Effects of combined netupitant and palonosetron (NEPA), a cancer supportive care antiemetic, on the ECG of healthy subjects: an ICH E14 thorough QT trial

Abstract

Chemotherapy-induced nausea and vomiting is ranked among the worst side effects of chemotherapy. NEPA is an oral fixed-dose combination antiemetic under development, consisting of netupitant 300 mg, a highly selective NK1 receptor antagonist (RA), and palonosetron 0.5 mg, a pharmacologically and clinically distinct 5-HT3 RA. Although palonosetron is not associated with relevant ECG effects, this study evaluated cardiovascular safety of netupitant in combination with palonosetron, as well as its tolerability.This randomised, placebo- and positively controlled study in 197 subjects included 4 treatment groups: placebo, 200 mg netupitant + 0.5 mg palonosetron (NEPA200/0.5), 600 mg netupitant + 1.5 mg palonosetron (NEPA600/1.5, a supratherapeutic dose), and 400 mg moxifloxacin. Assessments included a 24-h baseline ECG recording, followed by a single dose of treatment and ECG measurements for 2 days.Mean placebo-corrected time-averaged changes from baseline were similar in NEPA200/0.5 and NEPA600/1.5 groups primarily for individually heart rate-corrected QT interval (QTcI: +4.7 and +3.6 ms, respectively) and for heart rate (HR: –3.3 bpm and –3.0 bpm), PR interval (–0.4 ms and 0.2 ms), and QRS interval (1 ms and 0.5 ms). The time-matched analysis showed no upper confidence interval >10 ms, with no suggestion of a QTc effect by pharmacokinetic-pharmacodynamic modeling for parent/metabolites. Moxifloxacin showed the expected placebo-corrected change from baseline (+8.4 ms time average) and the expected profile to establish assay sensitivity. No new morphologic changes of clinical relevance were observed. Treatment-related adverse events were comparable among groups.This study showed that NEPA treatments produced no significant effects on QTcI, HR, PR interval, QRS interval, and cardiac morphology relative to placebo, even at supratherapeutic doses.

Phase IIIb Safety and Efficacy of Intravenous NEPA for Prevention of Chemotherapy-Induced Nausea and Vomiting (CINV) in Patients with Breast Cancer Receiving Initial and Repeat Cycles of Anthracycline and Cyclophosphamide (AC) Chemotherapy

“…In addition, as the cardiac safety of NEPA has been carefully evaluated previously, ECG assessments were not included in the current trial. Prior cardiac safety evaluations for NEPA have included a thorough QTc study , the oral NEPA phase III study in the AC setting , and the prior IV NEPA study in the cisplatin setting . Previously, there were no cardiac safety concerns based on ECGs observed with either IV or oral NEPA formulations during initial or repeated cycles in >1,500 patients participating in phase III studies.…”

Evaluation of the effect of food and age on the pharmacokinetics of oral netupitant and palonosetron in healthy subjects: A randomized, open‐label, crossover phase 1 study

“…In healthy subjects, no medically relevant changes in heart rhythm, pulse rate, individual heart rate-corrected QT interval, QRS interval, or cardiac morphology were observed for NEPA in a randomized, placebo-and positively controlled study conducted in 197 healthy subjects. 27 In addition, a phase 3 study in cancer patients receiving MEC showed no increased cardiac safety concern when patients received NEPA instead of palonosetron alone. 34 In line with these data, no medically relevant changes in ECG parameters and only slight decreases in blood pressure were observed in this study.…”

“…It has been previously demonstrated that these netupitant metabolites are pharmacologically active. 27,28 The bioanalysis of the obtained plasma samples was conducted in accordance with the Organisation for Economic Co-operation and Development Principles of Good Laboratory Practice. Palonosetron and netupitant and its metabolites (M1, M2, and M3) were determined using 2 fully validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods with stable isotope-labeled internal standards.…”

Netupitant/Palonosetron

“…20 Between-subject variability is between 42% and 56% for netupitant 200 to 600 mg and between 20% and 29% for palonosetron 0.5 to 1.5 mg. 20 At the doses studied, netupitant and palonosetron have no effect on the pharmacokinetic parameters of each other. 1,21 Following oral administration of netupitant and palonosetron in healthy subjects, the time to maximum concentration (T max ) is about 5 hours for both drugs.…”

“…1 A placebo-controlled QTc study showed that doses ranging from netupitant 200 mg/palonosetron 0.5 mg to netupitant 600 mg/palonosetron 1.5 mg did not clinically increase the QTc interval compared with placebo. 1,20 Netupitant is classified as Pregnancy Category C; no adequate and well-controlled studies have been performed in pregnant women. Netupitant/palonosetron should only be used in pregnancy if the benefits clearly outweigh the risks.…”