Phase I, double-blind, randomized, placebo-controlled trial in healthy volunteers to examine the safety, tolerability and plasma pharmacokinetics of TMC589337 and TMC589354 after increasing single oral doses and in an open-label part after different repeated oral doses in combination with a single oral dose of TMC310911.

TMC589337, TMC589354 and TMC310911 are in process of development for treatment
of Human Immunodeficiency Virus-Type 1 (HIV-1). TMC310911 is novel and potent
compound and belongs to a medication class called preotease inhibitors (PI). It
is being developed because it is assumed to be very active against the HIV-1
virus that causes AIDS, when other treatments will fail. TMC589337 and
TMC589354 are novel molecules with no antiviral activity to be used to enhance
the levels of TMC310911 in the blood. In this study, TMC589337 and TMC589354
will be administered for the first time to humans.

To investigate the safety, tolerability and behavior in the body (absorption
and excretion) of oral intake of TMC589337 and TMC589354 after ascending single
intakes. In addition, the safety, tolerability and behavior in the body after
multipe dose intakes of TMC589337 and/or TMC589354 in combination with a single
dose of TMC310911 will be examined.

The single ascending dose part of the study has a randomized, double-blind,
placebo-controlled design, which consists of
The multiple dose part of the study is open label.

Single Dose:
The SAD part of the study consists of Panel 1 and 2. In both panels, the
subjects will take 4 increasing oral doses of the study drug (active or
placebo) in 4 seperate sessions. Each dose will be taken once. In each session,
6 subjects will receive the study drug and 2 subjects will receive placebo. The
treatment schedule will be made in such a way that for both panels over 4
sessions each subject will receive the study drug 3 times and placebo once.
Each single dosing session will have a staggered approach meaning that first 4
subjects will be dosed and 48 hours later the next 4 subjects will be dosed. A
washout period of at least 10 days will be respected between consecutive single
oral TMC589337, TMC589354 or placebo dosing within each panel. During the
washout period no study drugs will be taken.

Multiple dose:
The MAD part of the study consists of Panel 3 through 7. Panels 3 through 6
will have 1 session in which TMC589337 (panel 3 and 5) or TMC589354 (panel 4
and 6) will be administered twice a day during 7 days. The subjects in panel 7
will have one session in which TMC589337 or TMC589354 will be administered
twice or once a day during 7 days. For panel 7 TMC589337 or TMC589354 will be
selected.
In addition, teh subjects Panels 3 through 6 will have an additional session of
3 days in which a single oral dose of 300mg TMC310911 will be administered.
Subjects of Panel 7 will receive either 300mg or 600mg of TMC310911.

The risks associated with this investigation are linked together with the
possible side effects of the investigational product. The burden on the
volunteer will continue to work with the recording periods, venapunctions and
the introduction of the cannula. All volunteers are closely monitored and
supervised by experienced doctors and studystaff for possible side effects.
The following tests will be performed during this trial: physical examination,
measuring bloodpressure and hart rate, blood- and urine tests, pregnancy test
(women only), drugscreen, alcohol tests, ECGs, restrictions in living habits,
standardized meals during admission. 8 Hours telemetry recording on dosing days
in the single ascending dose part of the study.
All volunteers will be closely monitored by experienced physicians and staff.