Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

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.

Highly Emetogenic Chemotherapy (HEC)
In a randomized, parallel, double-blind, active-controlled study, EMEND IV 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. EMEND IV 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 1.
Table 1
Percent of adult patients receiving Highly Emetogenic Chemotherapy responding by treatment group and phase — Cycle 1


ENDPOINTS*                             Fosaprepitant         Aprepitant              Difference† regimen             regimen                (95 % CI)
(N =1,106) **        (N =1,134) **
%                   %
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 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.

Moderately Emetogenic Chemotherapy (MEC)
In a randomized, parallel, double-blind, placebo-controlled study, EMEND IV 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 2 and was shown to be superior to the control regimen with regard to complete response in the delayed and overall phases.

Table 2
Percent of adult patients receiving Moderately Emetogenic Chemotherapy responding by treatment group and phase

ENDPOINTS*                           Fosaprepitant         Control                P-Value regimen             regimen
(N =502) **         (N =498) **
%                   %
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

100

80
Percent of Patients



60

40


20         Fosaprepitant Regimen(N=502)
Control Regimen(N=498)
0
0    12    24   36    48    60    72   84     96   108 120
Time(hours) Since the First MEC Administration


Paediatric population
Studies evaluating the use of fosaprepitant in paediatric patients are on-going (see section 4.2 for information on paediatric use).

Pharmacokinetic Properties