Integration of Modeling and Simulation to Support Changes to Ondansetron Dosing Following A Randomized, Double-Blind, Placebo-, and Active-Controlled Thorough QT Study

摘要

Prolongation of the QT interval has been observed with ondansetron and other members of the 5-HT3 antagonist class. This is the first thorough QTc study of ondansetron conducted in accordance with ICH E14 guidelines, designed to investigate the effect of single intravenous (IV) doses of ondansetron on cardiac conduction compared to placebo and a positive control, moxifloxacin, in healthy subjects. Statistical analysis of dose-response showed the maximum mean difference in QTcF, compared to placebo and corrected for baseline (ddQTcF), was less than 10 milliseconds (ms) after an 8 mg IV dose and approximately 20 ms after the 32 mg dose, each infused over 15 minutes. The concentration-response (Cp-ddQTcF) model resulted in similar predictions for the 8 and 32 mg and was used to predict the maximum mean ddQTcF (upper 90% CI bound) of 9.2 (11.2) ms for 16 mg IV. As a result, single IV doses of ondansetron greater than 16 mg should no longer be used. Adult cancer patients, under 75 years, may receive up to a maximum initial 15-minute IV dose of 16 mg, prior to chemotherapy, followed by 2 additional IV or IM doses of 8 mg for the management of chemotherapy-induced nausea and vomiting (CINV).