title: Rolapitant Absolute Bioavailability and PET Imaging Studies in Healthy Adult Volunteers.
abstract: 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.
authors.affiliation: Tesaro Inc, Waltham, Massachusetts, USA.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: Tesaro Inc, Waltham, Massachusetts, USA.
authors.forename: Z Y
authors.initials: ZY
authors.lastname: Zhang
authors.affiliation: Tesaro Inc, Waltham, Massachusetts, USA.
authors.forename: D
authors.initials: D
authors.lastname: Powers
authors.affiliation: Tesaro Inc, Waltham, Massachusetts, USA.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.affiliation: Tesaro Inc, Waltham, Massachusetts, USA.
authors.forename: S
authors.initials: S
authors.lastname: Lu
authors.affiliation: Tesaro Inc, Waltham, Massachusetts, USA.
authors.forename: V
authors.initials: V
authors.lastname: Kansra
mesh_terms: D000328:Adult; D001682:Biological Availability; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D064729:Neurokinin-1 Receptor Antagonists / Q000378:metabolism* / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography / Q000379:methods*; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D013141:Spiro Compounds / Q000378:metabolism* / Q000493:pharmacokinetics
chemical_list: D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1; D013141:Spiro Compounds; C578834:rolapitant