Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, The Netherlands
Pharmacotherapeutic group: Antiemetics and antinauseants
ATC code: A04AD12
Fosaprepitant is the prodrug of aprepitant and when administered intravenously is converted rapidly to aprepitant (see section 5.2). 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.
In a randomized, parallel, double-blind, active-controlled study, IVEMEND 150 mg (N=1,147) was compared with a 3-day aprepitant regimen (N=1,175) in adult patients receiving a HEC regimen that included cisplatin (≥70 mg/m²). The fosaprepitant regimen consisted of fosaprepitant 150 mg on Day 1 in combination with ondansetron 32 mg IV on Day 1 and dexamethasone 12 mg on Day 1, 8 mg on Day 2, and 8 mg twice daily on Days 3 and 4. The aprepitant regimen consisted of aprepitant 125 mg on Day 1 and 80 mg/day on Days 2 and 3 in combination with ondansetron 32 mg IV on Day 1 and dexamethasone 12 mg on Day 1 and 8 mg daily on Days 2 through 4. Fosaprepitant placebo, aprepitant placebo, and dexamethasone placebo (in the evenings on Days 3 and 4) were used to maintain blinding (see section 4.2). Although a 32 mg intravenous dose of ondansetron was used in clinical trials, this is no longer the recommended dose. See the product information for the selected 5-HT3 antagonist for appropriate dosing information.
Efficacy was based on evaluation of the following composite measures: complete response in both the overall and delayed phases and no vomiting in the overall phase. IVEMEND 150 mg was shown to be non-inferior to that of the 3-day regimen of aprepitant. A summary of the primary and secondary endpoints is shown in Table 7.
Table 7. Percent of adult patients receiving Highly Emetogenic Chemotherapy responding by treatment group and phase — Cycle 1:
| ENDPOINTS* | Fosaprepitant regimen (N=1,106)**% | Aprepitant regimen (N=1,134)**% | Difference† (95% CI) |
|---|---|---|---|
| Complete response‡ | |||
| Overall§ | 71.9 | 72.3 | -0.4 (-4.1, 3.3) |
| Delayed phase§§ | 74.3 | 74.2 | 0.1 (-3.5, 3.7) |
| No vomiting | |||
| Overall§ | 72.9 | 74.6 | -1.7 (-5.3, 2.0) |
* Primary endpoint is bolded.
** N: Number of adult patients included in the primary analysis of complete response.
† Difference and confidence interval (CI) were calculated using the method proposed by Miettinen and Nurminen and adjusted for gender.
‡ Complete response = no vomiting and no use of rescue therapy.
§ Overall = 0 to 120 hours post-initiation of cisplatin chemotherapy.
§§ Delayed phase = 25 to 120 hours post-initiation of cisplatin chemotherapy.
In a randomized, parallel, double-blind, placebo-controlled study, IVEMEND 150 mg (N=502) in combination with ondansetron and dexamethasone was compared with ondansetron and dexamethasone alone (control regimen) (N=498) in adult patients receiving a moderately emetogenic chemotherapy regimen. The fosaprepitant regimen consisted of fosaprepitant 150 mg on Day 1 in combination with oral ondansetron 8 mg for 2 doses and oral dexamethasone 12 mg. On Days 2 and 3, patients in the fosaprepitant group received placebo for ondansetron every 12 hours. The control regimen consisted of fosaprepitant placebo 150 mg IV on Day 1 in combination with oral ondansetron 8 mg for 2 doses and oral dexamethasone 20 mg. On Days 2 and 3, patients in the control group received 8 mg oral ondansetron every 12 hours. Fosaprepitant placebo and dexamethasone placebo (on Day 1) were used to maintain blinding.
The efficacy of fosaprepitant was evaluated based on the primary and secondary endpoints listed in Table 8 and was shown to be superior to the control regimen with regard to complete response in the delayed and overall phases.
Table 8. Percent of adult patients receiving Moderately Emetogenic Chemotherapy responding by treatment group and phase:
| ENDPOINTS* | Fosaprepitant regimen (N=502)**% | Control regimen (N=498)**% | P-Value |
|---|---|---|---|
| Complete response† | |||
| Delayed phase‡ | 78.9 | 68.5 | <0.001 |
| Complete response† | |||
| Overall§ | 77.1 | 66.9 | <0.001 |
| Acute phase§§ | 93.2 | 91 | 0.184 |
* Primary endpoint is bolded.
** N: Number of adult patients included in the intention to treat population.
† Complete response = no vomiting and no use of rescue therapy.
‡ Delayed phase = 25 to 120 hours post-initiation of chemotherapy.
§ Overall = 0 to 120 hours post-initiation of chemotherapy.
§§ Acute= 0 to 24 hours post-initiation of chemotherapy
The estimated time to first emesis is depicted by the Kaplan-Meier plot in Figure 1.
Figure 1. Percent of adult patients receiving Moderately Emetogenic Chemotherapy who remain emesis free over time:
In 3 active-controlled, open-label clinical studies, paediatric patients aged 6 months to 17 years received either highly or moderately emetogenic chemotherapy and a single dose of fosaprepitant at or above the recommended 1-day regimen dose (139 patients) or 3-day regimen (199 patients), in combination with ondansetron with or without dexamethasone.
The efficacy of the 1-day fosaprepitant regimen in paediatric patients was extrapolated from that demonstrated in adults receiving the 1-day fosaprepitant regimen as described in the 1-Day Regimen of Fosaprepitant in Adults subsection. The efficacy of a 1-day fosaprepitant regimen in paediatric patients is expected to be similar to that of the 1-day adult fosaprepitant regimen.
The efficacy of the 3-day fosaprepitant regimen in paediatric patients was based on that demonstrated in paediatric patients receiving the 3-day oral aprepitant regimen. The efficacy of a 3-day fosaprepitant regimen in paediatric patients is expected to be similar to that of the 3-day oral aprepitant regimen. See the summary of product characteristics for EMEND capsules and EMEND powder for oral suspension for complete clinical information regarding studies performed with oral 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.
Following a single intravenous 150-mg dose of fosaprepitant administered as a 20-minute infusion to healthy adult volunteers, the mean AUC0-∞ of aprepitant was 35.0 μg·hr/ml and the mean maximal aprepitant concentration was 4.01 μg/ml.
Aprepitant is highly protein bound, with a mean of 97%. The geometric mean volume of distribution at steady state (Vdss) of aprepitant estimated from a single 150 mg intravenous dose of fosaprepitant is approximately 82 l in humans.
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.
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.
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).
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 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 haemodialysis, 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 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.
As part of a 3-day IV/IV/IV regimen, simulated median AUC 0-24hr of aprepitant with median peak plasma concentration (Cmax) 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:
| Population | 3-day IV/IV/IV dose | AUC0-24hr. (ng*hr/mL) | Cmax (ng/mL) | C24 (ng/mL) | C48 (ng/mL) | C72 (ng/mL) |
|---|---|---|---|---|---|---|
| 12 – 17 years old | 115mg, 80mg, 80mg | 21172 | 2475 | 454 | 424 | 417 |
| 6 - <12 years old | 3mg/kg, 2mg/kg, 2mg/kg | 25901 | 2719 | 518 | 438 | 418 |
| 2 - <6 years old | 20568 | 2335 | 336 | 248 | 232 | |
| 6 months – <2 years old | 16979 | 1916 | 256 | 179 | 167 |
In the 1-day IV fosaprepitant setting, simulated median AUC0-24hr of aprepitant with median peak plasma concentration (Cmax) 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 AUC0-24hr with median peak plasma concentration (Cmax) 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:
| Population | 1-day IV dose | AUC0-24hr. (ng*hr/mL) | Cmax (ng/mL) | C24 (ng/mL) | C48 (ng/mL) | C72 (ng/mL) |
|---|---|---|---|---|---|---|
| 12 – 17 years old | 150 mg | 30400 | 3500 | 735 | NR | NR |
| 6 - <12 years old | 4 mg/kg | 35766 | 3637 | 746 | 227 | 69.2 |
| 2 - <6 years old | 28655 | 3150 | 494 | 108 | 23.5 | |
| 6 months – <2 years old | 5 mg/kg | 30484 | 3191 | 522 | 112 | 24.4 |
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.
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 Tmax, 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 Cmax 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.
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