title: 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.
abstract: 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 50 μg/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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine, University of Utah, Salt Lake City, UT, USA.
authors.forename: Jay W
authors.initials: JW
authors.lastname: Mason
authors.affiliation: Tarizona eHealth Services, Inc., San Carlos, CA, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Moon
authors.affiliation: AP Pharma, Redwood City, CA, USA.
authors.forename: Erin
authors.initials: E
authors.lastname: O'Boyle
authors.affiliation: Spaulding Clinical Research, West Bend, WI, USA.
authors.forename: Albert
authors.initials: A
authors.lastname: Dietz
keywords: APF530; QTc interval; chemotherapy-induced nausea and vomiting; extended-release; granisetron; subcutaneous
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