Fosaprepitant

Fosaprepitant is the prodrug of aprepitant and when administered intravenously is converted rapidly to aprepitant. The contribution of fosaprepitant to the overall antiemetic effect has not fully been characterised, but a transient contribution during the initial phase cannot be ruled out. Aprepitant is a selective high-affinity antagonist at human substance P neurokinin 1 (NK₁) receptors. The pharmacological effect of fosaprepitant is attributed to aprepitant.

Fosaprepitant, a prodrug of aprepitant, when administered intravenously is rapidly converted to aprepitant. Plasma concentrations of fosaprepitant are below quantifiable levels within 30 minutes of the completion of infusion.

Aprepitant after fosaprepitant administration

Following a single intravenous 150-mg dose of fosaprepitant administered as a 20-minute infusion to healthy adult volunteers, the mean AUC_0-∞ of aprepitant was 35.0 μg·hr/ml and the mean maximal aprepitant concentration was 4.01 μg/ml.

Distribution

Aprepitant is highly protein bound, with a mean of 97%. The geometric mean volume of distribution at steady state (Vd_ss) of aprepitant estimated from a single 150 mg intravenous dose of fosaprepitant is approximately 82 l in humans.

Biotransformation

Fosaprepitant was rapidly converted to aprepitant in in vitro incubations with liver preparations from humans. Furthermore, fosaprepitant underwent rapid and nearly complete conversion to aprepitant in S9 preparations from other human tissues including kidney, lung and ileum. Thus, it appears that the conversion of fosaprepitant to aprepitant can occur in multiple tissues. 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 19% of the radioactivity in plasma over 72 hours following a single intravenous administration 100 mg dose of [¹⁴C]-fosaprepitant, a prodrug for aprepitant, indicating a substantial presence of metabolites in the plasma. Twelve metabolites of aprepitant have been identified in human plasma. The metabolism of aprepitant occurs largely via oxidation at the morpholine ring and its side chains and the resultant metabolites were only weakly active. In vitro studies using human liver microsomes indicate that aprepitant is metabolised primarily by CYP3A4 and potentially with minor contribution by CYP1A2 and CYP2C19.

All metabolites observed in urine, faeces 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) to aprepitant, 23.9 mg of phosphoric acid and 95.3 mg of meglumine are liberated.

Elimination

Aprepitant is not excreted unchanged in urine. Metabolites are excreted in urine and via biliary excretion in faeces. Following a single intravenously administered 100 mg dose of [¹⁴C]-fosaprepitant to healthy subjects, 57% of the radioactivity was recovered in urine and 45% in faeces.

The pharmacokinetics of aprepitant is non-linear across the clinical dose range. The terminal half-life of aprepitant following a 150 mg intravenous dose of fosaprepitant was approximately 11 hours. The geometric mean plasma clearance of aprepitant following a 150 mg intravenous dose of fosaprepitant was approximately 73 ml/min.

Pharmacokinetics in special populations

Hepatic impairment

Fosaprepitant is metabolized in various extrahepatic tissues; therefore hepatic impairment is not expected to alter the conversion of fosaprepitant to aprepitant. Mild hepatic impairment (Child-Pugh class A) does not affect the pharmacokinetics of aprepitant to a clinically relevant extent. No dose adjustment is necessary for patients with mild hepatic impairment.

Conclusions regarding the influence of moderate hepatic impairment (Child-Pugh class B) on aprepitant pharmacokinetics cannot be drawn from available data. There are no clinical or pharmacokinetic data in patients with severe hepatic impairment (Child-Pugh class C).

Renal impairment

A single 240 mg dose of oral aprepitant was administered to patients with severe renal impairment (CrCl<30 ml/min) and to patients with end stage renal disease (ESRD) requiring haemodialysis.

In patients with severe renal impairment, the AUC_0-∞ of total aprepitant (unbound and protein bound) decreased by 21% and C_max decreased by 32%, relative to healthy subjects. In patients with ESRD undergoing haemodialysis, the AUC_0-∞ of total aprepitant decreased by 42% and C_max decreased by 32%. Due to modest decreases in protein binding of aprepitant in patients with renal disease, the AUC of pharmacologically active unbound aprepitant was not significantly affected in patients with renal impairment compared with healthy subjects. Haemodialysis 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 dose adjustment is necessary for patients with renal impairment or for patients with ESRD undergoing haemodialysis.

Paediatric population

As part of a 3-day IV/IV/IV regimen, simulated median AUC 0-24hr of aprepitant with median peak plasma concentration (C_max) on Day 1 and the median concentrations at the end of Day 1, Day 2 and Day 3 in paediatric patients (6 months to 17 years old) are shown in Table 9.

Table 9. Pharmacokinetic parameters of aprepitant for 3-day IV fosaprepitant regimen in paediatric patients:

In the 1-day IV fosaprepitant setting, simulated median AUC_0-24hr of aprepitant with median peak plasma concentration (C_max) on Day 1 and the median concentrations at the end of Day 1, Day 2 and Day 3 in paediatric patients (6 months to <12 years old) and observed mean AUC_0-24hr with median peak plasma concentration (C_max) on Day 1 and mean concentrations at the end of Day 1, Day 2 and Day 3 in paediatric patients (12 to 17 years old) are shown in Table 10.

Table 10. Pharmacokinetic parameters of aprepitant for 1-day IV fosaprepitant regimen in paediatric patients:

NR = Not Reported

A population pharmacokinetic analysis of aprepitant in paediatric patients (aged 6 months through 17 years) suggests that gender and race have no clinically meaningful effect on the pharmacokinetics of aprepitant.

Relationship between concentration and effect

Positron emission tomography (PET) imaging studies, using a highly specific NK₁ receptor tracer, in healthy young men administered a single intravenous dose of 150 mg fosaprepitant (N=8) demonstrated brain NK₁ receptor occupancy of ≥100% at T_max, and 24 hours, ≥97% at 48 hours, and between 41% and 75% at 120 hours, following dosing. Occupancy of brain NK₁ receptors, in this study, correlate well with aprepitant plasma concentrations.

Pre-clinical data obtained with intravenous administration of fosaprepitant and oral administration of aprepitant reveal no special hazard for humans based on conventional studies of single and repeated dose toxicity, genotoxicity (including in vitro tests), and toxicity to reproduction and development.

Carcinogenic potential in rodents was only investigated with orally administered aprepitant. However, it should be noted that the value of the toxicity studies carried out with rodents, rabbits and monkeys, including the reproduction toxicity studies, are limited since systemic exposures to fosaprepitant and aprepitant were only similar or even lower than therapeutic exposure in adult humans. In the performed safety pharmacology and repeated dose toxicity studies with dogs, fosaprepitant C_max and aprepitant AUC values were up to 3 times and 40 times, respectively, higher than clinical values.

In a toxicity study in juvenile dogs treated with fosaprepitant from postnatal day 14 to day 42, a decreased testicular weight and Leydig cell size were seen in the males at 6 mg/kg/day and increased uterine weight, hypertrophy of the uterus and cervix, and oedema of vaginal tissues were seen in females from 4 mg/kg/day. In a juvenile toxicity study in rats treated with aprepitant from postnatal day 10 to day 63, earlier vaginal opening in females from 250 mg/kg b.i.d. and delayed preputial separation in males from 10 mg/kg b.i.d was seen. There were no treatment-related effects on mating, fertility or embryonic/foetal survival, and no pathological changes in the reproductive organs. There were no margins to clinically relevant exposure of aprepitant. For short term treatment, these findings are considered unlikely to be clinically relevant.

In laboratory animals, fosaprepitant in non-commercial formulations caused vascular toxicity and hemolysis at concentrations below 1 mg/ml and higher, dependent on the formulation. In human washed blood cells also evidence of hemolysis was found with non-commercial formulations at fosaprepitant concentrations of 2.3 mg/ml and higher, although tests in human whole blood were negative. No hemolysis was found with the commercial formulation up to a fosaprepitant concentration of 1 mg/ml in human whole blood and washed human erythrocytes.

In rabbits, fosaprepitant caused initial transient local acute inflammation following paravenous, subcutaneous and intramuscular administration. At the end of the follow-up period (post-dose day 8), up to slight local subacute inflammation was noted following paravenous and intramuscular administration and additional up to moderate focal muscle degeneration/necrosis with muscle regeneration following intramuscular administration.