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

Abstract

Antiemetic treatment compliance is important to prevent chemotherapy-induced nausea and vomiting, a feared chemotherapy side effect. NEPA, a new oral fixed combination of netupitant, a highly selective NK1 receptor antagonist (RA), and palonosetron, a second-generation 5-HT3 RA, targets dual antiemetic pathways with a single dose. This study investigated the effect of food intake and age on NEPA pharmacokinetics (PK) and safety. In this open-label, single-center, randomized, phase 1 study, 24 adults (18-45 years) received NEPA in a fed or fasted state during the first treatment period and in the alternative state in the next treatment period. Twelve elderly subjects (≥65 years) received NEPA in a fasted state. Blood samples were taken for netupitant and palonosetron PK analysis. In the fed condition, netupitant plasma exposure increased, whereas palonosetron PK parameters were not affected. Furthermore, elderly subjects showed increased netupitant and palonosetron exposure compared with adults. All adverse events were mild/moderate, with constipation and headache the most common. Although food intake and age altered NEPA PK, dose adjustments were not needed, as netupitant and palonosetron exposure increases did not lead to safety concerns in healthy subjects.

Guideline for the prevention of acute chemotherapy‐induced nausea and vomiting in pediatric cancer patients: A focused update

“…Pharmacokinetic disposition of palonosetron : Twenty articles evaluating palonosetron pharmacokinetics were included in this systematic review (Supplementary Table S12).…”

Aprepitant in pediatric patients using moderate and highly emetogenic protocols: a systematic review and meta‐analyses of randomized controlled trials

“…Despite the lack of controlling risk factors, new molecules with few pharmacokinetic advantages are being tested in adults (e.g. netupitant), and might be tested in the paediatric population in future studies .…”

Timing flexibility of oral NEPA, netupitant-palonosetron combination, administration for the prevention of chemotherapy-induced nausea and vomiting (CINV)

“…Data used for PK/PD modeling of netupitant and palonosetron in this analysis were obtained from previous preclinical and clinical studies performed during the development of oral NEPA and palonosetron.

Fig. 1Design of studies included for the PK/PD modeling and for the correlation with antiemetic clinical efficacy [17, 27, 28]. BMI, body mass index; CP, complete protection (CR and no significant nausea); CR, complete response (no emesis, no rescue medication); HEC, highly emetogenic chemotherapy; LEC, low emetogenic chemotherapy; MEC, moderately emetogenic chemotherapy; NK 1 , neurokinin-1; oral NEPA, 300 mg netupitant/0.50 mg palonosetron; PD, pharmacodynamic; PET, positron emission tomography; PK, pharmacokinetics

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“…PK modeling of netupitant and palonosetron plasma concentration-time profiles was based on two-compartment model fitting to mean curves observed in an open-label, randomized phase I study in 22 healthy adults aimed at testing the effect of food on the PK of netupitant and palonosetron [28]. The subjects received single doses of oral NEPA in a fed or fasted state in the initial treatment period and in the alternative state in the following treatment period after a washout of 28 days.…”

“…Detailed design, methods, and patient eligibility criteria for the clinical studies have been published previously [17, 27, 28]. For each, the relevant study protocols were approved by the corresponding ethical review committees, and sites participating in the studies followed the International Conference on Harmonization E6 Good Clinical Practice guidelines, Declaration of Helsinki principles, and local laws and regulations.…”