An open-label, two-part study to determine the absolute bioavailability (BA) of OZ439 using simultaneous intravenous [14C] OZ439 microdose/800 mg oral dosing and to investigate the pharmacokinetics (PK) of OZ439 granules administered as single doses suspended in different volumes and when co-administered with a single dose of Cobicistat, a string CYP3A4 inhibitor, to healthy subjects in fasted state

Part 1 and 2:
Malaria is caused by an infection with the Plasmodium parasite. These parasites
can enter the body during a mosquito bite. The study compound OZ439 can damage
or even kill the malaria parasite.

OZ439 is not registered as a drug, but has been given to humans before (until
now approximately 886 humans).

Also for Part 2:
The other compound that will be given in this study is cobicistat which is an
approved drug and already available in the market. Cobicistat is used in the
treatment of human immunodeficiency virus infection (HIV/AIDS). Cobicistat is
not an HIV medicine and does not treat HIV. Cobicistat is an inhibitor of a
liver enzyme called cytochrome P450 3A4. Cobicistat is a type of medicine
called a pharmacokinetic enhancer and is used in HIV treatment to increase the
amount of other HIV medicines in the blood.

Part 1:
The purpose of Part 1 of the study is to investigate how much of the OZ439
compound is absorbed into, distributed in, and eliminated from the body (this
is called pharmacokinetics) when administered orally as compared to an
intravenous (iv; given to you through a vein) administration. The study
compound to be administered intravenously will be labeled with an extremely low
dose of 14 Carbon (14C) and is thus radioactive (also called radiolabeled).
Because of the difference in mass between 14C and 12C (the normal carbon) the
concentration of 14C-labeled molecules can be determined even at extremely low
concentrations using a very sensitive method. By comparing the amount of 14C
labeled OZ439 with the amount of non labeled OZ439 it is possible to determine
the part of orally administered study compound which is available to the body
(this is called absolute bioavailability). It will also be investigated how
safe OZ439 is and how well OZ439 is tolerated.
Furthermore, the study (comparing results of Part 1 and Part 2 of the study)
will also investigate what the effect is of different volumes of the OZ439 oral
solutions on the pharmacokinetics of OZ439.

Part 2:
The purpose of Part 2 of the study is to investigate what the effect is of
cobicistat on how quickly and to what extent OZ439 is absorbed into,
distributed in, and eliminated from the body (this is called pharmacokinetics).
It will also be investigated how safe OZ439 is and how well OZ439 is tolerated
when OZ439 is administered alone and in combination with cobicistat.
Furthermore, the study (comparing results of Part 1 and Part 2 of the study)
will also investigate what the effect is of different volumes of the OZ439 oral
solutions on the pharmacokinetics of OZ439.

Part 1:
The study will consist of 1 period during which you will stay in the clinical
research center for 3 days (2 nights) followed by 4 days during which you will
visit the clinical research center for an ambulatory visit on Days 3, 4, 5 and
8.
During the study the volunteer will receive OZ439 as an oral solution under
fasted conditions. This means that the volunteer is not allowed to eat for at
least 10 hours before administration of the study compound. During fasting
he/she is allowed to drink water with the exception of 2 hours prior to until 1
hour after administration of the study compound. Fasting will continue until 6
hours after administration of the study compound. Then the volunteer will
receive a lunch. At 3 hours after administration of OZ439 as oral solution
he/she will also receive 14C labeled OZ439 as an iv infusion of 15 minutes.

Part 2:
The study will consist of 3 treatment periods during which you will stay in the
clinical research center. The time interval between the different treatment
periods is 14 days.
During the study the volunteer will receive OZ439 alone (Treatments B and C)
and in combination with cobicistat (Treatment D). OZ439 will be given as an
oral solution and cobicistat will be given as an oral tablet. The cobicistat
tablet will be taken with the 64.5 milliliters of OZ439 oral solution (only
during Treatment D). The study compound will be given under fasted conditions.
This means that the volunteer is not allowed to eat for at least 10 hours
before administration of the study compound. During fasting he/she allowed to
drink water with the exception of 2 hours prior to until 1 hour after
administration of the study compound. Fasting will continue until 6 hours after
administration of the study compound. Then the volunteer will receive a lunch.

Part 1:
The study will consist of 1 period during which you will receive OZ439 as an
oral solution of 100 milliliters and 14C labeled OZ439 as an iv infusion of 10
milliliters and during 15 minutes.

Part 2:
The study will consist of 3 treatment periods during which you will receive
OZ439 alone and in combination with cobicistat. OZ439 will be given as an oral
solution of 64.5 milliliters. Cobicistat will be given as an oral tablet.

All potential drugs cause adverse events; the extent to which this occurs
differs.
The study compound OZ439 has been given to humans before and is already been
tested in several studies in healthy volunteers and in malaria patients. The
most important adverse effects of OZ439 in healthy volunteers are: nausea,
vomiting, increased bowel movements, diarrhea, headache and flushing. Malaria
patients reported besides these events also headache, dizziness and abdominal
pain, and also complaints which were at least partly related to malaria like
laboratory abnormalities, anemia and pyelonephritis (acute infection of the
kidney) were reported. Of note, one case of vasovagal syncope (i.e. with loss
of consciousness) was reported and considered as related to the study compound.

In this study radiolabeled OZ439 will be used. The amount of radioactivity in
this dose will be approximately 47 kBq (kBq = kiloBecquerel, this is a unit to
express the amount of radioactivity in the study compound). The average
environmental background radiation burden in The Netherlands is approximately 2
mSv per year (mSv = milliSievert, this unit indicates the burden on the human
body; thus the effect on the human body of the amount of radioactivity
administered). The additional radiation burden in this study due to the
administration of approximately 47 kBq radiolabeled OZ439 is calculated to be
negligible (that is, less than the natural background radiation in 1 month).