Estimation of brain NK₁ receptor occupancy after fosnetupitant administration and its contribution to antiemetic efficacy in Japanese patients

抄録

[Objective] This study estimated brain neurokinin-1 (NK₁) receptor occupancy (RO) after the administration of fosnetupitant (FosNTP), a prodrug of netupitant (NETU) which is an NK₁ receptor antagonist. Moreover, the contribution of NK₁ RO to the antiemetic efficacy of FosNTP in Japanese cancer patients was also examined. [Method] Brain (striatal) NK₁ RO was estimated for 168 h after the administration of FosNTP at the dose of 81 mg and 235 mg in the patients, using NETU plasma concentrations simulated by population PK and the reported PK/PD model¹⁾. [Results and discussion] NK₁ RO was highly maintained for a longer period after a dose of 235 mg compared with that after a dose of 81 mg. At 235 mg, NK₁ RO was estimated to be approximately 50% at 168 h. NK₁ RO was also related to the efficacy results observed in the no-vomiting rate every 24 h from 24-168 h across the two doses. [Conclusion] The long-lasting blockade of FosNTP (235 mg dose) to brain NK₁ receptors, based on the long plasma half-life of NETU, may contribute to its antiemetic efficacy not only in the delayed phase (24-120 h) but also beyond 120 h. [Reference] 1) Spinelli T, et al. J Clin Pharmacol. 2014;54:97-108.