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 (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.

<p>Management of Chemotherapy-Induced Nausea and Vomiting (CINV): A Short Review on the Role of Netupitant-Palonosetron (NEPA)</p>

“…The results suggested the possibility to administer NEPA closer to initiation of chemotherapy than the recommended 60 min. 37 Lastly, a very recent cost-effectiveness analysis conducted to compare NEPA versus an aprepitant plus granisetron regimens in patients receiving HEC suggests that NEPA, by achieving a superior CINV prevention, is highly cost-saving due mainly to lower medical costs of CINVrelated events. 38…”

Neurokinin-1 receptor antagonists: review of their role for the prevention of chemotherapy-induced nausea and vomiting in adults

“…The administration timing of oral NK 1 RAs is 1 h before the start of chemotherapy for aprepitant and NEPA, and 1 to 2 h for rolapitant [39,42,44]. For NEPA, in a recent study based on a pharmacokinetic/pharmacodynamic model, PET and clinical data suggest that NEPA could be administered closer to the time of chemotherapy initiation [119,120]. The administration timing of oral 5-HT 3 RAs before chemotherapy, although not a consideration for NEPA, is 30 min for granisetron, from 30 to 60 min for ondansetron, and 60 min for palonosetron [72,83,95].…”

Preventing Chemotherapy-Induced Nausea and Vomiting with Netupitant/Palonosetron, the First Fixed Combination Antiemetic: Current and Future Perspective

“…NEPA capsules are administered as a single oral dose, approximately 60 min prior to chemotherapy on day 1 of each cycle. However, recent PK/pharmacodynamic (PD) modeling studies suggest that shifting the timing of NEPA administration closer to the time of chemotherapy initiation, and possibly even co-administration with chemotherapy, may not affect its efficacy [68,69]. An iv.…”

“…For netupitant, 92.5% of striatal NK 1 receptors were occupied at 6 h postadministration of 300 mg oral netupitant [70], and NK 1 RO remained approximately 90% over 96 h in various brain regions [70]. PK/PD modeling has predicted that striatal 90% NK 1 RO is achieved at a netupitant plasma concentration of 225 ng/ml, reached at 2.2 h after oral NEPA administration [68].…”

“…PK/PD modeling has predicted that 90% 5-HT 3 RO could be achieved with a palonosetron plasma concentration of 188 pg/ml, reached at 1.1 h after administration of oral NEPA [68]. A single oral dose of NEPA results in a mean C max of 785 pg/ml, reached in 4.5 h [70].…”