Mechanism of Action
Palonosetron is a 5-HT3 receptor antagonist with a strong binding
affinity for this receptor and little or no affinity for other receptors.
Cancer chemotherapy may be associated with a high incidence of nausea and vomiting,
particularly when certain agents, such as cisplatin, are used. 5-HT3
receptors are located on the nerve terminals of the vagus in the periphery and
centrally in the chemoreceptor trigger zone of the area postrema. It is thought
that chemotherapeutic agents produce nausea and vomiting by releasing serotonin
from the enterochromaffin cells of the small intestine and that the released
serotonin then activates 5-HT3 receptors located on vagal afferents
to initiate the vomiting reflex.
Pharmacodynamics
The effect of palonosetron on blood pressure, heart rate, and ECG parameters
including QTc were comparable to ondansetron and dolasetron in clinical trials.
In non-clinical studies palonosetron possesses the ability to block ion channels
involved in ventricular de- and re-polarization and to prolong action potential
duration. In clinical trials, the dose-response relationship to the QTc interval
has not been fully evaluated.
Pharmacokinetics
After intravenous dosing of palonosetron in healthy subjects and cancer patients,
an initial decline in plasma concentrations is followed by a slow elimination
from the body. Mean maximum plasma concentration (Cmax) and area under the concentration-time
curve (AUC0-∞ ) are generally dose-proportional over the dose
range of 0.3-90 mcg/kg in healthy subjects and in cancer patients. Following
single IV dose of palonosetron at 3 mcg/kg (or 0.21 mg/70 kg) to six cancer
patients, mean (±SD) maximum plasma concentration was estimated to be
5.6 ± 5.5 ng/mL and mean AUC was 35.8 ± 20.9 ng•hr/mL. Following
IV administration of palonosetron 0.25 mg once every other day for 3 doses in
11 cancer patients, the mean increase in plasma palonosetron concentration from
Day 1 to Day 5 was 42±34%. Following IV administration of palonosetron
0.25 mg once daily for 3 days in 12 healthy subjects, the mean (±SD)
increase in plasma palonosetron concentration from Day 1 to Day 3 was 110±45%.
Distribution
Palonosetron has a volume of distribution of approximately 8.3 ± 2.5
L/kg. Approximately 62% of palonosetron is bound to plasma proteins.
Metabolism
Palonosetron is eliminated by multiple routes with approximately 50% metabolized
to form two primary metabolites: N-oxide-palonosetron and 6-S-hydroxy-palonosetron.
These metabolites each have less than 1% of the 5-HT3 receptor antagonist
activity of palonosetron. In vitro metabolism studies have suggested
that CYP2D6 and to a lesser extent, CYP3A4 and CYP1A2 are involved in the metabolism
of palonosetron. However, clinical pharmacokinetic parameters are not significantly
different between poor and extensive metabolizers of CYP2D6 substrates.
Elimination
After a single intravenous dose of 10 mcg/kg [14C]-palonosetron,
approximately 80% of the dose was recovered within 144 hours in the urine with
palonosetron representing approximately 40% of the administered dose. In healthy
subjects, the total body clearance of palonosetron was 160 ± 35 mL/h/kg
and renal clearance was 66.5± 18.2 mL/h/kg. Mean terminal elimination
half-life was approximately 40 hours.
Clinical studies
Efficacy of single-dose palonosetron injection in preventing acute and delayed
nausea and vomiting induced by both moderately and highly emetogenic chemotherapy
was studied in three Phase 3 trials and one Phase 2 trial. In these double-blind
studies, complete response rates (no emetic episodes and no rescue medication)
and other efficacy parameters were assessed through at least 120 hours after
administration of chemotherapy. The safety and efficacy of palonosetron in repeated
courses of chemotherapy was also assessed.
Moderately Emetogenic Chemotherapy
Two Phase 3, double-blind trials involving 1132 patients compared single-dose
IV ALOXI with either single-dose IV ondansetron (study 1) or dolasetron (study
2) given 30 minutes prior to moderately emetogenic chemotherapy including carboplatin,
cisplatin ≤50 mg/m², cyclophosphamide <1500 mg/m², doxorubicin
>25 mg/m², epirubicin, irinotecan, and methotrexate >250 mg/m².
Concomitant corticosteroids were not administered prophylactically in study
1 and were used by 4-6% of patients in study 2. The majority of patients in
these studies were women (77%), White (65%) and naïve to previous chemotherapy
(54%). The mean age was 55 years.
Highly Emetogenic Chemotherapy
A Phase 2, double-blind, dose-ranging study evaluated the efficacy of single-dose
IV palonosetron from 0.3 to 90 mcg/kg (equivalent to < 0.1 mg to 6 mg fixed
dose) in 161 chemotherapy-naïve adult cancer patients receiving highly-emetogenic
chemotherapy (either cisplatin 70 mg/m² or cyclophosphamide > 1100 mg/m²).
Concomitant corticosteroids were not administered prophylactically. Analysis
of data from this trial indicates that 0.25 mg is the lowest effective dose
in preventing acute nausea and vomiting induced by highly emetogenic chemotherapy.
A Phase 3, double-blind trial involving 667 patients compared single-dose IV
ALOXI with single-dose IV ondansetron (study 3) given 30 minutes prior to highly
emetogenic chemotherapy including cisplatin 60 mg/m², cyclophosphamide
> 1500 mg/m², and dacarbazine. Corticosteroids were co-administered
prophylactically before chemotherapy in 67% of patients. Of the 667 patients,
51% were women, 60% White, and 59% naïve to previous chemotherapy. The
mean age was 52 years.
Efficacy Results
The antiemetic activity of ALOXI was evaluated during the acute phase (0-24
hours) [Table 2], delayed phase (24-120 hours) [Table 3], and overall phase
(0-120 hours) [Table 4] post-chemotherapy in Phase 3 trials.
Table 2: Prevention of Acute Nausea and Vomiting (0-24 hours):
Complete Response Rates
| Chemotherapy |
Study |
Treatment
Group |
N
a |
%
with Complete
Response |
p-value b |
97.5% Confidence Interval
ALOXI minus Comparator c |
| Moderately Emetogenic |
1 |
ALOXI
0.25 mg |
189 |
81 |
0.009 |
|
Ondansetron
32 mg IV |
185 |
69 |
| 2 |
ALOXI
0.25 mg |
189 |
63 |
NS |
Dolasetron
100 mg IV |
191 |
53 |
| Highly Emetogenic |
3 |
ALOXI
0.25 mg |
223 |
59 |
NS |
Ondansetron
32 mg IV |
221 |
57 |
|
a Intent-to-treat cohort
b 2-sided Fisher's exact test. Significance level at α=0.025.
c These studies were designed to show non-inferiority. A
lower bound greater than -15% demonstrates non-inferiority between ALOXI
and comparator.
|
These studies show that ALOXI was effective in the prevention of acute nausea
and vomiting associated with initial and repeat courses of moderately and highly
emetogenic cancer chemotherapy. In study 3, efficacy was greater when prophylactic
corticosteroids were administered concomitantly. Clinical superiority over other
5-HT3 receptor antagonists has not been adequately demonstrated in the acute
phase.
Table 3: Prevention of Delayed Nausea and Vomiting (24-120
hours): Complete Response Rates
| Chemotherapy
|
Study
|
Treatment Group
|
N a
|
% with Complete Response
|
p-value b
|
97.5% Confidence Interval ALOXI minus Comparator
c
|
| Moderately Emetogenic |
1 |
ALOXI
0.25 mg |
189 |
74 |
<0.001 |
|
Ondansetron
32 mg IV |
185 |
55 |
| 2 |
ALOXI
0.25 mg |
189 |
54 |
0.004 |
Dolasetron
100 mg IV |
191 |
39 |
a Intent-to-treat cohort
b 2-sided Fisher's exact test. Significance level at α=0.025.
c These studies were designed to show non-inferiority. A lower
bound greater than -15% demonstrates non-inferiority between ALOXI and comparator.
|
These studies show that ALOXI was effective in the prevention of delayed nausea
and vomiting associated with initial and repeat courses of moderately emetogenic
chemotherapy.
Table 4: Prevention of Overall Nausea and Vomiting (0-120
hours): Complete Response Rates
| Chemotherapy |
Study |
Treatment Group |
N a |
% with Complete Response |
p-value b |
97.5% Confidence Interval ALOXI minus Comparator
c |
| Moderately Emetogenic |
1 |
ALOXI
0.25 mg |
189 |
69 |
<0.001 |
|
| Ondansetron32 mg IV |
185 |
50 |
| 2 |
ALOXI
0.25 mg |
189 |
46 |
0.021 |
Dolasetron
100 mg IV |
191 |
34 |
a Intent-to-treat cohort
b 2-sided Fisher's exact test. Significance level at α=0.025.
c These studies were designed to show non-inferiority. A lower
bound greater than -15% demonstrates non-inferiority between ALOXI and comparator.
|
These studies show that ALOXI was effective in the prevention of nausea and
vomiting throughout the 120 hours (5 days) following initial and repeat courses
of moderately emetogenic cancer chemotherapy.
Last updated on RxList: 9/27/2007