Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: Antiemetics and antinauseants, ATC code: A04AD12 
Aprepitant is a selective high-affinity antagonist at human substance P neurokinin 1 (NK1) receptors.

3-day regimen of aprepitant
In 2 randomised, double-blind studies encompassing a total of 1,094 adult patients receiving chemotherapy that included cisplatin ≥70 mg/m2, aprepitant in combination with an ondansetron/dexamethasone regimen (see section 4.2) was compared with a standard regimen (placebo plus ondansetron 32 mg intravenously administered on Day 1 plus dexamethasone 20 mg orally on Day 1 and 8 mg orally twice daily on Days 2 to 4). 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 measure: complete response (defined as no emetic episodes and no use of rescue therapy) primarily during Cycle 1. The results were evaluated for each individual study and for the 2 studies combined.


A summary of the key study results from the combined analysis is shown in Table 1.

Table 1
Percent of adult patients receiving Highly Emetogenic Chemotherapy responding by treatment group and phase — Cycle 1

Aprepitant         Standard                   Differences* regimen            therapy
COMPOSITE MEASURES                                        (N= 521) †        (N= 524) † %                  %               %           (95 % CI)

Complete response (no emesis and no rescue therapy)
Overall (0-120 hours)               67.7           47.8                                        19.9         (14.0, 25.8) 0-24 hours                          86.0           73.2                                        12.7         (7.9, 17.6) 25-120 hours                        71.5           51.2                                        20.3         (14.5, 26.1)

INDIVIDUAL MEASURES
No emesis (no emetic episodes regardless of use of rescue therapy)
Overall (0-120 hours)                71.9            49.7         22.2                                     (16.4, 28.0) 0-24 hours                           86.8            74.0         12.7                                     (8.0, 17.5) 25-120 hours                         76.2            53.5         22.6                                     (17.0, 28.2)
No significant nausea (maximum VAS <25 mm on a scale of 0-100 mm)
Overall (0-120 hours)                72.1            64.9         7.2                                      (1.6, 12.8) 25-120 hours                         74.0            66.9         7.1                                      (1.5, 12.6)
* The confidence intervals were calculated with no adjustment for gender and concomitant chemotherapy, which were included in the primary analysis of odds ratios and logistic models.
†
One patient in the Aprepitant regimen only had data in the acute phase and was excluded from the overall and delayed phase analyses; one patient in the Standard regimen only had data in the delayed phase and was excluded from the overall and acute phase analyses.

The estimated time to first emesis in the combined analysis is depicted by the Kaplan-Meier plot in Figure 1.

Figure 1
Percent of adult patients receiving Highly Emetogenic Chemotherapy who remain emesis free over time – Cycle 1

100%                                Aprepitant Regimen (N=520)
Standard Therapy (N=523)
90%
Percent of Patients


80%

70%

60%
50%

40%
0
0   12   24   36   48   60    72      84   96    108      120

Time (hours)
Statistically significant differences in efficacy were also observed in each of the 2 individual studies.


In the same 2 clinical studies, 851 adult patients continued into the Multiple-Cycle extension for up to 5 additional cycles of chemotherapy. The efficacy of the aprepitant regimen was apparently maintained during all cycles.

In a randomised, double-blind study in a total of 866 adult patients (864 females, 2 males) receiving chemotherapy that included cyclophosphamide 750-1,500 mg/m2; or cyclophosphamide 500- 1,500 mg/m2 and doxorubicin (≤60 mg/m2) or epirubicin (≤100 mg/m2), aprepitant in combination with an ondansetron/dexamethasone regimen (see section 4.2) was compared with standard therapy (placebo plus ondansetron 8 mg orally (twice on Day 1, and every 12 hours on Days 2 and 3) plus dexamethasone 20 mg orally on Day 1).

Efficacy was based on evaluation of the composite measure: complete response (defined as no emetic episodes and no use of rescue therapy) primarily during Cycle 1.

A summary of the key study results is shown in Table 2.

Table 2
Percent of adult patients responding by treatment group and phase —Cycle 1 Moderately Emetogenic Chemotherapy
Aprepitant      Standard              Differences* regimen        therapy
COMPOSITE MEASURES                   (N= 433)†      (N= 424)
%              %             %        (95 % CI)

Complete response (no emesis and no rescue therapy)
Overall (0-120 hours)               50.8           42.5                        8.3         (1.6, 15.0) 0-24 hours                          75.7           69.0                        6.7         (0.7, 12.7) 25-120 hours                        55.4           49.1                        6.3         (-0.4, 13.0)

INDIVIDUAL MEASURES
No emesis (no emetic episodes regardless of use of rescue therapy)
Overall (0-120 hours)                75.7            58.7         17.0                     (10.8, 23.2) 0-24 hours                           87.5            77.3         10.2                     (5.1, 15.3) 25-120 hours                         80.8            69.1         11.7                     (5.9, 17.5)
No significant nausea (maximum VAS <25 mm on a scale of 0-100 mm)
Overall (0-120 hours)                60.9            55.7         5.3                      (-1.3, 11.9) 0-24 hours                           79.5            78.3         1.3                      (-4.2, 6.8) 25-120 hours                         65.3            61.5         3.9                      (-2.6, 10.3)
* The confidence intervals were calculated with no adjustment for age category (<55 years, ≥55 years) and investigator group, which were included in the primary analysis of odds ratios and logistic models.
†
One patient in the aprepitant regimen only had data in the acute phase and was excluded from the overall and delayed phase analyses.

In the same clinical study, 744 adult patients continued into the Multiple-Cycle extension for up to 3 additional cycles of chemotherapy. The efficacy of the aprepitant regimen was apparently maintained during all cycles.

In a second multicentre, randomised, double-blind, parallel-group, clinical study, the aprepitant regimen was compared with standard therapy in 848 adult patients (652 females, 196 males) receiving a chemotherapy regimen that included any intravenous dose of oxaliplatin, carboplatin, epirubicin, idarubicin, ifosfamide, irinotecan, daunorubicin, doxorubicin; cyclophosphamide intravenously (< 1500 mg/m2); or cytarabine intravenously (> 1 g/m2). Patients receiving the aprepitant regimen were receiving chemotherapy for a variety of tumour types including 52 % with breast cancer, 21 % with gastrointestinal cancers including colorectal cancer, 13 % with lung cancer and 6 % with gynaecological cancers. The aprepitant regimen in combination with an ondansetron/dexamethasone regimen (see section 4.2) was compared with standard therapy (placebo in combination with 
ondansetron 8 mg orally (twice on Day 1, and every 12 hours on Days 2 and 3) plus dexamethasone 20 mg orally on Day 1).

Efficacy was based on the evaluation of the following primary and key secondary endpoints: No vomiting in the overall period (0 to 120 hours post-chemotherapy), evaluation of safety and tolerability of the aprepitant regimen for chemotherapy induced nausea and vomiting (CINV), and complete response (defined as no vomiting and no use of rescue therapy) in the overall period (0 to 120 hours post-chemotherapy). Additionally, no significant nausea in the overall period (0 to 120 hours post-chemotherapy) was evaluated as an exploratory endpoint, and in the acute and delayed phases as a post-hoc analysis.

A summary of the key study results is shown in Table 3.

Table 3
Percent of adult patients responding by treatment group and phase for Study 2 – Cycle 1 Moderately Emetogenic Chemotherapy

Aprepitant        Standard                 Differences* regimen           therapy
(N= 425)         (N= 406)
%                 %               %          (95 % CI)

Complete response (no emesis and no rescue therapy)
Overall (0-120 hours)                68.7             56.3        12.4                    (5.9, 18.9) 0-24 hours                           89.2            80.3         8.9                     (4.0, 13.8) 25-120 hours                         70.8            60.9         9.9                     (3.5, 16.3)
No emesis (no emetic episodes regardless of use of rescue therapy)
Overall (0-120 hours)                76.2             62.1        14.1                    (7.9, 20.3) 0-24 hours                           92.0             83.7        8.3                     (3.9, 12.7) 25-120 hours                         77.9             66.8        11.1                    (5.1, 17.1)
No significant nausea (maximum VAS < 25 mm on a scale of 0-100 mm)
Overall (0-120 hours)                73.6             66.4        7.2                     (1.0, 13.4) 0-24 hours                           90.9            86.3         4.6                     (0.2, 9.0) 25-120 hours                         74.9            69.5         5.4                     (-0.7, 11.5)

*The confidence intervals were calculated with no adjustment for gender and region, which were included in the primary analysis using logistic models.

The benefit of aprepitant combination therapy in the full study population was mainly driven by the results observed in patients with poor control with the standard regimen such as in women, even though the results were numerically better regardless of age, tumour type or gender. Complete response to the aprepitant regimen and standard therapy, respectively, was reached in 209/324 (65 %) and 161/320 (50 %) in women and 83/101 (82 %) and 68/87 (78 %) of men.

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

Pharmacokinetic Properties