A Three Part Study Evaluating the Pharmacokinetics of Intravenous (IV) Danoprevir (DNV)/Oral Low Dose Ritonavir (RTV), a Drug-Drug Interaction Study Between IV DNV/Oral Low Dose RTV and Oral Cyclosporine, and the Absolute Bioavailability of IV DNV as Compared to DNV Tablets Together With Oral Low Dose RTV in Healthy Adult Volunteers

Danoprevir (RO5190591) is a new compound that may be used in the treatment of
Hepatitis C.

The purpose of the study is to investigate how quickly Danoprevir is absorbed
and the extent of absorption and elimination from the body (this is called
pharmacokinetics and bioavailability) when it is administered intravenously
(IV) or orally alone and in combination with Ritonavir (RTV) and with or
without an cyclosporine. In addition, it will be investigated to what extent
Danoprevir is tolerated by the volunteer if administered orally or
intravenously with and without Ritonavir and cyclosporine. Ritonavir and
Cyclosporine are known to interfere with the activity of the enzyme CYP3A and
the transporter OATP, which are involved in the movement and metabolism of
Danoprevir in the body and may therefore interfere with the presence of
Danoprevir in the body.

This is a study in three parts:

In Part 1, 9 healthy volunteers will be dosed three times with IV doses of DNV
or placebo after an oral dose of 100 mg Ritonavir. The IV doses of the 2nd and
3rd dosing will be determined based on the results of the previous dosings.
Possibly 1, 2 or 3 additional periods are added,

In Part 2, 12 healthy volunteers will receive 3 IV doses DNV, 2 oral doses of
DNV and 100 mg RTV b.i.d. during 13 days. 1 DRV IV dose and 1 DNV oral dose
will be administered allone and 2 DNV IV doses and 1 DNV oral dose will be
dosed during steady state of RTV.

In Part 3, 8 healthy volunteers will receive DNV IV twice in combination with
100 mg RTV. In one period this will be combined with 100 mg cyclosporine.

Part 1:
Period 1: All volunteers will receive 100 mg Ritonavir (RTV). after 2 hours 2
mg Danoprevir (DNV) or placebo (2:1) will be administered as a 60 minutes IV.
Period 2: All volunteers will receive 100 mg Ritonavir (RTV). after 2 hours an
amount of DNV based on the results from period 1 or placebo (2:1) will be
administered as a 60 minutes IV.
Period 3: All volunteers will receive 100 mg Ritonavir (RTV). after 2 hours an
amount of DNV based on the results from periods 1 and 2 or placebo (2:1) will
be administered as a 60 minutes IV.

Part 2:
The volunteers will receive 1 IV dose of DNV as determined based on the results
of Part 1 and one 100 mg tablet DNV on two consecutive days. followed by 13
days of ritonavir 100 mg bid dosing combined with dosing of DNV IV (twice) or
tablet on days 1, 10 and 13.

Part 3:
The volunteers will receive 100 mg RTV once and DNV IV once, 2 hours after the
ritonavir dosing, as determined in Part 1 . They will also receive a single
dose of 100 mg Ritonavir and a oral dose of 100 mg ciclosporine, and a IV
dosering DNV zoals 2 hours after dosing, as determined in Part 1. The sequence
is based on the dosing schedule.

During the study several assessments will be performed that may be conceived as
more or less of a burden. This includes blood sampling using venopunction, a
canulla and the IV administration of medication.

Danoprevir: In previous studies with Danoprevir in healthy volunteers oral
doses up to 1600 mg were well tolerated. The most frequent side effects
reported in healthy volunteers were headache, fatigue, chills and fever, nausea
and vomiting, rash, muscle and joint pain, decreased appetite and GI disorders
such as diarrhea, abdominal pain, and flatulence.
In Phase II studies with DNV in patients with Hepatitis C doses up to 1800 mg
per day for up to 12 weeks were administered. The adverse events reported most
commonly include fatigue, chills, pyrexia, irritability, nausea, diarrhea,
vomiting, headache, rash, pruritus, insomnia, myalgia, arthralgia, and
decreased appetite. The majority of adverse events were of mild or moderate
intensity. In patients the following Serious Adverse Effects were observed:
increase liver enzymes in the blood, accumulation of fluids in the abdominal
cavity, pulmonary embolism, and changes in ECG parameters.

Ritonavir
Potential side effects of Ritonavir include:
feeling tired/weak, nausea and vomiting, diarrhea, loss of appetite, abdominal
pain, changes in taste, tingling feeling or numbness in hands or feet, abnormal
sensation, such as burning or prickling around the mouth, dizziness, insomnia
(inability to fall asleep), increase in laboratory values such as cholesterol
and liver enzymes, allergic reactions including skin eruptions, hives, and
rash, inflammation of the pancreas and high blood sugar
The most common side effects of Ritonavir therapy are the following: malaise,
diarrhea, nausea and vomiting, abdominal pain, dizziness, insomnia, sweating
and taste abnormality.

Cyclosporine:
The most common side effects of Cyclosporine are the following: Kidney
problems, high blood pressure, headache including migraine, tremor, increased
levels of lipids (for example cholesterol) in the blood, chest infections,
urinary tract infections and infection with CMV (cytomegalovirus). Numbness or
tingling, loss of appetite, feeling or being sick, stomach pain, diarrhea,
swollen gums, liver disorders, high level of uric acid or potassium in the
blood, low levels of magnesium in the blood, muscle pain or cramp, increased
hair growth on the body, tiredness, herpes infection, candida infection, blood
poisoning, skin disorders, cancers and overproduction of white blood cells.

Danoprevir in combination with Ritonavir:
Danoprevir and Ritonavir have been dosed as a combination in several studies in
healthy volunteers and patients and were well tolerated at doses up to 400/100
mg administered twice daily for up to 10 days. The most prevalent adverse event
reported in healthy volunteers is Diarrhea.

With the dose(s) used in this study no serious adverse effects are expected.
The occurrence of known or other effects cannot be excluded. All potential
drugs cause adverse events to some extent. Therefore you should take into
account that some risks are still unknown at this moment