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 (NK(1)RA) netupitant and the 5-hydroxytryptamine-3 RA (5-HT(3)RA) 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: NK(1) receptor occupancy (NK(1)RO) 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% NK(1)RO, assumed to correlate with NK(1)RA antiemetic efficacy, was predicted at netupitant plasma concentration of 225 ng/mL, reached at 2.23 h following NEPA administration. Palonosetron 90% 5-HT(3)RO 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 NK(1)RO and 5-HT(3)RO. CONCLUSIONS: Results suggest that administering oral NEPA closer to initiation of cisplatin administration would provide similar antiemetic efficacy. Prospective clinical validation is required.