CLINICAL PHARMACOLOGY
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.
Postoperative nausea and vomiting is influenced by
multiple patient, surgical, and anesthesia related factors and is triggered by
release of 5-HT in a cascade of neuronal events involving both the central
nervous system and the gastrointestinal tract. The 5-HT3 receptor
has been demonstrated to selectively participate in the emetic response.
Pharmacodynamics
The effect of palonosetron on blood pressure, heart rate,
and ECG parameters including QTc were comparable to ondansetron and dolasetron
in CINV clinical trials. In PONV clinical trials the effect of palonosetron on
the QTc interval was no different from placebo. 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.
The effect of palonosetron on QTc interval was evaluated
in a double blind, randomized, parallel, placebo, and positive (moxifloxacin)
controlled trial in adult men and women. The objective was to evaluate the ECG
effects of I.V. administered palonosetron at single doses of 0.25, 0.75, or
2.25 mg in 221 healthy subjects. The study demonstrated no significant effect
on any ECG interval including QTc duration (cardiac repolarization) at doses up
to 2.25 mg.
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 I.V. 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 5630 ± 5480 ng/L and mean AUC was 35.8 ± 20.9
h•mcg/L.
Following I.V. 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 I.V.
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%.
After intravenous dosing of palonosetron in patients
undergoing surgery (abdominal surgery or vaginal hysterectomy), the
pharmacokinetic characteristics of palonosetron were similar to those observed
in cancer patients.
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 0.160 ± 0.035
L/h/kg and renal clearance was 0.067± 0.018 L/h/kg. Mean terminal elimination
half-life is approximately 40 hours.
Specific Populations
Pediatric Patients
Single-dose I.V. ALOXI pharmacokinetic data was obtained
from a subset of pediatric cancer patients that received 10 mcg/kg or 20
mcg/kg. When the dose was increased from 10 mcg/kg to 20 mcg/kg a
dose-proportional increase in mean AUC was observed. Following single dose
intravenous infusion of ALOXI 20 mcg/kg, peak plasma concentrations (CT)
reported at the end of the 15 minute infusion were highly variable in all age
groups and tended to be lower in patients < 6 years than in older patients.
Median half-life was 29.5 hours in overall age groups and ranged from about 20
to 30 hours across age groups after administration of 20 mcg/kg.
The total body clearance (L/h/kg) in patients 12 to 17
years old was similar to that in healthy adults. There are no apparent
differences in volume of distribution when expressed as L/kg.
Table 3: Pharmacokinetics Parameters in Pediatric
Cancer Patients Following Intravenous Infusion of ALOXI at 20 mcg/kg over 15
min
PK Parameter a |
Pediatric Age Group |
< 2 y
N=12 |
2 to < 6 y
N=42 |
6 to < 12 y
N=38 |
12 to < 17 y
N=44 |
CT b, ng/L |
9025 (197) |
9414 (252) |
16275 (203) |
11831 (176) |
|
|
N=5 |
N=7 |
N=10 |
AUC0-∞, h•mcg/L |
|
103.5 (40.4) |
98.7 (47.7) |
124.5 (19.1) |
|
N=6 |
N=14 |
N=13 |
N=19 |
Clearance c, L/h/kg |
0.31 (34.7) |
0.23 (51.3) |
0.19 (46.8) |
0.16 (27.8) |
Vss c, L/kg |
6.08 (36.5) |
5.29 (57.8) |
6.26 (40.0) |
6.20 (29.0) |
a Geometric Mean (CV) except for t½ which is
median values.
b CT is the plasma palonosetron concentration at the end
of the 15 minute infusion.
c Clearance and Vss calculated from 10 and 20 mcg/kg and are weight
adjusted. |
Clinical Studies
Chemotherapy-Induced Nausea And Vomiting In Adults
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 I.V. ALOXI with either single-dose I.V. 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 only 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 I.V. 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 I.V. ALOXI with single-dose I.V. 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 4], delayed phase (24-120 hours) [Table 5], and
overall phase (0-120 hours) [Table 6] post-chemotherapy in Phase 3 trials.
Table 4: Prevention of Acute Nausea and Vomiting (0-24
hours): Complete Response Rates
Chemotherapy |
Study |
Treatment Group |
Na |
% 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 I.V. |
185 |
69 |
|
2 |
ALOXI 0.25 mg |
189 |
63 |
NS |
Dolasetron 100 mg I.V. |
191 |
53 |
Highly Emetogenic |
3 |
ALOXI 0.25 mg |
223 |
59 |
NS |
Ondansetron 32 mg I.V. |
221 |
57 |
a Intent-to-treat cohort
b 2-sided Fisher's exact test. Significance level at &apha;=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 5: Prevention of Delayed Nausea and Vomiting
(24-120 hours): Complete Response Rates
Chemotherapy |
Study |
Treatment Group |
Na |
% 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 I.V. |
185 |
55 |
2 |
ALOXI 0.25 mg |
189 |
54 |
0.004 |
Dolasetron 100 mg I.V. |
191 |
39 |
a Intent-to-treat cohort
b 2-sided Fisher's exact test. Significance level at &apha;=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 6: 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 |
6950 |
< 0.001 |
|
Ondansetron 32 mg I.V. |
185 |
|
2 |
ALOXI 0.25 mg |
189 |
46 |
0.021 |
Dolasetron 100 mg I.V. |
191 |
34 |
a Intent-to-treat cohort
b 2-sided Fisher's exact test. Significance level at &apha;=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.
Chemotherapy-Induced Nausea And Vomiting In Pediatrics
One double-blind, active-controlled clinical trial was
conducted in pediatric cancer patients. The total population (N = 327) had a
mean age of 8.3 years (range 2 months to 16.9 years) and were 53% male; and 96%
white. Patients were randomized and received a 20 mcg/kg (maximum 1.5 mg)
intravenous infusion of ALOXI 30 minutes prior to the start of emetogenic
chemotherapy (followed by placebo infusions 4 and 8 hours after the dose of
palonosetron) or 0.15 mg/kg of intravenous ondansetron 30 minutes prior to the
start of emetogenic chemotherapy (followed by ondansetron 0.15 mg/kg infusions
4 and 8 hours after the first dose of ondansetron, with a maximum total dose of
32 mg). Emetogenic chemotherapies administered included doxorubicin,
cyclophosphamide ( < 1500 mg/m²), ifosfamide, cisplatin,
dactinomycin, carboplatin, and daunorubicin. Adjuvant corticosteroids,
including dexamethasone, were administered with chemotherapy in 55% of
patients.
Complete Response in the acute phase of the first cycle
of chemotherapy was defined as no vomiting, no retching, and no rescue
medication in the first 24 hours after starting chemotherapy. Efficacy was
based on demonstrating non-inferiority of intravenous palonosetron compared to
intravenous ondansetron. Non-inferiority criteria were met if the lower bound
of the 97.5% confidence interval for the difference in Complete Response rates
of intravenous palonosetron minus intravenous ondansetron was larger than -15%.
The non-inferiority margin was 15%.
Efficacy Results
As shown in Table 7, intravenous ALOXI 20 mcg/kg (maximum
1.5 mg) demonstrated non-inferiority to the active comparator during the 0 to
24 hour time interval.
Table 7: Prevention of Acute Nausea and Vomiting (0-24
hours): Complete Response Rates
I.V. ALOXI 20 mcg/kg
(N=165) |
I.V. Ondansetron 0.15 mg/kg x 3
(N=162) |
Difference [97.5% Confidence Interval]*: I.V. ALOXI minus I.V. Ondansetron Comparator |
59.4% |
58.6% |
0.36% [-11.7%, 12.4%] |
* To adjust for multiplicity of treatment groups, a
lower-bound of a 97.5% confidence interval was used to compare to -15%, the
negative value of the non-inferiority margin. |
In patients that received ALOXI at a lower dose than the
recommended dose of 20 mcg/kg, non-inferiority criteria were not met.
Postoperative Nausea And Vomiting
In one multicenter, randomized, stratified, double-blind,
parallel-group, phase 3 clinical study (Study 1), palonosetron was compared
with placebo for the prevention of PONV in 546 patients undergoing abdominal
and gynecological surgery. All patients received general anesthesia. Study 1
was a pivotal study conducted predominantly in the US in the out-patient
setting for patients undergoing elective gynecologic or abdominal laparoscopic
surgery and stratified at randomization for the following risk factors: gender,
non-smoking status, history of post operative nausea and vomiting and/or motion
sickness.
In Study 1 patients were randomized to receive
palonosetron 0.025 mg, 0.050 mg or 0.075 mg or placebo, each given
intravenously immediately prior to induction of anesthesia. The antiemetic
activity of palonosetron was evaluated during the 0 to 72 hour time period
after surgery.
Of the 138 patients treated with 0.075 mg palonosetron in
Study 1 and evaluated for efficacy, 96% were women; 66% had a history of PONV
or motion sickness; 85% were non-smokers. As for race, 63% were White, 20% were
Black, 15% were Hispanic, and 1% were Asian. The age of patients ranged from 21
to 74 years, with a mean age of 37.9 years. Three patients were greater than 65
years of age.
Co-primary efficacy measures were Complete Response (CR)
defined as no emetic episode and no use of rescue medication in the 0-24 and in
the 24-72 hours postoperatively.
Secondary efficacy endpoints included:
- Complete Response (CR) 0-48 and 0-72 hours
- Complete Control (CC) defined as CR and no more than mild
nausea
- Severity of nausea (none, mild, moderate, severe)
The primary hypothesis in Study 1 was that at least one
of the three palonosetron doses were superior to placebo.
Results for Complete Response in Study 1 for 0.075 mg
palonosetron versus placebo are described in the following table.
Table 8: Prevention of Postoperative Nausea and
Vomiting: Complete Response (CR), Study 1, Palonosetron 0.075 mg Vs Placebo
Treatment |
n/N (%) |
Palonosetron Vs Placebo |
Δ |
p-value* |
Co-primary Endpoints |
CR 0-24 hours |
Palonosetron |
59/138 (42.8%) |
16.8% |
0.004 |
Placebo |
35/135 (25.9%) |
|
|
CR 24-72 hours |
Palonosetron |
67/138 (48.6%) |
7.8% |
0.188 |
Placebo |
55/135 (40.7%) |
|
* To reach statistical significance for each co-primary
endpoint, the required significance limit for the lowest p-value was
p < 0.017.
Δ Difference (%): palonosetron 0.075 mg minus placebo |
Palonosetron 0.075 mg reduced the severity of nausea
compared to placebo. Analyses of other secondary endpoints indicate that
palonosetron 0.075 mg was numerically better than placebo, however, statistical
significance was not formally demonstrated.
A phase 2 randomized, double-blind, multicenter, placebo-controlled,
dose ranging study was performed to evaluate I.V. palonosetron for the
prevention of post-operative nausea and vomiting following abdominal or vaginal
hysterectomy. Five I.V. palonosetron doses (0.1, 0.3, 1.0, 3.0, and 30
μg/kg) were evaluated in a total of 381 intent-to-treat patients. The
primary efficacy measure was the proportion of patients with CR in the first 24
hours after recovery from surgery. The lowest effective dose was palonosetron 1
μg/kg (approximately 0.075 mg) which had a CR rate of 44% versus 19% for
placebo, p=0.004. Palonosetron 1 μg/kg also significantly reduced the
severity of nausea versus placebo, p=0.009.