Netupitant versus aprepitant: model-predicted neurokinin-1 receptor occupancy and implications for long-delayed nausea and vomiting prevention.

Abstract

PURPOSE: Nausea and vomiting beyond 5&#xa0;days after emetogenic chemotherapy or antibody-drug conjugate (ADC) therapy are common, yet the role of neurokinin-1 (NK1) receptor antagonists in this setting remains underrecognized. We used pharmacokinetic/pharmacodynamic (PK/PD) modeling to estimate the NK1 receptor occupancy (RO), a proxy for clinical efficacy, for up to 20&#xa0;days after a single 300&#xa0;mg dose of oral netupitant, 3-day oral aprepitant (125&#xa0;mg on day 1; 80&#xa0;mg on days 2-3), or a single 165&#xa0;mg dose of oral aprepitant. METHODS: Data from previous PK studies were analyzed by compartmental modeling. Positron emission tomography studies assessing striatal NK1 RO were used to develop maximum drug effect PD models, which were fitted to NK1 RO data as a function of plasma concentrations. RESULTS: Model predicted NK1 RO exceeded 90% at 3&#xa0;h for all treatments. Thereafter, RO declined more gradually with netupitant (76%, 70%, 60%, and 21% on days 5, 7, 10, and 20, respectively) than with 3-day aprepitant (81%, 39%, 3%, and negligible) or single-dose aprepitant (45%, 10%, <&#x2009;1%, and negligible). The half-life of netupitant was ~&#x2009;6.1 times longer than aprepitant's. Netupitant plasma concentration remained above the effective concentration for 50% NK1 RO (EC50) through day 10, whereas aprepitant concentrations fell below the EC50 by ~&#x2009;days 7 and 5 after repeated and single dosing, respectively. CONCLUSIONS: Single-dose netupitant maintained NK1 RO substantially longer than repeated- and single-dose aprepitant, suggesting greater potential for prolonged prevention of nausea and vomiting in ADC-treated patients. Prospective clinical validation of these model predictions would be beneficial.