Source: Health Products and Food Branch (CA) Revision Year: 2018
Fosaprepitant is a prodrug of aprepitant and accordingly, its antiemetic effects are attributable to aprepitant.
Aprepitant has a unique mode of action; it 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 therapies.
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) studies with aprepitant have shown that it is brain penetrant and occupies brain NK1 receptors. Preclinical studies 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.
Table 5. Summary of pharmacokinetic parameters of EMEND in healthy subjects:
| Cmax (μg/mL) | AUC0-24hr (μg•hr/mL) | |
|---|---|---|
| Day 1 oral dose aprepitant 125 mg | 1.5 | 19.5 |
| Day 3 oral dose aprepitant 80 mg | 1.4 | 20.1 |
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 37.38 (± 14.75) mcg•hr/mL and the mean maximal aprepitant concentration was 4.15 (± 1.15) mcg/mL.
The mean absolute oral bioavailability of aprepitant is approximately 60 to 65% and the mean peak plasma concentration (Cmax) of aprepitant occurred at approximately 4 hours (Tmax). Oral administration of the capsule with a standard breakfast had no clinically meaningful effect on the bioavailability of aprepitant.
The pharmacokinetics of aprepitant are non-linear across the clinical dose range. In healthy young adults, the increase in AUC0-∞ was 26% greater than dose proportional between 80-mg and 125-mg single doses administered in the fed state.
Following oral administration of a single 125 mg dose of EMEND on Day 1 and 80 mg once daily on Days 2 and 3, the AUC0-24hr was approximately 19.5 μg•hr/mL and 20.1 μg•hr/mL on Day 1 and Day 3, respectively. The Cmax of 1.5 μg/mL and 1.4 μg/mL were reached in approximately 4 hours (Tmax) on Day 1 and Day 3, respectively.
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 studies in humans indicate that aprepitant crosses the blood brain barrier (see ACTION AND CLINICAL PHARMACOLOGY).
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.
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. In vitro studies 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.
Excretion: Following administration of a single IV 100 mg dose of [14C]-fosaprepitant to healthy subjects, 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 subjects, 5% of the radioactivity was recovered in urine and 86% in feces.
The apparent plasma clearance of aprepitant ranged from approximately 60 to 84 mL/min. The apparent terminal half-life ranged from approximately 9 to 13 hours.
NK1 Receptor Occupancy: A positron emission tomography study in healthy young men administered a single intravenous dose of 150 mg fosaprepitant (N=8) with coadministration of 32 mg IV ondansetron on Day 1 and oral dexamethasone (12/8/16/16-mg) on Days 1, 2, 3, and 4 demonstrated mean brain NK1 receptor occupancy values (%) and corresponding mean aprepitant plasma concentrations (µg/mL) at Tmax, 24, 48, and 120 hours post-dose, as shown below in Table 6.
Table 6. Brain NK1-Receptor Occupancy (%) and Aprepitant Plasma Concentration (µg/mL) Following Intravenous Administration of 150 mg Fosaprepitant:
| Postdose Time Points | N | Brain NK1-Receptor Occupancy Arithmetic Mean (%) | Aprepitant Plasma Concentration Arithmetic Mean (µg/mL) |
|---|---|---|---|
| Tmax | 2 | 100 | 2.4 |
| 24 hours | 5 | 100 | 0.8 |
| 48 hours | 4 | 99 | 0.3 |
| 120 hours | 3 | 62 | BLOQ |
BLOQ: Below the Limit of Quantitation of the Assay (<0.01 µg/mL).
However, the relationship between NK1 receptor occupancy and the clinical efficacy of aprepitant has not been established.
Cardiac Electrophysiology: In a randomized, double-blind, positive-controlled, thorough QTc study, a single 200 mg dose of fosaprepitant had no effect on the QTc interval.
Pediatrics: The pharmacokinetics of EMEND and EMEND IV have not been evaluated in patients below 18 years of age.
Geriatrics: Following oral administration of a single 125 mg dose of EMEND 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 for EMEND is necessary in elderly patients.
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 halflife of aprepitant is approximately 25% lower in females as compared with males and its Tmax occurs at approximately the same time. No dosage adjustment is necessary based on gender.
Race: Following oral administration of a single dose of aprepitant, there was no difference in the AUC0-24hr or Cmax between Caucasians and Blacks. Single dose administration of oral aprepitant in Hispanics resulted in a 27% and 19% increase in AUC0-24hr and Cmax, respectively, as compared to Caucasians. 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): For every 5 kg/m² increase in BMI, AUC0–24h decreased by 8.5% and Cmax decreased by 10.2%. These differences are not considered clinically meaningful. No dosage adjustment is necessary based on BMI.
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 subjects given the same regimen. In patients with moderate hepatic insufficiency (ChildPugh 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 subjects 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 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 subjects. 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 subjects. 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.
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.
Dexamethasone: Fosaprepitant 150 mg administered as a single intravenous dose on Day 1 increased the AUC0–24hr of dexamethasone, a CYP3A4 substrate, by approximately 2.01, 1.86 and 1.18-fold on Days 1, 2 and 3 respectively when dexamethasone was coadministered as a single 8 mg oral dose on Days 1, 2, and 3. The oral dexamethasone dose on Days 1 and 2 should be reduced by approximately 50% when coadministered with fosaprepitant 150 mg IV on Day 1 to achieve exposures of dexamethasone similar to those obtained when given without fosaprepitant 150 mg.
Oral aprepitant, when given as a regimen of 125 mg with dexamethasone coadministered orally as 20 mg on Day 1, and oral aprepitant when given as 80 mg/day with dexamethasone coadministered orally as 8 mg on Days 2 through 5, increased the AUC of dexamethasone, a CYP3A4 substrate by 2.2-fold, on Days 1 and 5. The daily dose of dexamethasone administered in clinical CINV studies with oral aprepitant reflects an approximate 50% reduction of the dose of dexamethasone (see DOSAGE AND ADMINISTRATION).
Methylprednisolone: Oral aprepitant, when given as a regimen of 125 mg on Day 1 and 80 mg/day on Days 2 and 3, increased the AUC of methylprednisolone, a CYP3A4 substrate, by 1.3-fold on Day 1 and by 2.5-fold on Day 3, when methylprednisolone was coadministered intravenously as 125 mg on Day 1 and orally as 40 mg on Days 2 and 3.
Warfarin: A single 125 mg dose of aprepitant was administered on Day 1 and 80 mg/day on Days 2 and 3 to healthy subjects who were stabilized on chronic warfarin therapy. Although there was no effect of oral aprepitant on the plasma AUC of R(+) or S( - ) warfarin determined on Day 3, there was a 34% decrease in S( - ) warfarin (a CYP2C9 substrate) trough concentration accompanied by a 14% decrease in the prothrombin time (reported as International Normalized Ratio or INR) 5 days after completion of dosing with oral aprepitant. In patients on chronic warfarin therapy, the prothrombin time (INR) should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of fosaprepitant with each chemotherapy cycle (see WARNINGS AND PRECAUTIONS).
Tolbutamide: Oral aprepitant, when given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, decreased the AUC of tolbutamide (a CYP2C9 substrate) by 23% on Day 4, 28% on Day 8, and 15% on Day 15, when a single dose of tolbutamide 500 mg was administered orally prior to the administration of the 3-day regimen of oral aprepitant and on Days 4, 8, and 15.
Oral contraceptives: Aprepitant, when given once daily for 14 days as a 100-mg capsule with an oral contraceptive containing 35 mcg of ethinyl estradiol and 1 mg of norethindrone, decreased the AUC of ethinyl estradiol by 43%, and decreased the AUC of norethindrone by 8%; therefore the efficacy of hormonal contraceptives during and for 28 days after administration of fosaprepitant may be reduced. Alternative or back-up methods of contraception should be used during treatment with fosaprepitant and for 1 month following administration (see WARNINGS AND PRECAUTIONS).
Midazolam: Fosaprepitant 150 mg administered as a single intravenous dose on Day 1 increased the AUC0-∞ of midazolam by approximately 1.8-fold on Day 1 and had no effect (1.0-fold) on Day 4 when midazolam was coadministered as a single oral dose of 2 mg on Days 1 and 4. Fosaprepitant 150 mg IV is a weak CYP3A4 inhibitor as a single dose on Day 1 with no evidence of inhibition or induction of CYP3A4 observed on Day 4.
In addition, when fosaprepitant was administered as a dose of 100 mg over 15 minutes along with a single dose of midazolam 2 mg, the plasma AUC of midazolam was increased by 1.6-fold.
Oral aprepitant increased the AUC of midazolam, a sensitive CYP3A4 substrate, by 2.3-fold on Day 1 and 3.3-fold on Day 5, when a single oral dose of midazolam 2 mg was coadministered on Day 1 and Day 5 of a regimen of oral aprepitant 125 mg on Day 1 and 80 mg/day on Days 2 through 5. The potential effects of increased plasma concentrations of midazolam or other benzodiazepines metabolized via CYP3A4 (alprazolam, triazolam) should be considered when coadministering these agents with fosaprepitant or aprepitant.
In another study with intravenous administration of midazolam, oral aprepitant was given as 125 mg on Day 1 and 80 mg/day on Days 2 and 3, and midazolam 2 mg IV was given prior to the administration of the 3-day regimen of oral aprepitant and on Days 4, 8, and 15. Oral aprepitant increased the AUC of midazolam by 25% on Day 4 and decreased the AUC of midazolam by 19% on Day 8 relative to the dosing of oral aprepitant on Days 1 through 3. These effects were not considered clinically important. The AUC of midazolam on Day 15 was similar to that observed at baseline.
An additional study was completed with intravenous administration of midazolam and oral aprepitant. Intravenous midazolam 2 mg was given 1 hour after oral administration of a single dose of oral aprepitant 125 mg. The plasma AUC of midazolam was increased by 1.5-fold. Depending on clinical situations (e.g., elderly patients) and degree of monitoring available, dosage adjustment for intravenous midazolam may be necessary when it is coadministered with aprepitant for the chemotherapy induced nausea and vomiting indication (125 mg on Day 1 followed by 80 mg on Days 2 and 3).
Ketoconazole: When a single 125 mg dose of oral aprepitant was administered on Day 5 of a 10-day regimen of 400 mg/day of ketoconazole, a strong CYP3A4 inhibitor, the AUC of aprepitant increased approximately 5-fold and the mean terminal half-life of aprepitant increased approximately 3-fold. Concomitant administration of fosaprepitant with strong CYP3A4 inhibitors should be approached cautiously.
Rifampin: When a single 375 mg dose of oral aprepitant was administered on Day 9 of a 14-day regimen of 600 mg/day of rifampin, a strong CYP3A4 inducer, the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased approximately 3-fold. Coadministration of fosaprepitant with drugs that induce CYP3A4 activity may result in reduced plasma concentrations and decreased efficacy.
Diltiazem: In a study in 10 patients with mild to moderate hypertension, intravenous infusion of 100 mg of fosaprepitant over 15 minutes with diltiazem 120 mg 3 times daily, resulted in a 1.5-fold increase of aprepitant AUC and a 1.4-fold increase in diltiazem AUC. It also resulted in a small but clinically meaningful further maximum decrease in diastolic blood pressure [mean (SD) of 24.3 (± 10.2) mm Hg with fosaprepitant versus 15.6 (± 4.1) mm Hg without fosaprepitant] and resulted in a small further maximum decrease in systolic blood pressure [mean (SD) of 29.5 (±7.9) mm Hg with fosaprepitant versus 23.8 (± 4.8) mm Hg without fosaprepitant], which may be clinically meaningful, but did not result in a clinically meaningful further change in heart rate or PR interval, beyond those changes induced by diltiazem alone.
Paroxetine: Coadministration of once daily doses of aprepitant, as a tablet formulation comparable to 85 mg or 170 mg of the capsule formulation, with paroxetine 20 mg once daily, resulted in a decrease in AUC by approximately 25% and Cmax by approximately 20% of both aprepitant and paroxetine.
The approximate oral LD50 of aprepitant was >2000 mg/kg in female mice and rats. The approximate intraperitoneal LD50 of aprepitant was >800 mg/kg, but <2000 mg/kg in female rats and >2000 mg/kg in female mice.
The approximate LD50 of fosaprepitant following intravenous administration was >500 mg/kg in female mice and >200 mg/kg in female rats
Fosaprepitant, when administered intravenously, is rapidly converted to aprepitant.
The toxicity potential of aprepitant was evaluated in a series of repeated-dose oral toxicity studies in rats and in dogs for up to 1 year.
In rats, oral administration of aprepitant for 6 months at doses up to the maximum feasible dose of 1000 mg/kg twice daily (approximately equivalent to [females] or lower than [males] the adult human dose based on systemic exposure following oral aprepitant 125 mg) produced increased hepatic weights that correlated with hepatocellular hypertrophy, increased thyroidal weights that correlated with thyroid follicular cell hypertrophy and/or hyperplasia, and pituitary cell vacuolation. These findings are a species-specific consequence of hepatic CYP enzyme induction in the rat, and are consistent with changes observed in rats with other structurally and pharmacologically dissimilar compounds that have been shown to induce hepatic CYP enzymes.
In dogs administered aprepitant orally for 9 months at doses ≥5 mg/kg twice daily (greater than or equal to 13 times the adult human dose based on systemic exposure following oral aprepitant 125 mg), toxicity was characterized by slight increases in serum alkaline phosphatase activity and decreases in the albumin/globulin ratio. Significantly decreased body weight gain, testicular degeneration, and prostatic atrophy were observed at doses ≥25 mg/kg twice daily (greater than or equal to 31 times the adult human dose based on systemic exposure following oral aprepitant 125 mg). A slight increase in hepatic weights with no histologic correlate was seen at 500 mg/kg twice daily (70 times the adult human dose based on systemic exposure following oral aprepitant 125 mg). No toxicity was observed in dogs administered 32 mg/kg/day (6 times the adult human dose based on systemic exposure following oral aprepitant 125 mg) for 1 year.
In rabbits, EMEND IV caused initial focal acute inflammation when administered intravenously, paravenously, and subcutaneously. Focal skeletal muscle degeneration and necrosis with associated neutrophilic inflammation were noted with intramuscular injection. At the end of the follow-up period (post-dose day 8), paravenous injection sites showed focal subacute inflammation. Intramuscular injection site changes consisted of focal skeletal muscle necrosis and mineralization bordered by subacute inflammation and focal skeletal muscle regeneration.
Carcinogenicity studies were conducted in mice and rats for approximately 2 years with oral aprepitant. In mice, aprepitant was not carcinogenic at doses up to 500 mg/kg/day (approximately 2 times the adult human dose based on systemic exposure). Rats developed hepatocellular adenomas at a dose of 25 mg/kg twice daily (females) and 125 mg/kg twice daily (females and males), thyroid follicular cell adenomas at a dose of 125 mg/kg twice daily (females and males), and thyroid follicular cell carcinomas at a dose of 125 mg/kg twice daily (males). Systemic exposures at these doses in rats were approximately equivalent to or lower than exposures in humans at the recommended dose. Tumors of these types are a speciesspecific consequence of hepatic CYP enzyme induction in the rat, and are consistent with changes observed in rats with other structurally and pharmacologically dissimilar compounds that have been shown to induce hepatic CYP enzymes. Carcinogenicity studies were not conducted with fosaprepitant.
Fosaprepitant and aprepitant were neither mutagenic nor genotoxic in assays conducted to detect mutagenicity, DNA strand breaks, and chromosomal aberrations. Aprepitant was negative in the in vitro microbial and TK6 human lymphoblastoid cell mutagenesis assays, the in vitro alkaline elution/rat hepatocyte DNA strand break test, the in vitro chromosomal aberration assay in Chinese hamster ovary cells, and the in vivo mouse micronucleus assay in bone marrow.
Fosaprepitant, when administered intravenously, is rapidly converted to aprepitant. In the fertility studies conducted with fosaprepitant and aprepitant, the highest systemic exposures to aprepitant were obtained following oral administration of aprepitant.
Aprepitant administered to female rats at doses up to the maximum feasible dose of 1000 mg/kg twice daily (approximately equivalent to the adult human dose based on systemic exposure following oral aprepitant 125 mg) had no effects on mating performance, fertility, or embryonic/fetal survival.
Administration of aprepitant to male rats at doses up to the maximum feasible dose of 1000 mg/kg twice daily (lower than the adult human dose based on systemic exposure following oral aprepitant 125 mg) produced no effects on mating performance, fertility, embryonic/fetal survival, sperm count and motility, testicular weights, or the microscopic appearance of the testes and epididymides.
Fosaprepitant, when administered intravenously, is rapidly converted to aprepitant. In the teratology studies conducted with fosaprepitant and aprepitant, the highest systemic exposures to aprepitant were obtained following oral administration of aprepitant.
In rats and rabbits administered oral doses of aprepitant up to 1000 mg/kg twice daily and 25 mg/kg/day, respectively (up to 1.5 times the systemic exposure at the adult human dose following oral aprepitant 125 mg), there was no evidence of developmental toxicity as assessed by embryonic/fetal survival, fetal body weight, and fetal external, visceral, and skeletal morphology. Placental transfer of aprepitant occurred in rats and rabbits at these doses. Concentrations of aprepitant in fetal plasma were approximately 27% and 56% of maternal plasma concentrations in rats and rabbits, respectively.
Significant concentrations of aprepitant were observed in the milk of lactating rats administered 1000 mg/kg twice daily. At this dose, the mean milk drug concentration was 90% of the mean maternal plasma concentration.
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