND: Regulatory concern about potential QT-interval prolongation by serotonin-receptor antagonist antiemetics prompted product-label changes. The first-generation serotonin-receptor antagonist granisetron is available in oral (PO), intravenous (IV), and transdermal formulations. APF530 is a formulation that provides sustained release of granisetron when administered as a single subcutaneous (SC) injection. The Phase I study reported here evaluated effects of APF530 on electrocardiographic intervals.
METHODS: This single-site, double-blind, placebo-controlled, four-period crossover trial randomized healthy men and women to receive varying sequences of APF530 1 g SC, granisetron 50μg/kg IV, moxifloxacin 400 mg PO, and placebo. Subjects were assessed for 49 hours after each treatment. The primary objective was to evaluate differences between baseline-adjusted, heart rate-corrected QT-interval change using the Fridericia rate correction (dQTcF) for APF530 1 g SC and placebo. Electrocardiograms were performed at various times throughout the assessment period. Pharmacokinetics and safety were evaluated.
RESULTS: The upper one-sided 95% confidence interval (CI) for mean baseline-adjusted dQTcF at each post-dose time point between APF530 and placebo excluded 10 ms, indicating that APF530 1 g SC had no clinically significant effect on QTcF. Maximum observed QTcF change was 4.15 ms (90% CI, 0.94 to 7.36) at Hour 3. No clinically significant changes in other electrocardiogram intervals were observed. APF530 SC pharmacokinetics were as expected, with slow absorption (maximum plasma concentration 35.8 ng/mL, median time to maximum plasma concentration 11.1 hours) and slow elimination (mean half-life 18.6 hours; systemic clearance 20.2 L/hour) of granisetron versus the expected early peak concentration and elimination of granisetron IV. APF530 SC was well tolerated. Adverse events, most commonly constipation and SC injection-site reactions, were generally mild and quickly resolved.
CONCLUSION: APF530 1 g SC did not induce clinically significant QTcF interval prolongation or changes in the other electrocardiogram intervals, and was well tolerated at twice the recommended dose.
Department of Medicine, University of Utah, Salt Lake City, UT, USA.