Pharmacokinetics and metabolism of [14C] BMS-986195 in healthy male subjects

BMS-986195 is a new investigational compound that may eventually be used for
the treatment of rheumatoid arthritis (RA). BMS-986195 blocks an enzyme
(Bruton*s tyrosine kinase [BTK]) which is present in certain white blood cells
(B-Cells). In patients with autoimmune diseases like RA
these B-Cells react against the own body. Lowering the sensitivity of these
cells can reduce the reaction against the own body. BMS-986195 is in
development and is not registered as a drug but has been given to humans before.

During this study the volunteer will also receive xylocaine (lidocaine), a drug
registered for use as a local anesthetic, and milk of magnesia (magnesium
hydroxide), a compound registered for use as a laxative.

The purpose of the study is to investigate how quickly and to what extent
BMS-986195 is absorbed, distributed, metabolized (broken down) and eliminated
from the body (this is called pharmacokinetics). BMS-986195 to be administered
will be labeled with 14-Carbon (14C) and is thus radioactive (also called
radiolabeled). In this way BMS-986195 can be traced in blood, urine, feces, and
bile. It will also be investigated to what extent BMS-986195 is tolerated.

Part 1:
The actual study will consist of 1 period during which the volunteer will stay
in the clinical research center in Groningen (location Martini Hospital) for at
least 6 days (5 nights) but no more than 16 days (15 nights).

During the study the volunteer will receive radiolabeled BMS-986195 after an
overnight fast (at least 10 hours no eating and drinking) as an oral solution
of 1 mL which will be given using a syringe. After this the volunteer is also
required to drink 240 mL water. Fasting will continue until 4 hours after
administration of the study compound. Then the volunteer will receive a lunch.
During fasting the volunteer is allowed to drink water with the exception of 2
hours prior to until 1 hour after administration of the study compound.

During the first 8 hours after administration of the study compound the
volunteer will not be allowed to lie down (except when indicated as such by one
of the investigators), as this may influence the uptake of the study compound

Part 2:
The actual study will consist of 1 period during which the volunteer will stay
in the clinical research center in Groningen (location Martini Hospital) for at
least 6 days (5 nights) but no more than 16 days (15 nights).

During the study the volunteer will receive radiolabeled BMS-986195 after an
overnight fast (at least 10 hours no eating and drinking) as an oral solution
of 1 mL which will be given using a syringe. After this the volunteer is also
required to drink 240 milliliters water. Fasting will continue until 6 hours
after administration of the study compound. After removal of the nasoduodenal
tube the volunteer will receive a meal.

During fasting the volunteer is allowed to drink water until 2 hours prior to
administration of the study compound. In the period between 2 hours before and
6 hours after administration of the study compound the consumption of water is
limited to 3 moments on which the volunteer will have to drink a measured
amount of water. This is related to the placement of a nasoduodenal tube from 2
hours before until 6 hours after administration of the study compound. A
nasoduodenal tube is a slim flexible tube that under local anesthesia via the
nose, esophagus and stomach will be placed with its tip in the duodenum. Thirty
minutes before the tube is placed, as well as 1.5 and 2.5 hours after
administration of the study compound the volunteer will have to consume 125 mL
tap water. In addition, as described above, the volunteer will have to drink
240 mL tap water during administration of the study compound.
During the first 6 hours after administration of the study compound the
volunteer has to remain upright in bed (except when indicated as such by one of
the investigators). From 4 hours after administration of the study compound the
volunteer is allowed to recline to an angle of no more than 45 degrees. After
removal of the nasoduodenal tube the volunteer is allowed to leave the bed.

The volunteer will receive a single dose of 10 mg radiolabeled BMS-986195 as
oral solution of 1 milliliter (mL).

All potential drugs cause adverse effects; the extent to which this occurs
differs. To date BMS 986195 has been administered to healthy volunteers in 2
ongoing studies. The adverse effects observed after a single dose of BMS-986195
in one of these studies were: headache, upper respiratory tract infection,
dizziness, nausea, rash, throat irritation, myalgia, dysgeusia, dysmenorrhea,
oral herpes, influenza like illness, malaise, hot flush, tongue ulceration, and
dry lips. No additional data from the ongoing studies is available yet.

Based on the working mechanism of the study compound it can be expected that
the study compound will affect the immune system. Therefore, the volunteers
will be checked for any signs of infections and additional laboratory tests are
performed to monitor their health throughout the study.

Xylocaine (lidocaine) side effects are hypersensitivity reactions (1 to 10 in
1000 users), severe allergic reactions (with hypotension, paleness, anxiety,
weak and fast pulse, sweating, and decreased consciousness as a result of a
sudden vasodilation [anaphylactic shock]), loss of voice, hoarseness, sore
throat, local irritation on the place of application (incidence cannot be
assessed based on the current data).

Milk of magnesia has been used for over 100 years as a treatment for heartburn
and a laxative. The most frequently observed adverse effects are diarrhea and
gastrointestinal discomfort. In rare cases severe allergic reactions (rash,
hives, itching, difficulty breathing, tightness in the chest, swelling of the
mouth, face, lips, or tongue), loss of appetite, muscle weakness, nausea, slow
reflexes, and vomiting were observed.

The volunteer should be aware that the aforementioned adverse effects and
possibly other, still unknown adverse effects, may occur during the study.
However, with the dose used in this study no serious adverse effects are
expected.

In this study radiolabeled BMS-986195 will be used. The amount of radioactivity
in this dose will be approximately 3.0 MBq (MBq = megaBecquerel, 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 3.0 MBq radiolabeled BMS-986195 is calculated
to be 0.66 mSv. This is approximately 33% of the average annual radiation
burden.