A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Emend Pharmacology, Pharmacokinetics, Studies, Metabolism - Aprepitant
Emend Pharmacology, Pharmacokinetics, Studies, Metabolism - Aprepitant
CLINICAL PHARMACOLOGY
Mechanism of Action
Aprepitant is a selective high-affinity antagonist of human
substance Plneurokinin 1 (NK1) receptors. Aprepitant has little or
no affinity for serotonin (5-HT3), dopamine, and corticosteroid receptors,
the targets of existing therapies for chemotherapy-induced nausea and vomiting
(CI NV) .
Aprepitant has been shown in animal models to inhibit emesis
induced by cytotoxic chemotherapeutic agents, such as cisplatin, via central
actions. Animal and human Positron Emission Tomography (PET) studies with aprepitant
have shown that it crosses the blood brain barrier and occupies brain NK1
receptors. Animal and human studies show that aprepitant augments the antiemetic
activity of the 5-HT3-receptor antagonist ondansetron and the corticosteroid
dexamethasone and inhibits both the acute and delayed phases of cisplatininduced
emesis.
Pharmacokinetics
Absorption
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 19.6 mcg.hr/mL and 21.2 mcg.hr/mL on Day 1 and Day 3, respectively.
The Cmax of 1.6 mcg/mL and 1.4 mcg/mL were reached in approximately
4 hours (Tmax) on Day 1 and Day 3, respectively.
Distribution
Aprepitant is greater than 95% bound to plasma proteins. The
mean apparent volume of
distribution at steady state (Vd,,) is approximately 70 L in
humans.
Aprepitant crosses the placenta in rats and rabbits and crosses
the blood brain barrier in
humans (see CLINICAL PHARMACOLOGY,
Mechanism of Action).
Metabolism
Aprepitant undergoes extensive metabolism. In vitro studies
using human liver microsomes indicate that aprepitant is metabolized primarily
by CYP3A4 with minor metabolism by CYPlA2 and CYP2C19. Metabolism is largely
via oxidation at the morpholine ring and its side chains. No metabolism by CYP2D6,
CYP2C9, or CYP2E1 was detected. 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.
Excretion
Following administration of a single IV 100-mg dose of [14C]-aprepitant
prodrug to healthy subjects, 57% of the radioactivity was recovered in urine
and 45% in feces. A study was not conducted with radiolabeled capsule formulation.
The results after oral administration may differ.
Aprepitant is eliminated primarily by metabolism; aprepitant
is not renally excreted. The
apparent plasma clearance of aprepitant ranged from approximately
62 to 90 mL/min. The apparent terminal half-life ranged from approximately 9
to 13 hours.
Special Populations
Gender
Following oral administration of a single 125-mg dose of EMEND,
no difference in AUC0-24hr was observed between males and females.
The Cmax for aprepitant is 16% higher in females as compared with
males. The half-life of aprepitant is 25% lower in females as compared with
males and,,T occurs at approximately the same time. These differences are not
considered clinically meaningful. No dosage adjustment for EMEND is necessary
based on gender.
Geriatric
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 (265
years) relative to younger adults. The Cmax was 10% higher on Day
1 and 24% higher on Day5 in elderly relative to younger adults. These differences
are not considered clinically meaningful. No dosage adjustment for EMEND is
necessary in elderly patients.
Pediatric
The pharmacokinetics of EMEND have not been evaluated in patients
below 18 years of age.
Race
Following oral administration of a single 125-mg dose of EM,END,
the AUC0-24hr is approximately 25% and 29% higher in Hispanics as
compared with Whites and Blacks, respectively. The Cmax is 22% and
31% higher in Hispanics as compared with Whites and Blacks, respectively. These
differences are not considered clinically meaningful. There was no difference
in AUC0-24hr or C,,, between Whites and Blacks. No dosage adjustment
for EMEND is necessary based on race.
Hepatic Insufficiency
EMEND was well tolerated in patients with mild to moderate
hepatic insufficiency. Following administration of a single 125-mg dose of EMEND
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 (Child-Pugh
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 for EMEND 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) (see PRECAUTIONS).
Renal Insufficiency
A single 240-mg dose of EMEND 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 hernodialysis, 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 for EMEND is necessary for patients with
renal insufficiency or for patients with ESRD undergoing hemodialysis.
Clinical Studies
Oral administration of EMEND in combination with ondansetron
and dexamethasone (aprepitant regimen) has been shown to prevent acute and delayed
nausea and vomiting associated with highly emetogenic chemotherapy including
high-dose cisplatin.
In 2 multicenter, randomized, parallel, double-blind, controlled
clinical studies, the aprepitant regimen (see table below) was compared with
standard therapy in patients receiving a chemotherapy regimen that included
cisplatin >50 mg/m2 (mean cisplatin dose = 80.2 mg/m2).
Of the 550 patients who were randomized to receive the aprepitant regimen, 42%
were women, 58% men, 59% White, 3% Asian, 5% Black, 12% Hispanic American, and
21% Multi-Racial. The aprepitant-treated patients in these clinical studies
ranged from 14 to 84 years of age, with a mean age of 56 years. 170 patients
were 65 years or older, with 29 patients being 75 years or older.
Patients (N = 1105) were randomized to either the aprepitant
regimen (N = 550) or standard therapy (N = 555). The treatment regimens are
defined in the table below.
Treatment Regimens
|
Treatment Regimen
|
Day1
|
Days 2 to 4
|
|
Aprepitant
|
Aprepitant 125 mg PO
|
Aprepitant 80mg PO Daily (Days 2 and 3 only
|
| |
Dexamethasone 12 mg PO
|
Dexamethasone 8 mg PO-Daily (morning)
|
| |
Ondansetron 32mg IV
|
|
|
Standard Theraphy
|
Dexamethasone 20mg PO
|
Dexamethasone 8mg PO Daily (morning)
|
| |
Ondansetron 32mg IV
|
Dexamethasone 8mg PO Daily (evening)
|
During these studies 95% of the patients in the aprepitant
group received a concomitant chemotherapeutic agent in addition to protocol-mandated
cisplatin. The most common chemotherapeutic agents and the number of aprepitant
patients exposed follows: etoposide (106), fluorouracil (100), gemcitabine (89),
vinorelbine (82), paclitaxel (52), cyclophosphamide (50), doxorubicin (38),
docetaxel (11).
The antiemetic activity of EMEND was evaluated during the acute
phase (0 to 24 hours postcisplatin treatment), the delayed phase (25 to 120
hours post-cisplatin treatment) and overall (0 to 120 hours post-cisplatin treatment)
in Cycle 1. Efficacy was based on evaluation of the following endpoints:
Primary endpoint:
· complete response (defined as no
emetic episodes and no use of rescue therapy) Other prespecified (secondary
and exploratory) endpoints:
· complete protection
(defined as no emetic episodes, no use of rescue therapy, and a maximum nausea
visual analogue scale VAS] score <25 mm on a 0 to 100 mm scale)
· no emesis (defined
as no emetic episodes regardless of use of rescue therapy)
· no nausea (maximum
VAS <5 mm on a 0 to 100 mm scale)
· no significant
nausea (maximum VAS < 2 5 mm on a 0 to 100 mm scale)
A summary of the key study results from each individual study
analysis is shown in Table 1 and Table 2.
|
Table 1
|
|
Percent of Patients Responding by Treatment Group and
Phase for Study 1 - Cycle 1
|
|
ENDPOINTS
|
Aprepitant Regimen (N= 260)† %
|
Standard Therapy (N= 261) † %
|
p-Value
|
|
PRIMARY ENDPOINT
|
|
|
|
|
Complete Response
|
|
|
|
|
Overall ‡
|
73
|
52
|
<0.001
|
|
OTHER PRESPECIFIED (SECONDARY AND EXPLORATORY) ENDPOINTS
|
|
Complete Response
|
|
Acute phase §
|
89
|
78
|
<0.001
|
|
Delayed phase"
|
75
|
56
|
<0.001
|
|
Complete Protection
|
|
Overall
|
63
|
49
|
0.001
|
|
Acute phase
|
85
|
75
|
0.005
|
|
Delayed phase
|
66
|
52
|
<0.001
|
|
No Emesis
|
|
Overall
|
78
|
55
|
<0.001
|
|
Acute phase
|
90
|
79
|
0.001
|
|
Delayed phase
|
81
|
59
|
<0.001
|
|
No Nausea
|
|
Overall
|
48
|
44
|
>0.050
|
|
Delayed phase
|
51
|
48
|
>0.050
|
|
No Significant Nausea
|
|
Overall
|
73
|
66
|
>0.050
|
|
Delayed phase
|
75
|
69
|
>0.050
|
|
†N: Number of patients (older than 18 years
of age) who received cisplatin, study drug, and had at least one post-treatment
efficacy evaluation.
|
|
Overall: 0 to 120 hours post-cisplatintreatment.
|
|
§Acute phase: 0 to 24 hours post-cisplatintreatment.
|
|
"Delayed phase: 25 to 120 hours post-cisplatin treatment.
|
|
Visual analogue scale (VAS) score range: 0 mm
no nausea: 100 mm nausea as bad as it could be.
|
|
Table 1 includes nominal p-values not adjusted for multiplicity.
|
|
Table 2
|
|
Percent of Patients Responding by Treatment Group and
Phase for Study 2 - Cycle 1
|
|
ENDPOINTS
|
Aprepitant Regimen (N= 261)† %
|
Standard Therapy (N= 263) † %
|
p-Value
|
|
PRIMARY ENDPOINT
|
|
|
|
|
Complete Response
|
|
|
|
|
Overall ‡
|
63
|
43
|
<0.001
|
|
OTHER PRESPECIFIED (SECONDARY AND EXPLORATORY) ENDPOINTS
|
|
Complete Response
|
|
Acute phase §
|
a3
|
68
|
<0.001
|
|
Delayed phase"
|
68
|
47
|
<0.001
|
|
Complete Protection
|
|
Overall
|
56
|
41
|
<0.001
|
|
Acute phase
|
a0
|
65
|
<0.001
|
|
Delayed phase
|
61
|
44
|
<0.001
|
|
No Emesis
|
|
Overall
|
66
|
44
|
<0.001
|
|
Acute phase
|
84
|
69
|
<0.001
|
|
Delayed phase
|
72
|
48
|
<0.001
|
|
No Nausea
|
|
Overall
|
49
|
39
|
0.021
|
|
Delayed phase
|
53
|
40
|
0.004
|
|
No Singnificant Nausea
|
|
Overall
|
71
|
64
|
>0.050
|
|
Delayed phase
|
73
|
65
|
>0.050
|
|
† N: Number of patients (older than 18 years
of age) who received cisplatin, study drug, and had at least one post-treatment
efficacy evaluation.
|
|
Overall: 0 to 120 hours post-cisplatintreatment.
|
|
§ Acute phase: 0 to 24 hours post-cisplatintreatment.
|
|
"Delayed phase: 25 to 120 hours post-cisplatintreatment.
|
|
Visual analogue scale (VAS) score range: 0 mm = no nausea;
100 mm = nausea as bad as it could be.
|
|
Table 2 includes nominal p-values not adjusted for multiplicity.
|
In both studies, a statistically significantly higher proportion
of patients receiving the aprepitant regimen in Cycle 1 had a complete response
(primary endpoint), compared with patients receiving standard therapy. A statistically
significant difference in complete response in favor of the aprepitant regimen
was also observed when the acute phase and the delayed phase were analyzed separately.
In both studies, the estimated time to first emesis after initiation
of cisplatin treatment was longer with the aprepitant regimen, and the incidence
of first emesis was reduced in the aprepitant regimen group compared with standard
therapy group as depicted in the Kaplan-Meier curves in Figure 1.
Patient-Reported Outcomes: The impact of nausea and vomiting
on patients’ daily lives was assessed in Cycle 1 of both Phase III studies using
the Functional Living Index-Emesis (FLIE), a validated nausea- and vomiting-specific
patient-reported outcome measure. Minimal or no impact of nausea and vomiting
on patients’ daily lives is defined as a FLIE total score >108. In each of
the 2 studies, a higher proportion of patients receiving the aprepitant regimen
reported minimal or no impact of nausea and vomiting on daily life (Study 1:
74% versus 64%; Study 2: 75% versus 64%).
Multiple-Cycle Extension: In the same 2 clinical studies,
patients continued into the Multiple- Cycle extension for up to 5 additional
6 cycles of chemotherapy. The proportion of patients with no emesis and no significant
nausea by treatment group at each cycle is depicted in Figure 2. Antiemetic
effectiveness for the patients receiving the aprepitant regimen is maintained
throughout repeat cycles for those patients continuing in each of the multiple
cycles.
top
