Evaluation of the PK and PD of Ganciclovir (GCV) in Premature Infants Receiving Treatment for CMV Infection

This is an open-label, multi-center, clinical sampling study to assess ganciclovir
pharmacokinetics and pharmacodynamics in premature infants. Only those subjects who receive
ganciclovir for clinical reasons will be enrolled. The decision to initiate ganciclovir
therapy will be made by the attending physician based upon his/her clinical decision to treat
virologically-confirmed CMV infection; infants receiving such therapy and meeting entry
criteria will then be eligible for this study. Therefore, ganciclovir will not provided under
this protocol.

Subjects meeting enrollment criteria will be entered into this clinical trial. Subjects will
be stratified by gestational age and by chronologic age as follows: 1) ≤ 27 weeks 6 days
gestational age at birth and ≤ 30 days chronologic age at study enrollment; 2) ≤ 27 weeks 6
days gestational age at birth and > 30 days chronologic age at study enrollment; 3) ≥ 28
weeks 0 days gestational age at birth and ≤ 30 days chronologic age at study enrollment; 4) ≥
28 weeks 0 days gestational age at birth and > 30 days chronologic age at study enrollment.
Eight subjects will enroll in each of the four groups, for a total sample size of 32
subjects. Subjects in each cohort with inadequate pharmacokinetic data for analysis (e.g.,
due to dropping out of the study before PK assessments are performed, or blood sampling
obtained but is inadequate for analysis) will be replaced and will not count toward the total
of eight subjects in each of the four groups. Additionally, enrollment of an additional 2-3
subjects may be allowed for operational reasons.

A full pharmacokinetic profile will be obtained with one of the ganciclovir doses received
after enrollment. PK assessments will be obtained after the subject has received study
assessment dose 3, 4, 5, 6, 7, or 8 of intravenous ganciclovir. Specimens will be shipped for
processing at that time. The pharmacokinetic data will then be provided to the study site,
including the AUC and CL values for information purposes.

Duration of intravenous ganciclovir therapy is at the discretion of the treating physician
and will not be dictated by the research protocol. Both whole blood for CMV PCR and urine for
CMV detection will be obtained once in each study period as long as the subject is receiving
intravenous ganciclovir therapy. These specimens will be used to determine blood viral load
and ganciclovir resistance. Since ganciclovir is a renally excreted drug, serum creatinine
will be drawn for the research protocol on the day that the ganciclovir pharmacokinetic
specimens are obtained in order to calculate creatinine clearance using a method such as the
modified Schwartz formula, and thus correlate ganciclovir clearance with renal function.
Otherwise, data from hematology assessments (WBC count and differential, hemoglobin, platelet
count) and from chemistry labs (serum creatinine, AST, and ALT) will be recorded on the study
case report forms during each study period if they are being obtained for clinical reasons,
but will not be drawn only for the purposes of the study. Ganciclovir dosing information
(mg/dose, dosing interval, and patient weight) will be recorded on the day of the
pharmacokinetic blood draws, and weekly from Period 1 through Period 7 as long as the subject
is receiving intravenous ganciclovir therapy.

If the patient continues to receive intravenous ganciclovir from Study Assessment Day 18
through Study Assessment Day 24 (Period 4), a second PK assessment may be performed at the
request of the treating physician if the subject weighs 575 grams or more at the time of
specimen collection.

Inclusion Criteria:

1. Signed informed consent from parent(s) or legal guardian(s)

2. Confirmation of CMV infection from urine, blood, or saliva by culture, shell vial, or
PCR tests (local lab)

3. Receiving intravenous ganciclovir, prescribed by the patient's physician

4. < 32 weeks gestational age at birth

5. ≥ 500 grams at study enrollment

Exclusion Criteria:

1. Imminent demise

2. Current receipt of valganciclovir or foscarnet

3. Receiving breast milk from a mother who is being treated with ganciclovir or
valganciclovir

4. Current receipt of other investigational drugs

5. Major congenital anomaly that in the site investigator's opinion may impact drug
metabolism or the patient's volume of distribution