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Rolapitant Absolute Bioavailability and PET Imaging Studies in Healthy Adult Volunteers
Author(s) -
Wang X,
Zhang ZY,
Powers D,
Wang J,
Lu S,
Kansra V
Publication year - 2017
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.637
Subject(s) - bioavailability , vomiting , pharmacokinetics , microdose , pharmacodynamics , chemotherapy induced nausea and vomiting , nausea , pharmacology , medicine , nk1 receptor antagonist , receptor , antiemetic , substance p , neuropeptide
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.