Rolapitant, a selective, long-acting neurokinin-1 (NK-1) receptor antagonist, demonstrated efficacy in preventing chemotherapy-induced nausea and vomiting (CINV) in patients receiving highly or moderately emetogenic chemotherapy. Two studies in healthy volunteers evaluated 1) absolute bioavailability and 2) NK-1 receptor occupancy of oral rolapitant. Absolute bioavailability, determined by the ratio of dose-normalized exposure following a 180-mg oral dose vs. an intravenous microdose, was ∼100%. Brain imaging by positron emission tomography 120 h after a single dose showed that NK-1 receptor occupancy increased with escalating doses (4.5–180 mg) but was not dose-proportional; a 180-mg dose resulted in near-saturable binding to NK-1 receptors (mean ± standard deviation: 94% ± 9%). A pharmacokinetic-pharmacodynamic model predicted that rolapitant plasma concentrations >348 ng/mL would result in >90% NK-1 receptor occupancy in the cortex up to 120 h postdose. These results support administration of a single 180-mg oral dose of rolapitant for CINV prevention.