An open-label, individual study groups, fixed sequence, four-period crossover study comparing three proportionate sizes of HP 3020 patch applied for 24 hours with intravenous palonosetron injection (ALOXI®) and a one-period study with one size of HP-3020 patch applied for 168 hours, to investigate the pharmacokinetics, tolerability and safety of HP-3020 patches in healthy male subjects

The drug to be given is an existing compound, palonosetron hydrochloride
(registered under the tradename Aloxi®) in a new application form (transdermal
patches).

Palonosetron is used against chemotherapy induced nausea and vomiting (CINV).
Palonosetron hydrochloride is a serotonin (5-hydroxytryptamine or 5-HT)
receptor antagonist which exerts its effect by interacting with the 5-HT3
receptors as an antagonist.

In this study, a new administration method of palonosetron hydrochloride
(palonosetron HCl), in the form of transdermal application, is tested. The
advantages of this new transdermal delivery system may include the avoidance of
gastrointestinal side effects after oral administration, and of complaints and
complications related to administration via an injection. Thus, transdermal
delivery systems may provide a wider range of therapeutic options for
physicians to use in optimising their patient care

Primary:
To investigate the pharmacokinetics of palonosetron in plasma from three
different sizes of HP-3020 transdermal patch applied for 24 hours as compared
to intravenous palonosetron (Cohort 1) and to investigate the pharmacokinetics
of palonosetron in plasma from a 54 cm2 surface of HP-3020 transdermal patches
applied for 168 hours (Cohort 2) in healthy male volunteers.
To evaluate the excreted amounts of palonosetron in urine after each
application of HP-3020 transdermal patches in Cohorts 1 and 2.

Secondary :
To assess the safety and tolerability of HP-3020 transdermal system in healthy
male subjects
To analyse residual palonosetron in the HP-3020 transdermal system after
removal from the application site at the end of the application period.

Design:
This Phase 1 study will be conducted in two sequential Cohorts of twelve
healthy male subjects per Cohort.
In Cohort 1 there will be a fixed sequence four-period crossover design: all
subjects in Cohort 1 will receive a single intravenous dose of 0.25 mg
palonosetron in the first period, and they will receive three sizes of HP-3020
transdermal systems (6, 18 and 54 cm2, containing a total of 0.6, 1.8 and 5.4
mg palonosetron hydrochloride, respectively) in the second to fourth period.
The transdermal patches will be removed 24 hours after application in Cohort 1.
The wash-out between applications will be at least 168 hours.
Cohort 2 will receive three 18 cm2 (so a total surface of 54 cm2 HP-3020
transdermal system (containing a total of 5.4 mg palonosetron hydrochloride))
which will be removed after 168 hours.

Procedures and assessments
Screening and follow-up:
Clinical laboratory, vital signs, full physical examination, 12-lead ECG, at
eligibility screening: medical history, alcohol, nicotin metabolites and drug
screen, HBsAg, anti-HCV, anti HIV 1/2; clinical laboratory, alcohol, nicotin
metabolites and drug screen, vital signs and 12-lead ECG to be repeated on
admission.


Cohort 1:
Observation period:
Admission in clinic from -17 hours before the first drug administration up to
168 hours after removal of the last patch (Day 33).

Blood sampling:
For pharmacokinetics of palonosetron: pre-dose and 1, 3, 5, 15 and 30 minutes
and 1, 2, 4, 6, 12, 24, 48, 72, 96, 120, 144, 168 and 192 hour post-dose
(Period 1, Aloxi® injection) and at 0, 2, 4, 6, 12, 18, 24 (before removal of
the patches), 28, 32, 40, 48, 72, 96, 120, 144, 168 and 192 hours post-dose
(Periods 2, 3 and 4)

Urine collection:
For pharmacokinetics of palonosetron: during each period pre-dose and intervals
0-24, 24-48, 48-72, 72-96, 96-120, 120-144, 144 168 and 168-192 hours post-dose.

Safety assessments:
Adverse events (throughout the study); vital signs and ECG: pre-dose and 2, 4,
12, 24, 48, 72, 96, 120 and 192 hours post-dose (all 4 study periods, for
periods 2-4 the 192 hour recording of the previous period is the pre-dose);
visual inspections of the application sites 0 hr (immediately prior to the
patch application), 25, 48, 72, 96, 120, 144, 168 and 192 hours after the
application of each transdermal patch; clinical laboratory: on Day -1 and 48
and 168 hours post-dose in Periods 1-3 and at 48 and 192 hours post-dose in
Period 4.

Adhesion Evaluation:
2, 4, 8 and 24 hours after the application of each transdermal patch; Adhesive
Residue.

Bioanalysis:
Analysis of plasma and urine samples for palonosetron using a validated method
by PRA International.


Cohort 2:
Observation period:
Admission in clinic from -17 hours before patch application up to 168 hours
after removal of the patch (Day15).

Blood sampling:
For pharmacokinetics of palonosetron : pre-dose and 2, 4, 6, 12, 18, 24, 28,
32, 40, 48, 72, 96, 120, 144 and 168 (before removal of the patches), 172, 176,
184, 192, 216, 240, 264, 288, 312, 336 hours post dose.

Urine collection:
For pharmacokinetics of palonosetron: pre-dose and intervals 0-24, 24-48,
48-72, 72-96, 96-120, 120-144, 144 168, 168-192, 192-216, 216-240, 240-264,
264-288, 288- 312 and 312-336 hours.

Safety assessments:
Adverse events (throughout the study); vital signs and ECG: pre-dose and 4, 12,
24, 48, 72, 96, 120, 168, 192 hour post-dose (before removal of the patches)
and 216, 240, 288 and 336 hour post-dose; visual inspections of the application
sites 0 hr (immediately prior to the patch application), 169, 192, 216, 240,
264, 288, 312 and 336 hours after the application of the transdermal patch;
clinical laboratory: day -1 and 48 and 192, 240 and 336 hour post-dose.

Adhesion Evaluation:
2, 4, 8, 24, 48, 72, 96, 120, 144 and 168 hours after the application of each
transdermal patch; Adhesive Residue.

Bioanalysis:
Analysis of plasma and urine samples for palonosetron using a validated method
by PRA International

Study madication: palonosetron in transdermal patch (HP-3020, 0.6 mg
palonosetron HCl per 6 cm2) and solution for intravenous injection (Aloxi®,
0.25 mg).

Procedures: pain, light bleeding, heamatoma, possibly an infection, irritation
patch.