WP16302 A Bioequivalence Study Comparing Ganciclovir From the Valganciclovir Syrup Formulation and the Commercial Valganciclovir 450mg Tablet (Valcyte®) at a Dose of 900mg in Kidney Transplant Recipients

Each patient will receive 900 mg of Valcyte® daily with food for the period specified in
that center (typically 100 days), starting as soon as possible after the transplant.
According to routine practice, intravenous ganciclovir (5 mg/kg) may be substituted if the
patient is unable to tolerate oral medication, during which time the patient will not be
enrolled into the study. The dose of Valganciclovir may be reduced or interrupted at the
discretion of the Investigator if he, or she, suspects that ganciclovir-related toxicity has
occurred, or if the estimated creatinine clearance of the patient drops below 60 ml/min For
the actual study, each patient will receive 2 days treatment on consecutive days with each
Valganciclovir syrup formulation (900 mg once a day.) and the tablet formulation (900 mg
once a day) in a randomized order, before continuing with Valcyte® prophylaxis (commercially
available tablets). The following three treatments will be administered in this study:
Randomization will occur through the IDS pharmacy and a computerized system will randomize
the subjects.

Treatment A (Reference): Valganciclovir tablets 2 x 450 mg once a day for 2 days

Treatment B (Test): Valganciclovir tutti-frutti flavored syrup, 900 mg once a day for 2 days

Treatment C: (First formulation) Valganciclovir strawberry flavored syrup, 900 mg once a day
for 2 days

All formulations will be administered orally within 15 minutes of completion of a standard
breakfast (400-800 kcal). Patients will be seen at that GCRC (General Clinic Research
Center) on the 8th floor of Montefiore Hospital for all study visits except follow-up. This
visit will take place in the Infectious Disease Clinic, 7th floor Falk Clinic.

Screening:

A screening examination will be performed between 1 and 14 days before the start of the
study (the day of first dosing with study drug). Patients who fulfill all of the inclusion
and none of the exclusion criteria will be accepted on to the study. Patients who fail the
renal or hematological function criteria may be re-screened if these parameters improve and
if they are still being treated with Valcyte®. The following procedures will be performed to
establish each patient's general health and eligibility for enrollment into the study:
Record medical history, including etiology of end-stage organ disease, details of transplant
(date and type), any previous disease (including CMV) and treatments, immunosuppressive
drugs and doses within the previous month or from transplantation, whichever is the shorter,
Record CMV serology of donor and recipient., perform physical examination; record
demographic information including sex, age and race/ethnicity; Obtain vital signs, height
and weight; Draw blood samples for laboratory screening of hematology (about one teaspoon of
blood) and routine serum chemistry, including calculation of estimated creatinine clearance;
Obtain a mid-stream urine sample for urinalysis and a pregnancy test (females only). This
visit will take about 30 minutes. Patient will be seen while in hospital by the research
coordinators and research physicians, while recovering from the kidney transplant procedure.

Day 1

Patients will come to the GCRC the evening before, or during the morning of Day 1, within 14
days of screening. The following procedures will be carried out on all patients:

- Assessment that the patient is on stable calcineurin inhibitors and Valganciclovir
therapy ( ≥ 4 days); assignment of patient identification number; physical examination;
concomitant medication since the last visit will be collected; vital signs and weight;
blood samples for hematology and serum chemistry (5 cc); mid-stream sample of urine for
urinalysis and pregnancy testing (females of childbearing potential only); and
breakfast.

- Study drug will be administered (either two Valganciclovir tablets or 900 mg (18 mL) of
syrup formulation of Valganciclovir) with breakfast (must be within 15 minutes of
completion of breakfast). Adverse events and concomitant medications will be recorded.
Patients may be discharged after dosing. This visit will take about 2-3 hours to
complete.

Days 2, 4 and 6

Patients will return to the GCRC during the morning of these days. The following procedures
will be carried out on all patients:

- Pre-dose PK blood sample for determination of trough levels of ganciclovir (5cc)

- Breakfast will start within 15 minutes of the pre-dose PK blood sample. The study drug
(either two Valganciclovir tablets or 900 mg (18 mL) of syrup formulation of
Valganciclovir) will be administered with breakfast (must be within 15 minutes of
completion of breakfast).

- The following procedures will be carried out after dosing: pharmacokinetic blood
samples (total blood collected each day is 11cc) for determination of plasma levels of
ganciclovir 0.5, 0.75, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, and 12 hours post-dose (time
windows of ± 5 minutes are allowed for all samples up to 4 hours and ± 20 minutes for
samples between 6 and 12 hours)

- Adverse events and concomitant medications will be documented. Patients may be
discharged after the 12-hour sample. This day will take twelve -thirteen hours to
complete.

Days 3 and 5

Patients will return to the GCRC during the morning. The following procedures will be
carried out on all patients:

- Vital signs and weight; 24 hour PK blood sample (± 30 minutes) for determination of
trough levels of ganciclovir before dosing with the next formulation of study drug
(1cc); Breakfast will start within 15 minutes of the pre-dose PK blood sample.

- Study drug will be administer (either two Valganciclovir tablets or 900 mg (18 mL) of
syrup formulation of Valganciclovir) with breakfast (must be within 15 minutes of
completion of breakfast). Adverse events and concomitant medications will be recorded.
Patients may be discharged after dosing. This visit will take about 2-3 hours to
complete.

Day 7

Patients will return to the GCRC during the morning. The following procedures will be
carried out on all patients:

- Blood samples for hematology and serum chemistry (5cc); mid-stream sample of urine for
urinalysis; 24 hour PK blood sample (± 30 minutes) for determination of trough levels
of ganciclovir before dosing (5cc). Breakfast will start within 15 minutes of the
pre-dose PK blood sample.

- Two Valcyte® tablets will be administered (supplied by the center) with breakfast (must
be within 15 minutes of completion of breakfast). Adverse events and concomitant
medications will be recorded and patients may then be discharged from the GCRC. This
visit will take about 2-3 hours to complete.

During the Study The following safety assessments will be made throughout the study, from
screening to follow-up, as applicable: adverse events (AE's), including rejection and graft
loss, opportunistic infections (CMV and others) and treatments; concomitant treatments,
including immunosuppressive therapy (induction, maintenance and treatment of rejection) and
patient survival will be documented.

Follow-up Phase Patients will return between Days 13 to 20 for follow-up. The follow-up
procedures will include a physical examination, body weight, vital signs, clinical
laboratory safety tests (hematology, serum chemistry and urinalysis) (5cc), urine pregnancy
test (females of childbearing potential only) and the recording of adverse events and
concomitant medications. Once this visit is complete the patient will have completed the
study. This visit should take about one hour to complete.

Inclusion Criteria:

1. Patient has received first or second kidney transplant.

2. Transplantation occurred at least 14 days before screening.

3. Patient at risk of CMV disease (serostatus, D+R-, D+R+ or D-R+).

4. Patient aged 18 to 68 years inclusive.

5. Patient able to tolerate oral medication from screening to follow-up.

6. Patient being treated with Valganciclovir for prophylaxis of CMV disease according to
current center practice.

7. Patient on stable calcineurin inhibitor and 900 mg Valganciclovir therapy (≥ 4 days
prior to Day 1).

8. Patient with stable serum creatinine (± 0.2 mg/dL) for duration of at least 4 days
prior to dosing on Day 1.

9. Patient with adequate hematological and renal function defined as:

- Estimated creatinine clearance ≥ 60 ml/min

- Absolute neutrophil count ≥ 2500 cells/µL

- Platelet count ≥ 100,000 cells/µL

- Hemoglobin ≥ 9.0g/dL

10. Patient agrees to use an effective method of contraception (or abstinence from sexual
activity) throughout the study period and for 90 days after follow-up, if female of
child-bearing potential, or if male with a female partner of child-bearing potential.

11. Females of childbearing potential with a negative pregnancy test at screening.

12. Patient able to participate, willing to give written, informed consent and comply
with the study restrictions.

Exclusion Criteria:

- Patients with any of the following will be excluded from the study:

1. Patient is simultaneously participating in another clinical trial, except as
approved by the Sponsor.

2. Patient has used an investigational drug within three months of screening.

3. Patient has exhibited in the past an allergic, or other significant adverse
reaction to acyclovir, Val acyclovir, ganciclovir or Valganciclovir.

4. Patient has severe, uncontrolled diarrhea.

5. Evidence of graft rejection as determined by the Investigator.

6. Patient requires the use of any prohibited concomitant medications (Section
4.4).

7. Patient has previously participated (i.e. completed Day 1) in this clinical
trial.

8. Patient is pregnant or a lactating female who will not discontinue nursing prior
to study entry.

9. Patient has received anti-CMV prophylaxis with a treatment other than
intravenous cytogam, intravenous ganciclovir or Valganciclovir between
transplant and enrollment.

10. Patient with active bacterial, viral, fungal or protozoal infection.