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

PurposeThe 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 (NK(1)RA) netupitant and the 5-hydroxytryptamine-3 RA (5-HT(3)RA) palonosetron, is recommended to be administered approximately 60min 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.MethodsNK(1) 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.ResultsStriatal 90% NK1RO, assumed to correlate with NK(1)RA antiemetic efficacy, was predicted at netupitant plasma concentration of 225ng/mL, reached at 2.23h following NEPA administration. Palonosetron 90% 5-HT3RO was predicted at a 188-ng/L plasma concentration, reached at 1.05h postdose. The mean time to first treatment failure for the 1.5% of NEPA-treated patients without complete response receiving highly emetogenic chemotherapy was 8h. Antiemetic efficacy was sustained over 5days despite the expected decrease of NK1RO and 5-HT3RO.ConclusionsResults suggest that administering oral NEPA closer to initiation of cisplatin administration would provide similar antiemetic efficacy. Prospective clinical validation is required.