Annals of Oncology 15: 330–337, 2004

Original article DOI: 10.1093/annonc/mdh047

Efficacy, safety and pharmacokinetics of palonosetron in patients

receiving highly emetogenic cisplatin-based chemotherapy:
a dose-ranging clinical study
P. Eisenberg1, F. R. MacKintosh2, P. Ritch3, P. A. Cornett4 & A. Macciocchi5*
1
California Cancer Care, Greenbrae, CA; 2VA Medical Center, Reno, NV; 3Medical College of Wisconsin, Milwaukee, WI; 4University of California at San Francisco,
San Francisco, CA, USA; 5Helsinn Healthcare SA, Lugano, Switzerland

Received 12 March 2003; revised 28 July 2003; accepted 4 September 2003

Background: Although currently available 5-hydroxytryptamine type 3 receptor (5-HT3) antagonists are
effective, not all patients receiving these agents achieve adequate control of chemotherapy-induced nausea and
vomiting (CINV). Palonosetron, a potent and highly selective 5-HT3 antagonist with a strong affinity for 5-HT3
and a prolonged plasma elimination half-life, may provide a longer duration of action than other approved
agents.
Patients and methods: One hundred and sixty-one patients were randomly assigned to receive a single intra-
venous bolus dose of palonosetron (0.3, 1, 3, 10, 30 or 90 µg/kg) before administration of highly emetogenic
chemotherapy, with no pretreatment with corticosteroids.
Results: The four highest doses of palonosetron were similarly effective during the first 24 h, producing clearly
higher complete response (CR) (no emesis, no rescue medication) rates in the 3, 10, 30 and 90 µg/kg groups
(46%, 40%, 50% and 46%, respectively) than in the 0.3–1 µg/kg group (24%) of evaluable patients (n = 148).
The 3 µg/kg dose was identified as the lowest effective dose. A single dose of palonosetron showed prolonged
efficacy in preventing delayed emesis, with approximately one-third of patients who received palonosetron
10 or 30 µg/kg maintaining a CR throughout the 7-day period following chemotherapy administration. Dose-
proportional increases in pharmacokinetic parameters and a long plasma half-life (43.7–128 h) were observed.
Palonosetron was well-tolerated, with no dose–response effect evident for the incidence or intensity of adverse
events.
Conclusions: Palonosetron is an effective and well-tolerated agent for the prevention of CINV following
highly emetogenic chemotherapy, with 3 and 10 µg/kg identified as the lowest effective palonosetron doses.
Key words: chemotherapy, dose-ranging, emesis, 5-hydroxytryptamine type 3 receptor antagonist, nausea,
palonosetron

Introduction ard therapy for preventing CINV, not all patients achieve adequate
control with these agents, and those currently marketed agents
Nausea and vomiting associated with highly emetogenic chemo-
have limited efficacy in the treatment of delayed emesis [2, 6, 7].
therapy such as cisplatin-based regimens are mediated by 5-
Therefore, there is a need to investigate new treatments and regi-
hydroxytryptamine release by gut enterochromaffin cells [1].
mens in an effort to improve the therapeutic response.
Emesis can be acute (occurring within 24 h of chemotherapy),
Palonosetron is a potent and selective 5-HT3 antagonist with a
delayed (beginning 24–48 h after chemotherapy), or in antici-
high affinity for 5-HT3 receptors (pKi = 10.45 in cultured mouse
pation of chemotherapy [2]. Chemotherapy-induced nausea and
neuroblastoma–rat glioma hybridoma cells) [8] compared with
vomiting (CINV) may result in dehydration, malnutrition or
granisetron (pKi = 8.91 in cultured mouse neuroblastoma–rat
electrolyte imbalance, which can affect quality of life, the desire to
glioma hybridoma cells) [8], ondansetron (pKi = 8.39 in cultured
continue antitumor therapy, and survival [3, 4]. Since their intro-
mouse neuroblastoma–rat glioma hybridoma cells) [8], dolasetron
duction, 5-hydroxytryptamine type 3 receptor (5-HT3) antagonists
(pKi = 7.6 in cultured neuroblastoma glioma cells) [9], tropisetron
have become the most frequently used agents in the control of
(pKi = 8.81 in cultured mouse neuroblastoma–rat glioma hybrid-
emesis resulting from moderately to highly emetogenic chemo-
oma cells) [8, 10], and azasetron (Ki = 0.33 nM in the small intes-
therapy [5]. Although 5-HT3 antagonists are currently the stand-
tines of rats) [11]. In contrast to other 5-HT3 antagonists that exist
as racemic mixtures, palonosetron exists as a single stereoisomer,
with improved pharmacological and pharmacokinetic profiles
*Correspondence to: Dr A. Macciocchi, Helsinn Healthcare SA, via Pian
Scairolo 9, 6912 Pazzallo, Lugano, Switzerland. Tel: +41-91-985-21-21; [12]. In preclinical studies, palonosetron demonstrated potent
Fax: +41-91-993-21-22; E-mail: [email protected] antiemetic properties in several standard animal models [13]. In

© 2004 European Society for Medical Oncology

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previous phase I studies in healthy volunteers, intravenous (i.v.) site. All patients provided written informed consent before being enrolled in
palonosetron (0.3–90 µg/kg) was found to be well-tolerated, with the study.
mean plasma elimination half-life (T1/2) values of ∼40 h [13], sub-
stantially longer than that of ondansetron (4–6 h) [14], hydrodola- Study visits and assessment procedures
setron (the active metabolite of dolasetron; 7 h) [15], granisetron During the week before palonosetron dosing, patients underwent a complete
(5–8 h), tropisetron (7 h) and azasetron (9 h) [2, 16, 17]. Its high physical examination, laboratory assessment (i.e. hematology, blood chem-
antiemetic potency, high binding affinity, and longer T1/2 give istry, urinalysis), vital sign measurement, and 12-lead electrocardiogram
palonosetron the potential to provide more complete and pro- (ECG). One hour before the start of chemotherapy, sitting blood pressure and
longed protection against CINV compared with currently available heart rate were measured, and patients completed a pre-dose nausea assess-
ment that consisted of a categorical scale of nausea (none, mild, moderate, or
5-HT3 antagonists. The primary objective of this study was to
severe). Blood pressure and heart rate were measured 20 min before chemo-
determine the dose–response relationship of single i.v. doses of
therapy initiation, throughout the 6-h observation period following treatment,
palonosetron (0.3–90 µg/kg) in chemotherapy-naive patients and at 24 h after the start of chemotherapy. Patients used diary cards to report
receiving highly emetogenic chemotherapy, in order to identify the number of emetic episodes and degree of nausea at 2, 4, 8, 12 and 24 h after
the lowest effective palonosetron dose that produces maximal the start of chemotherapy, as well as time of their first emetic episode (if any).
efficacy. Additional objectives included the assessment of safety Patient satisfaction with control of nausea and vomiting was evaluated every
and the pharmacokinetics of palonosetron over the range of doses 24 h via a 100-mm visual analog scale ranging from 0 (not at all satisfied) to
evaluated. 100 (completely satisfied). Patients were instructed to continue to record
emetic episodes for 1 week after dosing and to rate, on a daily basis, the degree
of nausea or the sensation of having to vomit and the degree of satisfaction
Subjects and methods with the control of nausea and vomiting.
Twenty-four hours following chemotherapy initiation, patients returned to
Subjects the clinic (if not hospitalized) to report adverse events (AEs) and concomitant
Patients at least 18 years of age with histologically proven cancer who were medications and to undergo a limited physical examination, a 12-lead ECG,
chemotherapy-naive and scheduled to receive their first dose of highly emeto- blood tests and urinalysis. Patients again returned to the clinic 1 week after
genic chemotherapy (≥70 mg/m2 cisplatin or >1100 mg/m2 cyclophosphamide) dosing for a limited physical examination, clinical laboratory evaluation, and a
[18] were enrolled. Patients were required to have a Karnofsky performance 12-lead ECG if the 24-h ECG was significantly different from the screening
status ≥60% and acceptable hepatic function (transaminases <2× upper limit of ECG. AEs and concomitant medications were recorded and diary cards were
normal) and renal function (creatinine clearance ≥50 ml/min). collected. All patients were contacted 14 days after dosing and questioned
Exclusion criteria included severe, uncontrolled, concurrent illness other regarding nausea and vomiting, concomitant medications and AEs. Any AEs
than neoplasia; unstable metastases to the brain; a history of seizures during that persisted beyond the 14-day follow-up period were followed until resolu-
adulthood; gastric outlet or intestinal obstruction; known vomiting within 24 h tion or explanation, or until 1 month after the dose.
preceding palonosetron dosing; a known hypersensitivity to other 5-HT3 Therapeutic response was evaluated by recording the occurrence of an
antagonists; previous or current exposure to highly emetogenic chemotherapies emetic episode, the degree of nausea, and the need for rescue medication. An
(i.e. dacarbazine, nitrosoureas or mechlorethamine); and participation in emetic episode was defined as (i) a single vomit of solid or liquid gastric con-
another drug study or receipt of any investigational agents within 30 days of tents; (ii) a single retch, or ‘dry heave’, that did not produce solid or liquid
study entry. Patients were excluded if they had received, within 24 h before gastric contents; or (iii) any episode of continuous vomiting or retching. Epi-
receipt of study medication, any antiemetic, sedative, corticosteroid, or other sodes separated from each other by the absence of retching or vomiting for at
drug, that, in the opinion of the investigator, could influence the results of the least 1 min were considered separate emetic episodes. Rescue medication
study. All patients (men and women) were required to practice adequate con- could be administered according to standard practice at each participating
traception for 1 month after palonosetron dosing. institution following the first emetic episode or succeeding episodes, or at
the request of the patient. A complete response (CR) was defined as no emetic
episode and no rescue medication; complete control (CC) was defined as no
Study design
emetic episode, no rescue medication, and no more than mild nausea. Efficacy
This was a randomized, double-blind, multicenter, parallel-design study con- for acute (0–24 h) and delayed (2–7 days) CINV was determined. Treatment
ducted within the United States. Thirty minutes before the start of scheduled was considered to be a failure (i.e. unsatisfactory therapeutic response) if a
administration of highly emetogenic chemotherapy, patients received a single patient had at least one emetic episode or received rescue medication.
i.v. bolus of palonosetron 0.3, 1, 3, 10, 30 or 90 µg/kg over 30 s. Initial palon- For patients participating in the pharmacokinetic portion of the study, 7 ml
osetron dosing ranged from 0.3–30 µg/kg. However, because the lowest dose of whole blood were drawn into heparinized vacuum tubes 30 min before, and
(0.3 µg/kg) was thought to possibly be too low to provide adequate protection 0.25, 0.5, 1, 2, 3, 4, 5, 6, 12, 24, 48, 72, 120 and 168 h after the administration
against CINV, a protocol amendment eliminated the use of this dose and a of palonosetron. As only two patients received palonosetron 0.3 µg/kg, this
90 µg/kg dose group was added, without breaking the study-blind. Efficacy dose level was not included in the pharmacokinetic portion of the study.
data from the two patients who received the 0.3 µg/kg dose were pooled with Plasma was separated from whole blood by centrifugation and stored at –20°C.
the 1 µg/kg group data. No concomitant corticosteroids were administered Plasma samples were assayed for palonosetron and its N-oxide metabolite
prophylactically. For ethical reasons, placebo was not a feasible option for a (metabolite M9) using a validated high-pressure liquid chromatography
control group. method, with detection and quantification of each analyte via single-ion moni-
All patients were observed in the hospital or clinic for a minimum of 6 h toring mass spectrometry. The lower limit of quantification was 0.020 ng/ml
after dosing and subsequently followed for 14 days after administration of for palonosetron and 0.050 ng/ml for metabolite M9. Standard pharmaco-
palonosetron. Blood samples from patients at selected study sites were col- kinetic parameters were calculated by non-compartmental methods.
lected at specific intervals for pharmacokinetic analysis. The study protocol AEs occurring in the study were documented during the 24 h after dosing,
was approved by the Institutional Review Board of each participating study on day 7, and on day 14. Events were assessed by the investigator for intensity
332

and possible association with study medication. All reported events were
followed until the overall clinical outcome was ascertained or until 1 month
after dosing.
The primary outcome variable was the proportion of patients with a CR
during the 24-h period following the start of chemotherapy. This was also evalu-
ated each day cumulatively for 7 days following chemotherapy. Secondary
measures, assessed each day for 7 days after chemotherapy initiation, included:
proportion of patients experiencing CC of emesis following the start of chemo-
therapy; time to treatment failure (first emetic episode or rescue medication);
time to first emetic episode; time to rescue medication; number of patients free
from emetic episodes and with a maximum of mild nausea; number of patients
free of emetic episodes with no rescue medication; number of patients free
from emetic episodes with no rescue medication and no nausea; and global
assessment of nausea (assessed only at 24 h).

Study drug
Palonosetron was supplied in 5 ml glass vials at a concentration of 500 µg/ml, Figure 1. Complete response rates in the first 24 h following administration
with normal saline provided for dilution. Before the dosing protocol amend- of a single intravenous dose of palonosetron (PP population). *P ≤0.05
ment each dose was diluted with normal saline to 10 ml; subsequent to the compared with palonosetron 0.3–1 µg/kg.
amendment each dose was diluted to 25 ml. The label strength for all solutions
was quantified as the free base.

Statistical analyses efficacy analyses were carried out on the ITT population (156
The primary efficacy hypothesis of the study was that there was no difference patients) and the PP population (148 patients). The majority (156
in the proportion of patients with a CR between the 0.3 or 1 µg/kg dose and any of 161) of enrolled patients received cisplatin (median dose
of the higher i.v. doses (3, 10, 30 and 90 µg/kg). The number of patients to be 96 mg/m2). To provide for a more homogeneous study population,
included in the study was estimated to be 115 patients (23 patients for five dose the five patients who received cyclophosphamide-based therapy
groups), assuming a responder rate of the lowest dose group of 20% and a CR were excluded from efficacy analyses. An additional eight patients
rate of the higher dose group of at least 70%. were excluded from efficacy analyses due to receipt of prohibited
Statistical analyses were carried out using SAS software, Version 6.08 concomitant medication (four patients), low cisplatin dose and/or
(SAS Institute, Inc., Cary, NC, USA). Significance of group differences in a slow infusion time (three patients), and patient unreliability (one
efficacy parameters was determined at an alpha level of 0.05 using two-sided
patient).
tests; comparability among groups with respect to baseline characteristics was
made at the 0.10 level. The Cochran–Mantel–Haenszel test, stratified by
Patient characteristics are summarized in Table 1. Treatment
center, was used to test the significance of differences in CR rates between the groups were generally balanced with respect to demographic vari-
lowest-dose group (pooled 0.3 and 1 µg/kg doses) and each of the other dose ables and medical history. There were no clinically meaningful
groups. Additionally, a 95% confidence interval (CI) (adjusted for multiple differences between groups with regard to age, gender, race, weight,
CIs) for the true difference in CR rates between the combined 0.3 and 1 µg/kg height, emetogenic chemotherapy agent, body surface area and
groups and each of the other dose groups was obtained using Dunnett’s tobacco and alcohol use within the past 6 months.
method, modified for a dichotomous response [19]. Treatment group differ-
ences for the other binary efficacy variables were analyzed similarly. Compar- Efficacy
isons in the time-to-event distributions were assessed using the log-rank test.
The Wilcoxon rank-sum test was used for comparisons of the area under the In the PP population, a CR was achieved in 24%, 46%, 40%, 50%
categorical NIT curve, while tests involving overall assessment of nausea were and 46% of patients in the 0.3–1, 3, 10, 30 and 90 µg/kg groups,
based on the Cochran–Mantel–Haenszel test stratified by center. For the CR respectively, during the first 24 h following chemotherapy admin-
rate at 24 h, analyses were carried out for both intention-to-treat (ITT) and istration (Figure 1). The lowest-dose group (0.3–1 µg/kg) had a
per-protocol (PP) populations; the other parameters were analyzed only for the
clearly inferior response rate compared with the higher-dose
evaluable patients (PP population). Safety data were tabulated and summar-
groups, with differences between groups reaching significance in
ized descriptively. Maximum plasma concentration (Cmax) and area under the
the 30 µg/kg group (P <0.05). Rates of CC were only slightly
plasma concentration–time curve (AUC) were tested for dose-proportionality
with a one-way analysis of variance controlling for dose level. Dose propor-
lower than rates of CR, with the lowest-dose group again appear-
tionality of plasma elimination T1/2, total body clearance (CLT), and apparent ing to show a lesser response to antiemetic therapy than those
volume of distribution (Vd) was evaluated without adjusting for dose. receiving the higher doses. The percentage of patients free from
emetic episodes during the 24 h following chemotherapy ranged
from 31% (for the 0.3–1 µg/kg group) to 58% (for the 3 and 30 µg/kg
Results groups), with 29–57% of patients free from emetic episodes and
experiencing none-to-mild nausea (0.3–1 µg/kg group and 30 µg/kg
Patients
group, respectively). In general, about one-third of patients in the
One hundred and sixty-one patients were enrolled in the study at higher-dose groups experienced a total response (i.e. no emetic
23 sites. All patients were included in the safety evaluation, while episodes, no rescue medication, and no nausea).
 333

Table 1. Baseline demographic and clinical characteristics (enrolled patients)

Characteristic Palonosetron dose (µg/kg) Total (n = 161)

0.3–1 (n = 32) 3 (n = 26) 10 (n = 26) 30 (n = 27) 90 (n = 50)
Age (years)
Mean ± SD 59 ± 10 60 ± 10 59 ± 13 61 ± 10 62 ± 11 60 ± 11
Range 37–75 43–75 30–77 40–79 23–78 23–79
Gender
Male 26 (81%) 20 (77%) 21 (81%) 25 (93%) 37 (74%) 129 (80%)
Female 6 (19%) 6 (23%) 5 (19%) 2 (7%) 13 (26%) 32 (20%)
Race
Caucasian 27 (84%) 21 (81%) 22 (85%) 20 (74%) 40 (80%) 130 (81%)
Black 3 (9%) 2 (8%) 3 (12%) 5 (19%) 8 (16%) 21 (13%)
Hispanic 1 (3%) 1 (4%) 1 (4%) 2 (7%) 2 (4%) 7 (4%)
Asian 0 (0%) 1 (4%) 0 (0%) 0 (0%) 0 (0%) 1 (1%)
Other 1 (3%) 1 (4%) 0 (0%) 0 (0%) 0 (0%) 2 (1%)
Weight (kg)
Mean ± SD 70 ± 17 73 ± 17 73 ± 13 74 ± 17 76 ± 20 74 ± 17
Range 45–121 48–105 49–113 47–104 39–132 39–132
Height (cm)
Mean ± SD 175 ± 11 175 ± 8 174 ± 10 177 ± 8 172 ± 12 174 ± 11
Range 148–193 159–190 150–192 160–193 145–193 145–193
Body surface area (m2)
Mean ± SD 1.85 ± 0.25 1.88 ± 0.23 1.87 ± 0.19 1.90 ± 0.22 1.89 ± 0.27 1.88 ± 0.24
Range 1.46–2.4 1.49–2.29 1.5–2.41 1.56–2.3 1.3–2.5 1.3–2.5
Tobacco use (past 6 months)
No 19 (59%) 13 (50%) 12 (46%) 16 (59%) 22 (44%) 82 (51%)
Yes 13 (41%) 13 (50%) 14 (54%) 11 (41%) 28 (56%) 79 (49%)
Alcohol use (past 6 months)
None 17 (53%) 11 (42%) 9 (35%) 14 (52%) 25 (50%) 76 (47%)
Occasional 6 (19%) 7 (27%) 9 (35%) 7 (26%) 14 (28%) 43 (27%)
1–2 drinks/day 7 (22%) 4 (15%) 4 (15%) 3 (11%) 7 (14%) 25 (16%)
>2 drinks/day 2 (6%) 4 (15%) 4 (15%) 3 (11%) 4 (8%) 17 (11%)
Chemotherapy
Cisplatin 31 (97%) 25 (96%) 26 (100%) 27 (100%) 47 (94%) 156 (97%)
Cyclophosphamide 1 (3%) 1 (4%) 0 0 3 (6%) 5 (3%)

SD, standard deviation.

Median time to first emetic episode was also longer in the four even more striking. Median time to treatment failure was 5.6, 22.7,
highest dose groups compared with the 0.3–1 µg/kg group. 19.0, >24 and 21.8 h, respectively. Patients who received higher
Median times to first emetic episode were statistically signifi- doses of palonosetron also experienced less nausea during the first
cantly higher in the 3, 30 and 90 µg/kg groups than in the lowest- 24 h after chemotherapy than those who received 0.3–1 µg/kg
dose group (P = 0.008, 0.012 and 0.007, respectively) (Table 2). doses, with significant differences in the 3, 30 and 90 µg/kg
Similarly, time to rescue medication was significantly longer in groups.
the 3, 30 and 90 µg/kg dose groups than in the 0.3–1 µg/kg group A single dose of palonosetron showed prolonged efficacy in
(P = 0.043, 0.022 and 0.015, respectively) (Table 2). When preventing delayed emesis, with approximately one-third of patients
patients were assessed according to time to treatment failure (i.e. who received palonosetron 10 or 30 µg/kg maintaining a CR
time to first emetic episode or time to rescue medication), the dif- throughout the 7-day period following chemotherapy administra-
ferences between the lowest-dose and the higher-dose groups were tion (Figure 2). These data suggest a prolonged efficacy of palono-
334

Table 2. Median time to first emetic episode, time to rescue medication and time to treatment failure
(h) following administration of a single intravenous dose of palonosetron

Palonosetron dose (µg/kg)

0.3–1 (n = 29) 3 (n = 24) 10 (n = 25) 30 (n = 24) 90 (n = 46)
Emetic episode 7.5 >24 19.5 >24 >24
P – 0.008 0.186 0.012 0.007
Rescue medication 19 >24 >24 >24 >24
P – 0.043 0.158 0.022 0.015
Treatment failure 5.6 22.7 19.0 >24 21.8
P – 0.011 0.088 0.010 0.004

>24 h denotes a median that is undefined but >24 h, since <50% of patients had the event ≤24 h.

response relationship for the occurrence of AEs. The incidence,

intensity and relationship of AEs to study medication were gener-
ally similar between the various palonosetron dose levels, indicat-
ing no apparent dose–response relationship for the occurrence of
AEs (data not shown). No clinically meaningful differences
between treatment groups were observed for heart rate, blood
pressure or other laboratory parameters evaluated. Results of ECG
recordings showed no dose-dependent changes in any interval,
including QT/QTc intervals (Table 4).

Pharmacokinetics
Available data allowed for calculation of palonosetron pharmaco-
kinetics in 35 patients. Mean palonosetron plasma concentrations
for the various dosage groups are illustrated in Figure 3 and the
computed pharmacokinetic parameters of palonosetron and meta-
bolite M9 are summarized in Table 5. Plasma palonosetron
Figure 2. Effect of a single intravenous dose of palonosetron in preventing concentrations declined biexponentially—with an initial rapid dis-
delayed emesis (complete response rates). tribution phase followed by a slower elimination from the body —
and were measurable up to 168 h after the dose. Mean Cmax values
ranged from 0.89 to 336 ng/ml and were generally proportional to
the dose. Similarly, AUC values increased dose-proportionally,
setron in the delayed phase of CINV. The proportion of patients
with AUC from time zero to infinity (AUC0–∞) ranging from
who were free from emetic episodes throughout days 1–7 ranged
13.8 ng•h/ml in the 1 µg/kg group to 957 ng•h/ml in the 90 µg/kg
from 26% to 38% for the four highest palonosetron doses, with
group. Mean CLT of palonosetron ranged from 1.51 to 2.23 ml/min/kg,
25–50% free from rescue medication.
indicating low clearance compared with hepatic blood flow
(approximately 20 ml/min/kg). Vd was large, with mean values
Safety
ranging from 6.83 to 12.5 l/kg, consistent with extensive distribu-
One hundred and twenty-nine of 161 patients (80.1%) experienced tion into tissue. The low CLT and large Vd resulted in a long T1/2,
at least one AE during the 14-day study period after administra- with mean values ranging from 43.7 to 128 h. Although there was
tion of palonosetron, with the majority of AEs (86%) considered interpatient variability for many of the pharmacokinetic para-
not related to the study medication. The most frequently reported meters, there were no statistically significant differences between
drug-related AEs (i.e. adverse reactions) were headache and dosage groups for any parameter, demonstrating dose-proportion-
constipation (Table 3). Most AEs (83.9%) were rated as mild or ality. Mean plasma concentrations of metabolite M9 were low
moderate in intensity by the investigator. Serious AEs were relative to the parent compound, with plasma concentrations not
reported for 25 patients (15.5%). However, none of these serious measurable in most samples at the 1 and 3 µg/kg dose levels.
AEs were considered to be related to study drug; instead, they Mean Cmax values for metabolite M9 ranged from 0.055 to
were usually considered to be secondary to the patient’s chemo- 0.855 ng/ml across the five dose levels. The ratios of AUC0–∞ for
therapy or underlying disease. There was no apparent dose– metabolite to parent drug averaged between 0.079 and 0.118.
 335

Table 3. Most frequently reported treatment-related adverse events (≥2% overall incidence): values are no. of patients

Palonosetron dose (µg/kg) Total (n = 161)

0.3–1 (n = 32) 3 (n = 26) 10 (n = 26) 30 g (n = 27) 90 (n = 50)
Headache 9 (28.1%) 6 (23.1%) 4 (15.4%) 8 (29.6%) 4 (8.0%) 31 (19.3%)
Constipation 1 (3.1%) 3 (11.5%) 1 (3.8%) 3 (11.1%) 6 (12.0%) 14 (8.7%)
Abdominal pain 1 (3.1%) 0 (0%) 0 (0%) 1 (3.7%) 2 (4.0%) 4 (2.5%)
Dizziness 0 (0%) 0 (0%) 1 (3.8%) 2 (7.4%) 1 (2.0%) 4 (2.5%)

Table 4. Mean changes in electrocardiogram QT and QTc intervals (milliseconds) from baseline to 24 h
after palonosetron dosing

Palonosetron dose (µg)

1 (n = 22) 3 (n = 21) 10 (n = 19) 30 (n = 21) 90 (n = 35)
QT –6 5 11 4 7
QTc (Fridericia correction) –3 5 11 –1 6
QTc (Bazett correction) –1 4 9 –4 4

Figure 3. Mean plasma concentration of palonosetron after a single intravenous dose.

Discussion ships for efficacy above a minimal threshold dose are generally
not found. For example, a single i.v. dose of granisetron 40 µg/kg
The results of this study show that palonosetron, administered in was found to be as effective as 160 µg/kg in three dose-ranging
the absence of pretreatment with corticosteroids, is an effective studies, with efficacy clearly lower at doses <10 µg/kg. Two
antiemetic agent among patients receiving highly emetogenic studies of dolasetron also failed to demonstrate a dose–response
cisplatin-based chemotherapy. A CR (no emetic episode and no relationship [24, 26], with one of the studies identifying a dose of
rescue medication) was achieved in 40–50% of the patients in the 1.8 mg/kg as suboptimal [26]. Results of two dose-ranging studies
3–90 µg/kg dose groups in the 24-h period following chemo- of ondansetron are inconsistent, with one study reporting no dif-
therapy, with 39–48% of patients experiencing CC (no emetic ference in efficacy between a single i.v. dose of ondansetron 8 and
episode, no rescue medication, and no more than mild nausea) 32 mg [25], and the other study reporting substantially greater
during the same time period. A single i.v. dose of palonosetron efficacy with the higher dose following moderately and highly
also showed prolonged efficacy in preventing delayed emesis, emetogenic chemotherapy [27].
with approximately one-third of patients who received palono- Palonosetron was well-tolerated, with no unexpected AEs
setron 10 or 30 µg/kg experiencing a CR through the 7 days after reported. Only a small proportion of events (approximately 15%)
administration of chemotherapy. A dose–response relationship were considered possibly or probably related to study medication,
for efficacy of the higher doses of palonosetron was not observed with the majority (>80%) of AEs considered mild-to-moderate in
at doses above the lowest effective dose of 3.0 µg/kg [20–25]. intensity. Importantly, incidences, frequencies, intensities and
Similarly, with other 5-HT3 antagonists, dose–response relation- drug relationships of AEs appear to be equally distributed among
336

Table 5. Pharmacokinetic parameters (means ± standard deviation) of palonosetron and metabolite M9 after administration of an
intravenous dose in patients receiving chemotherapy

Palonosetron dose (µg/kg) P

1 (n = 6) 3 (n = 6) 10 (n = 5) 30 (n = 8) 90 (n = 12)
Palonosetron
Cmax (ng/ml) 0.89 ± 0.92 5.63 ± 5.48 13.0 ± 20.1 35.7 ± 37.0 336 ± 940 0.85
T1/2 (h) 128 ± 93.8 56.4 ± 5.8 49.8 ± 14.4 86.4 ± 121 43.7 ± 12.2 0.20
AUC0–24 (ng·h/ml) 4.17 ± 4.97 8.57 ± 4.22 26.6 ± 5.99 82.6 ± 25.5 310 ± 155 0.50
AUC0–∞ (ng·h/ml) 13.8 ± 7.58 35.8 ± 20.9 81.8 ± 23.9 348 ± 295 957 ± 450 0.42
CLT (ml/min/kg) 1.51 ± 0.70 1.66 ± 0.59 2.23 ± 0.83 2.13 ± 1.21 1.90 ± 0.82 0.65
Vd (l/kg) 12.5 ± 4.19 7.91 ± 2.53 9.56 ± 4.21 9.18 ± 4.61 6.83 ± 2.67 0.08
Metabolite M9
Cmax (ng/ml) 0.055a 0.489a 0.141 ± 0.104 0.481 ± 0.262 0.855 ± 0.679 <0.001
AUC0–∞ (ng·h/ml) NC NC NC 25.1 ± 11.3 72.7 ± 45.5 0.72
AUC0–∞ ratio (M9/palonosetron) NC NC NC 0.118 ± 0.059 0.0789 ± 0.047 NC

a
Data are means of parameters calculated from only two subjects.
AUC0–24, area under the plasma concentration–time curve for hours 0–24; AUC0–∞, area under the plasma concentration-time curve for time
0 to infinity; CLT, total body clearance; Cmax, maximum plasma concentration; Vd, apparent volume of distribution; NC, not calculated.

the various palonosetron dose levels, with no apparent dose– Financial disclosures and potential conflicts of interest
response relationships.
P. Eisenberg is a consultant for Merck, MGI, Ortho Biotech, L.P.,
Over the range of doses evaluated, both Cmax and AUC0–∞
and Doctors Medical Center (San Pablo); he has ownership
values increased with increasing dose in a dose-proportional
interests in BMS and Schering; he has received research funding
manner, within the range 1–90 µg/kg. Vd of palonosetron was
from Aesgen, Allos Therapeutics, Amgen, AstraZeneca, Aventis,
large (6.8–2.5 l/kg) and CLT was low (1.51–2.23 ml/min/kg),
Bayer, Berlex, BioMedicines, BioTechnology General, Celgene,
resulting in a long plasma elimination T1/2 (>44 h). The exposure
Cell Pathways, Cell Therapeutics, Chiron, Corixa, Daiichi, Genen-
of metabolite M9 relative to palonosetron as determined by AUC
tech, Genta, Genitope, GlycoDesign, Helsinn, ImClone, Inex, Isis,
ratio was low (0.079–0.118). This finding, coupled with the neg-
Johnson & Johnson, Ligand, Lilly, Merck, MGI, Oncotech, Ortho
ligible pharmacological activity of metabolite M9 (data on file),
Biotech, L.P., Pfizer, Pharmacia, Sanofi-Synthelabo, Searle and
suggests that the antiemetic effect observed in patients is mainly
Serono; he has received honoraria from Pharmacia, MGMA and
due to palonosetron. Pharmacokinetics of palonosetron in this
ASCO; and he has served on the Board of Directors or on the
dose-ranging study were similar to studies in healthy volunteers
Advisory Board of MGI, Ortho Biotech, L.P. and Merck. F. R.
[28], and are improved over other 5-HT3 antagonists due to its long
MacKintosh, P. Ritch and P. A. Cornett have no financial dis-
T1/2, dose-proportional pharmacokinetics, large Vd, and low CLT.
closures or potential conflicts of interest to declare. A. Macciocchi
In summary, palonosetron showed substantial efficacy in the
is employed by Helsinn Healthcare SA.
prevention of CINV in patients receiving highly emetogenic
cisplatin-based chemotherapy. The prolonged protection observed
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