A Study to Describe the Pharmacokinetics of Acyclovir in Premature Infants (PTN_Acyclo)

Neonatal herpes infection carries a major risk of death if untreated. Prognosis is related to disease extent and timing of therapy, making early diagnosis crucial. Mortality in the pre-antiviral era was 90% for disseminated disease and 50% for central nervous system (CNS) disease. Institution of high-dose (60 mg/kg/day) antiviral therapy with acyclovir has reduced mortality to 31% for disseminated disease and 6% for CNS disease.1 Although acyclovir has reduced mortality dramatically, morbidity remains high.

Study population: Infants < 45 days postnatal age, suspected to have a systemic infection divided into groups by gestational and postnatal age:

Group-1: 23-29 weeks gestational age, <14 days postnatal age Group-2: 23-29 weeks gestational age, 14-44 days postnatal age Group-3: 30-34 weeks gestational age, <45 days postnatal age

Intravenous acyclovir will be administered for 3 days.

Timing of PK sample collection will be with respect to the end of each IV infusion. Timed PK sampling will be drawn at doses 1, and doses 5, 6, 7, 8, or 9.

Dose 1:

0-15 minutes after completion of the 1st dose; Within 30 minutes prior to administration of 2nd dose

Steady state [doses 5 or 6 (groups 1 and 2), doses 8 or 9 (group 3)]:

Within 30 minutes prior to dose; 0-15 minutes after completion of the dose; 2-3 hours after completion of the dose; Within 30 minutes prior to administration of the next dose

Last dose:

6-7 hours after the last dose (groups 1 and 2)and 10-11 hours after the last dose (group 3)

The investigator or other study site personnel will document in the source documents (e.g., the hospital chart) that informed consent was obtained. Laboratory tests or non-pharmacologic treatment procedures that were performed as standard of care within 72 hours prior to first dose of study drug may be used for screening procedures and recorded in the CRF.

Inclusion criteria

• < 45 days of age at the time of initial study drug administration.
• Sufficient venous access to permit administration of study medication.
• Availability and willingness of the parent/legal guardian to provide written informed consent.
• Suspected HSV sepsis OR At least two (2) of the following

• Signs of sepsis AND negative blood cultures for >24 hours7
• Respiratory distress8
• Lethargy8
• Fever ≥ 38.0°C7
• Skin lesions7,8
• Seizures (clinical OR EEG confirmed)7
• Irritability7
• AST OR ALT >2 X upper limit of normal7,8
• >20 WBCs/µL or >500 RBCs/µL7

Exclusion criteria

• History of anaphylaxis attributed to acyclovir.
• Serum creatinine >1.7 mg/dL.
• Urine output <0.5 mL/kg/hour over the previous 12 hours
• Previous participation in the study.
• Concomitant condition, which in the opinion of the investigator would preclude a participant's participation in the study