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

Abstract

Purpose: The administration timing of antiemetic and chemotherapeutic regimens is often determined by regulatory indications, based on registration studies. Oral NEPA, fixed combination of the neurokinin-1 receptor antagonist (NK₁RA) netupitant and the 5-hydroxytryptamine-3 RA (5-HT₃RA) palonosetron, is recommended to be administered approximately 60 min before chemotherapy. Reducing chair time for chemotherapy administration at oncology day therapy units would improve facility efficiency without compromising patient symptom management. The objective was to determine if oral NEPA can be administered closer to chemotherapy initiation without compromising patient symptom management.

Methods: NK₁ receptor occupancy (NK₁RO) time course in the brain was determined using positron emission tomography; netupitant and palonosetron plasma concentration-time profiles were described by pharmacokinetic (PK) models; and the rate, extent, and duration of RO by netupitant and palonosetron were predicted by pharmacodynamic modeling. Clinical efficacy data from a pivotal study in cisplatin and oral NEPA-receiving patients were reviewed in the context of symptom management.

Results: Striatal 90% NK₁RO, assumed to correlate with NK₁RA antiemetic efficacy, was predicted at netupitant plasma concentration of 225 ng/mL, reached at 2.23 h following NEPA administration. Palonosetron 90% 5-HT₃RO was predicted at a 188-ng/L plasma concentration, reached at 1.05 h postdose. The mean time to first treatment failure for the 1.5% of NEPA-treated patients without complete response receiving highly emetogenic chemotherapy was 8 h. Antiemetic efficacy was sustained over 5 days despite the expected decrease of NK₁RO and 5-HT₃RO.

Conclusions: Results suggest that administering oral NEPA closer to initiation of cisplatin administration would provide similar antiemetic efficacy. Prospective clinical validation is required.

Keywords: Administration timing; CINV; Chemotherapy-induced nausea and vomiting; NEPA; Netupitant; Palonosetron.

Fig. 1

Design 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; NK₁, neurokinin-1; oral NEPA, 300 mg netupitant/0.50 mg palonosetron; PD, pharmacodynamic; PET, positron emission tomography; PK, pharmacokinetics

Fig. 2

Model-predicted netupitant NK₁RO in different brain regions and netupitant plasma concentrations as a function of time after administration of 300-mg netupitant. NK₁RO, neurokinin-1 receptor occupancy

Fig. 3

Model-predicted palonosetron 5-HT₃RO and predicted palonosetron plasma concentrations as a function of time after administration of 0.5-mg palonosetron. 5-HT₃RO, 5-hydroxytryptamine-3 receptor occupancy