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

Nausea and vomiting beyond 5 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 days after a single 300 mg dose of oral netupitant, 3-day oral aprepitant (125 mg on day 1; 80 mg on days 2-3), or a single 165 mg dose of oral aprepitant.

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.

Model predicted NK₁ RO exceeded 90% at 3 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%, < 1%, and negligible). The half-life of netupitant was ~ 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 ~ days 7 and 5 after repeated and single dosing, respectively.

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.