A Single‐Dose Bioequivalence and Food Effect Study With Aprepitant and Fosaprepitant Dimeglumine in Healthy Young Adult Subjects

Abstract

Fosaprepitant dimeglumine, a lyophilized prodrug, is rapidly converted to aprepitant, a substance P/neurokinin 1 (NK1 ) receptor antagonist. Intravenous (IV) fosaprepitant and oral aprepitant are used in combination with other antiemetics to prevent chemotherapy-induced nausea and vomiting. This randomized, phase 1 study was designed to assess the aprepitant area under the curve (AUC0-∞ ) equivalence of a single, oral 165-mg or 185-mg dose of aprepitant to a single 150-mg fosaprepitant IV dose infused over 20 minutes, and to evaluate the effect of food on the bioavailability of the oral 165-mg and 185-mg aprepitant doses. Plasma samples were analyzed for aprepitant, and linear mixed-effects models were applied to natural log-transformed aprepitant AUC data. A 2 one-sided tests procedure was used to evaluate bioequivalence; the adjusted P values for the AUC0-∞ of both oral doses versus the IV dose were < .05, supporting the hypothesis that each single, oral dose of aprepitant is equivalent to the AUC0-∞ of a single IV infusion of fosaprepitant. Food effect results suggest that dose adjustment would not be necessary with a single oral dose of aprepitant. Single-dose administration of oral 165 mg and 185 mg aprepitant and IV 150 mg fosaprepitant was generally well tolerated.

Differential clinical pharmacology of rolapitant in delayed chemotherapy-induced nausea and vomiting (CINV)

“…Fosaprepitant is the active prodrug of aprepitant that could be administered intravenously, and the dose of fosaprepitant is 150 mg on day 1 only and it has similar kinetics and efficacy to oral aprepitant. 25 NEPA (netupitant and palonosetron combination) has the privilege of being an exclusively oral regimen that can be administered once before chemotherapy. 26 With all of the previously mentioned NK-1 inhibitors, dose modifications for dexamethasone and precautions in concurrent use with warfarin are required; many drug interactions develop as a result of the activation of CYP3A4.…”

Relative bioavailability of an extemporaneously prepared aprepitant oral suspension in healthy adults

“…Based on the two one-sided test procedure, ensuring that the entire 90% CI of the geometric mean ratio of AUC 0–inf falls completely between 80% and 125%, using 80% power and α=0.05, assuming a maximum difference between test and reference products of 5%, and using an average intrasubject variability for AUC of 18.8% based on aprepitant capsule data in adolescents and adults, 6,16,21,22 17 evaluable study volunteers were required.…”