AN OPEN-LABEL, STUDY WITH THREE PROPORTIONATE SIZES OF HPS-328 PATCH APPLIED FOR 168 HOURS AND ONE ORAL DOSE REGIMEN OF 5 MG BISOPROLOL FUMARATE ONCE DAILY FOR ONE WEEK, TO INVESTIGATE THE PHARMACOKINETICS, TOLERABILITY AND SAFETY OF HPS-328 PATCHES IN HEALTHY MALE SUBJECTS

The drug to be given is an existing compound, bisoprolol (registered under the
tradename Emcor®) in a new application form (transdermal patches).
Bisoprolol belongs to the class of *-blockers and can reduce blood pressure and
heart rate, and decrease the oxygen-consumption of the heart muscle. Therefore
it can be used, and is in fact widely used, for the treatment of high blood
pressure and pain on the chest as a result of a lack of oxygen of the heart
muscle (angina pectoris).
In this study a new administration method of bisoprolol, in the form of
transdermal application, is tested.
An advantage of this new administration system would be the ease of use for the
patient, with a once weekly application of a dermal patch in stead of daily
oral tablet ingestion. Another possible advantage could be the much more stable
blood concentration of the transdermal administration, compared with the rather
strong variation of the usual once daily oral dose regimen.

The purpose of the study is to investigate how safe the compound is and how
well the compound is tolerated when it is applied in the form of transdermal
patches. The study will also investigate how quickly and to what extent
bisoprolol is absorbed and eliminated from the body, when it is administered in
the form of transdermal patches (during 168 hours), for Group 1 in comparison
to bisoprolol fumarate in the form of tablets.

Group 1: in one period the study drug will be administered as tablet (sinlge
daily dose of 5 mg for the duratian of 7 days); in the other periode the study
drug will be administered as transdermal patch (singe dose of 90 mg). The
transdermal patch will be removed after 168 hours.
Group 2: the volunteers of this group will receive two transdermal patches for
168 hours with a total dose of 180 mg study drug.
Group 3: the volunteers of this group will receive four transdermal patches for
168 hours with a total dose of 360 mg study drug.

Procedures and assessments:
Screening and follow-up:
clinical laboratory, vital signs, physical examination, body weight, body
height (screening only), 12-lead ECG; at eligibility screening: medical
history, alcohol and drug screen and nicotine metabolites, HBsAg, anti HCV,
anti-HIV 1/2; alcohol and drug screen and nicotine metabolites, clinical
laboratory, vital signs and 12-lead ECG to be repeated upon admission.

Group 1:
Observation period:
2 periods, in the clinkic from 40 uur before first administration of study drug
until 240 hours after administration of the study drug on Day 1.

Blood sampling:
patch administration period for pharmacokinetics of bisoprolol: pre-dose
(before application) and 2, 4, 6, 8, 12, 18, 24, 28, 32, 40, 48, 60, 72, 74,
76, 78, 80, 84, 90, 96, 120, 144, 146, 148, 150, 152, 156, 162, 168 (before
removal), 170, 172, 176, 180, 192, 204, 216 and 240 h post patch application
oral administration period for pharmacokinetics of bisoprolol: pre-dose (before
1st dosing) and 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24 (before 2nd dosing), 27, 48
(before 3rd dosing), 51, 72 (before 4th dosing), 72.5, 73, 74, 75, 76, 78, 80,
82, 84, 96 (before 5th dosing), 99, 120 (before 6th dosing), 123, 144 (before
7th dosing), 144.5, 145, 146, 147, 148, 150, 152, 154, 156, 168, 180, 192, 204,
216 and 240 h after 1st dosing

Urine sampling:
for pharmacokinetics of bisoprolol: pre-dose and intervals 0-24, 24-48, 48-72,
72-96, 96-120, 120-144, 144-168, 168-192, 192-216 and 216-240 hours post dosing
for both periods.

Ambulatory Blood Pressure Recordings: for 24 hours on Days -1, 1, 4 and 7
(first 16 hours every half hour, last 8 hours once per hour) in both study
periods.

Safety assessments:
adverse events: throughout the study;
vital signs: at screening, and at admission, once daily on Days 1 to 11 in both
study periods; clinical
ECG: at screening and admission, at pre-dose and 1, 2, 3, 5, 7 and 12 h
post-dose and on Days 1, 4 and 7 and once on Days 2, 3, 5, 6, 8, 9, 10 and 11;
on day -1 on the scheduled timepoints of day 1 for both study periods.
clinical laboratory: at screening and at admission and on Day 11 in both study
periods
visual inspection application site: screening, 0 h (before application), at
169, 192, 204, 216 and 240 h after application;
adhesion evaluation: 2, 8, 24, 48, 72, 96, 120, 144, and 168 hours after
application

Bioanalysis: analysis of plasma and urine bisoprolol samples using validated
methods by Sponsor

Group 2 and 3:
In the clinic from 40 hours before first administration until 240 hours after
administration of the study drug on Day 1.

Blood sampling:
for pharmacokinetics of bisoprolol: pre-dose (before application) and 2, 4, 6,
8, 12, 18, 24, 28, 32, 40, 48, 60, 72, 74, 76, 78, 80, 84, 90, 96, 120, 144,
146, 148, 150, 152, 156, 162, 168 (before removal), 170, 172, 176, 180, 192,
204, 216 and 240 h post patch application

Urine sampling:
for pharmacokinetics of bisoprolol: pre-dose and intervals 0-24, 24-48, 48-72,
72-96, 96-120, 120-144, 144-168, 168-192, 192-216 and 216-240 hours post dosing

Ambulatory Blood Pressure Recordings: for 24 hours on Days -1, 1, 4 and 7
(first 16 hours every half hour, last 8 hours once per hour).

Safety assessments:
adverse events: throughout the study;
vital signs: at screening, and at admission, once daily on Days 1 to 11
ECG: at screening and admission, at pre-dose and 1, 2, 3, 5, 7 and 12 h
post-dose and on Days 1, 4 and 7 and once on Days 2, 3, 5, 6, 8, 9, 10 and 11;
on Day -1 on the scheduled timepoints of Day 1.
clinical laboratory: at screening and at admission and on Day 11 in both study
periods
visual inspection application site: screening, 0 h (before application), at
169, 192, 204, 216 and 240 h after application;
adhesion evaluation: 2, 8, 24, 48, 72, 96, 120, 144, and 168 hours after
application

Bioanalysis: analysis of plasma and urine bisoprolol samples using validated
methods by Sponsor

Active compound: bisoprolol in transdermal patch (HPS-328, 90 mg bisoprolol per
15 cm2) or bisopolol fumarate as tablets, 5 mg per tablet (Emcor®).

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