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Integration of modeling and simulation to support changes to ondansetron dosing following a randomized, double-blind,

Peiying Zuo1, Lynda J Haberer, Lei Fang

  • 1GlaxoSmithKline, Research Triangle Park, NC, USA.

Journal of Clinical Pharmacology
|May 1, 2014
PubMed

Insights

Ondansetron can prolong the QT interval. This study found single IV doses above 16 mg are not recommended, with 16 mg IV as the maximum initial dose for CINV management.

Area of Science:

  • Pharmacology
  • Cardiology
  • Clinical Pharmacology

Background:

  • Ondansetron, a 5-HT3 antagonist, is associated with QT interval prolongation.
  • Previous studies on ondansetron's cardiac effects have been limited.
  • ICH E14 guidelines necessitate thorough QT studies for drug safety evaluation.

Purpose of the Study:

  • To assess the cardiac electrophysiological effects of single intravenous ondansetron doses.
  • To establish a safe dosing regimen for ondansetron in accordance with ICH E14 guidelines.
  • To compare ondansetron's effect on QT interval against placebo and moxifloxacin.

Main Methods:

  • A thorough QT study in healthy subjects.
  • Administration of single intravenous doses of ondansetron (8 mg and 32 mg) over 15 minutes.
  • Comparison with placebo and moxifloxacin (positive control).
  • Dose-response and concentration-response modeling (QTcF, ddQTcF).

Main Results:

  • The maximum mean difference in QTcF corrected for baseline (ddQTcF) was <10 ms for 8 mg IV and ~20 ms for 32 mg IV.
  • Concentration-response modeling predicted a maximum mean ddQTcF upper 90% CI bound of 9.2 (11.2) ms for 16 mg IV.
  • Single IV doses of ondansetron exceeding 16 mg are not advised.

Conclusions:

  • Single intravenous doses of ondansetron greater than 16 mg should be avoided.
  • Adult cancer patients under 75 may receive a maximum initial 15-minute IV dose of 16 mg for CINV.
  • Subsequent doses for CINV should not exceed 8 mg IV or IM.
Keywords:
5HT3 antagonistQT intervalQT prolongationdrug safetyondansetronrepolarizaitonthorough QT/QTc study

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