Fosemred Mechanism of Action

Pharmacology: Pharmacodynamics: 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.
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 at human substance P neurokinin 1 (NK1) receptors. Counter-screening assays showed that aprepitant was at least 3,000-fold selective for the NK1 receptor over other enzyme, transporter, ion channel and receptor sites including the dopamine and serotonin receptors that are targets for existing CINV therapy.
NK1-receptor antagonists have been shown pre-clinically to inhibit emesis induced by cytotoxic chemotherapeutic agents, such as cisplatin, via central actions. Preclinical and human Positron Emission Tomography (PET) data with aprepitant have shown that it is brain penetrant and occupies brain NK1 receptors. Preclinical data show that aprepitant has a long duration of central activity, inhibits both the acute and delayed phases of cisplatin-induced emesis, and augments the antiemetic activity of the 5-HT3-receptor antagonist ondansetron and the corticosteroid dexamethasone against cisplatin-induced emesis.
Pharmacokinetics: Absorption: Following a single intravenous 150 mg dose of fosaprepitant administered as a 20-minute infusion to healthy volunteers the mean AUC0-∞ of aprepitant was 35.0 mcg∙hr/ml and the mean maximal aprepitant concentration was 4.01 mcg/ml.
Distribution: Fosaprepitant is rapidly converted to aprepitant.
Aprepitant is greater than 95% bound to plasma proteins. The geometric mean apparent volume of distribution at steady state (Vdss) is approximately 66 L in humans.
Aprepitant crosses the placenta in rats, and crosses the blood brain barrier in rats and ferrets. PET data in humans indicate that aprepitant crosses the blood brain barrier (see Pharmacology: Pharmacodynamics: Mechanism of Action as previously mentioned).
Metabolism: Fosaprepitant was rapidly converted to aprepitant 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.
Aprepitant undergoes extensive metabolism. In healthy young adults, aprepitant accounts for approximately 24% of the radioactivity in plasma over 72 hours following a single oral 300-mg dose of [14C]-aprepitant, indicating a substantial presence of metabolites in the plasma. Seven metabolites of aprepitant, which are only weakly active, have been identified in human plasma. The metabolism of aprepitant occurs largely via oxidation at the morpholine ring and its side chains. Data using human liver microsomes indicate that aprepitant is metabolized primarily by CYP3A4 with minor metabolism by CYP1A2 and CYP2C19, and no metabolism by CYP2D6, CYP2C9, or CYP2E1.
All metabolites observed in urine, feces and plasma following an intravenous 100 mg [14C]- fosaprepitant dose were also observed following an oral dose of [14C]-aprepitant. Upon conversion of 245.3 mg of fosaprepitant dimeglumine (equivalent to 150 mg fosaprepitant free acid) to aprepitant, 23.9 mg of phosphoric acid and 95.3 mg of meglumine are liberated.
Elimination: Following administration of a single IV 100 mg dose of [14C]-fosaprepitant to healthy patients, 57% of the radioactivity was recovered in urine and 45% in feces.
Aprepitant is eliminated primarily by metabolism; aprepitant is not renally excreted. Following administration of a single oral 300 mg dose of [14C]-aprepitant to healthy patients, 5% of the radioactivity was recovered in urine and 86% in feces.
The apparent terminal half-life of aprepitant ranged from approximately 9 to 13 hours.
Characteristics in Patients: Fosaprepitant, a prodrug of aprepitant, when administered intravenously is rapidly converted to aprepitant.
Gender: Following oral administration of a single dose of aprepitant, the AUC0-24hr and Cmax for aprepitant are 9% and 17% higher, respectively, in females as compared with males. The half-life of aprepitant is approximately 25% lower in females as compared with males and its Tmax occurs at approximately the same time. These differences are not considered clinically meaningful. No dosage adjustment is necessary based on gender.
Elderly: Following oral administration of a single 125 mg dose of aprepitant on Day 1 and 80 mg once daily on Days 2 through 5, the AUC0-24hr of aprepitant was 21% higher on Day 1 and 36% higher on Day 5 in elderly (≥ 65 years) relative to younger adults. The Cmax was 10% higher on Day 1 and 24% higher on Day 5 in elderly relative to younger adults. These differences are not considered clinically meaningful. No dosage adjustment is necessary in elderly patients.
Race: Following oral administration of a single dose of aprepitant, the AUC0-24hr is approximately 27% and 31% higher in Hispanics as compared with Caucasians and Blacks, respectively. The Cmax is 19% and 29% higher in Hispanics as compared with Caucasians and Blacks, respectively. Single dose administration of oral aprepitant in Asians resulted in a 74% and 47% increase in AUC0-24hr and Cmax, respectively, as compared to Caucasians. These differences are not considered clinically meaningful. No dosage adjustment is necessary based on race.
Body Mass Index (BMI): Body Mass Index (BMI) had no clinically meaningful effect on the pharmacokinetics of aprepitant.
Hepatic Insufficiency: Fosaprepitant is metabolized in various extrahepatic tissues; therefore, hepatic insufficiency is not expected to alter the conversion of fosaprepitant to aprepitant.
Oral aprepitant was well tolerated in patients with mild to moderate hepatic insufficiency. Following administration of a single 125 mg dose of oral aprepitant on Day 1 and 80 mg once daily on Days 2 and 3 to patients with mild hepatic insufficiency (Child-Pugh score 5 to 6), the AUC0-24hr of aprepitant was 11% lower on Day 1 and 36% lower on Day 3, as compared with healthy patients given the same regimen. In patients with moderate hepatic insufficiency (Child-Pugh score 7 to 9), the AUC0-24hr of aprepitant was 10% higher on Day 1 and 18% higher on Day 3, as compared with healthy patients given the same regimen. These differences in AUC0- 24hr are not considered clinically meaningful; therefore, no dosage adjustment is necessary in patients with mild to moderate hepatic insufficiency.
There are no clinical or pharmacokinetic data in patients with severe hepatic insufficiency (Child-Pugh score >9).
Renal Insufficiency: A single 240 mg dose of oral aprepitant was administered to patients with severe renal insufficiency (CrCl<30 ml/min) and to patients with end stage renal disease (ESRD) requiring hemodialysis.
In patients with severe renal insufficiency, the AUC0-∞ of total aprepitant (unbound and protein bound) decreased by 21% and Cmax decreased by 32%, relative to healthy patients. In patients with ESRD undergoing hemodialysis, the AUC0-∞ of total aprepitant decreased by 42% and Cmax decreased by 32%. Due to modest decreases in protein binding of aprepitant in patients with renal disease, the AUC of pharmacologically active unbound drug was not significantly affected in patients with renal insufficiency compared with healthy patients. Hemodialysis conducted 4 or 48 hours after dosing had no significant effect on the pharmacokinetics of aprepitant; less than 0.2% of the dose was recovered in the dialysate.
No dosage adjustment is necessary for patients with severe renal insufficiency or for patients with ESRD undergoing hemodialysis.