Fosaprepitant, a prodrug of aprepitant, when administered intravenously is rapidly converted to aprepitant, a substance P/neurokinin 1 (NK1) receptor antagonist. Plasma concentrations of fosaprepitant are below the limits of quantification (10 ng/mL) within 30 minutes of the completion of infusion (see CLINICAL PHARMACOLOGY, Pharmacokinetics). Upon conversion of 115 mg of fosaprepitant to aprepitant, 18.3 mg of phosphate and 73 mg of meglumine are liberated from fosaprepitant.

Mechanism of Action

Fosaprepitant is a prodrug of aprepitant and accordingly, its antiemetic effects are attributable to aprepitant.

Aprepitant is a selective high-affinity antagonist of human substance P/neurokinin 1 (NK₁) receptors. Aprepitant has little or no affinity for serotonin (5-HT₃), dopamine, and corticosteroid receptors, the targets of existing therapies for chemotherapy-induced nausea and vomiting (CINV). Aprepitant has been shown in animal models to inhibit emesis induced by cytotoxic chemotherapeutic agents, such as cisplatin, via central actions. Animal and human Positron Emission Tomography (PET) studies with aprepitant have shown that it crosses the blood brain barrier and occupies brain NK₁ receptors. Animal and human studies show that aprepitant augments the antiemetic activity of the 5-HT₃-receptor antagonist ondansetron and the corticosteroid dexamethasone and inhibits both the acute and delayed phases of cisplatin-induced emesis.

Pharmacokinetics

Aprepitant after Fosaprepitant Administration

Following a single intravenous dose of fosaprepitant administered as a 15-minute infusion to healthy volunteers the mean AUC_0-∞ of aprepitant was 31.7 (± 14.3) mcg•hr/mL and the mean maximal aprepitant concentration (Cmax) was 3.27 (± 1.16) mcg/mL. The mean aprepitant plasma concentration at 24 hours postdose was similar between the 125-mg oral aprepitant dose and the 115-mg intravenous fosaprepitant dose (See Figure 1).

Figure 1: Mean Plasma Concentration of Aprepitant Following 125-mg Oral Aprepitant and 115-mg I.V. Fosaprepitant

Distribution

Fosaprepitant is rapidly converted to aprepitant. Aprepitant is greater than 95% bound to plasma proteins. The mean apparent volume of distribution at steady state (Vd_ss) is approximately 70 L in humans.

Aprepitant crosses the placenta in rats and rabbits and crosses the blood brain barrier in humans (see CLINICAL PHARMACOLOGY, Mechanism of Action).

Metabolism

Fosaprepitant was rapidly converted to aprepitant in in vitro incubations with liver preparations from nonclinical species (rat and dog) and humans. Furthermore, fosaprepitant underwent rapid and nearly complete conversion to aprepitant in S9 preparations from multiple other human tissues including kidney, lung and ileum. Thus, it appears that the conversion of fosaprepitant to aprepitant can occur in multiple extrahepatic tissues in addition to the liver. In humans, fosaprepitant administered intravenously was rapidly converted to aprepitant within 30 minutes following the end of infusion.

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