A Phase I randomized, open-label, single dose, 3-period crossover trial in healthy subjects to evaluate the relative oral bioavailability of the 25 mg and 100 mg tablets of TMC125.

TMC125 is a new investigational product that is in process to be used for the
treatment of HIV-1, the virus that causes AIDS. It slows down the replication
of HIV and belongs to the class of NNRTIs (the so called Non-Nucleoside Reverse
Transcriptase Inhibiters). TIBOTEC Pharmaceuticals developed a 25 mg tablet for
pediatric purposes. The dose that will be investigated in this trial is 100 mg
(treatment A: 1 tablet of 100 mg; treatment B: 4 tablets of 25 mg; and
treatment C: 1 tablet of 100 mg dissolved in 100 mL water).
TMC125 is not yet marketed as drug, but it has already been administered to
humans in previous studies.
TIBOTEC Pharmaceuticals Ltd. intends to marketing this drug.

The objective of this study is to evaluate the concentrations in blood after a
single administration of 100 mg TMC125. The various administration formulations
will be compared to demonstrate that the formulations can be exchanged. The
administration of 1 tablet of 100 mg will be compared to the administration of
4 tablets of 25 mg; and the administration of 1 tablet of 100 mg will be
compared to the administration of 1 tablet of 100 mg dissolved in 100 mL water.
Furthermore, the safety and tolerability will be evaluated.

A medical screening preceeds participation in the study. The study consists of
3 periods of 5 consecutive days. The three single intakes will be separated by
a period of at least 14 days, the washout period.
The study is ended by two follow-up visits.
The subject is treated once with the reference formulation (treatment A) and
twice with a test formulation (treatments B and C). The sequence of the
different treatments is determined bij chance.

Treatment:
A: 100 mg TMC125, 1 tablet of 100 mg (tablet F060)
B: 100 mg TMC125, 4 tablets of 25 mg (tablet F066)
C: 100 mg TMC125, 1 tablet of 100 mg (tablet F060), dissolved in 100 mL water.

The concentrations of TMC125 in blood will be determined. Therefore, in every
period on Day 1, blood samples will be collected before and until 96 hours
after intake of the trial medication.

One dose per period.

Preceding participation, subjects will be screened including drawing a blood
sample for laboratory tests. Afterwards, 3 periods will follow. A single dose
of trial medication will be administered each period. Blood will be collected
16 times each period to evaluate the absorption on the blood and excretion of
TMC125. Between 2 consecutive periods is a washout of 2 weeks. During the study
blood is collected 10 times for laboratory tests.

TMC125 has been studied in both healthy subjects and in HIV-1 patients. As of
June 2006, about 900 healthy subjects and approximately 500 HIV-1 patients have
already received TMC125.
In healthy subjects who received more than one dose of TMC125, the most common
side effects were headache, diarrhea, flatulence, abdominal pain and pruritus.
There was one death in a healthy volunteer but the trial doctor did not think
the death was related to TMC125. Other medically important events that were
reported were also not related to TMC125.
In HIV-1 patients, the most common side effects that have been reported and
were sometimes considered by the trial doctor related to TMC125 were: diarrhea,
feeling tired (fatigue), rash, fever, headache, pain in the abdomen, vomiting,
and nausea. Most of these side effects were mild to moderate in nature and went
away on their own without treatment.
Some healthy subjects developed rash with mouth ulcers (sores) or vesicles
(blister-like) after treatment with TMC125. This side effect can be serious and
therefore need immediate medical attention. If a subject develops any skin
changes with any one of these symptoms: fever, nausea, vomiting, diarrhea,
abdominal pain, extreme tiredness, aches, generally ill feelings, sore throat,
shortness of breath or cough, he or she has to inform the trial doctor
immediately and make an appointment for a detailed evaluation.
Some rare serious side effects which occurred in HIV-1 infected subjects and
were considered possibly related to TMC125 are decrease in blood cells, pain
and swelling in the pancreas (pancreatitis), chest pain, stroke due to
decreased blood supply to brain, seizure due to fever, dehydration, excess of
lactic acid in blood (chemical byproduct of body cells that can cause
dysfunction of body organs) and heart attack leading to decrease in heart
function. The patient whose heart function decreased due to the heart attack
died. The patient had risk factors for development of cardiac problems but a
possible relation to TMC125 could not be excluded.
In both the healthy subjects and HIV-1 patients, there were no significant
changes in vital signs (pulse, breathing rate and blood pressure), heart rhythm
or laboratory test results.