A Study to Describe the Pharmacokinetics of Acyclovir in Premature Infants (PTN_Acyclo)
| Status: | Completed |
|---|---|
| Conditions: | Infectious Disease, Hospital, Women's Studies |
| Therapuetic Areas: | Immunology / Infectious Diseases, Other, Reproductive |
| Healthy: | No |
| Age Range: | Any |
| Updated: | 1/10/2019 |
| Start Date: | September 2011 |
| End Date: | June 2012 |
An Open Label Study to Describe the Pharmacokinetics of Acyclovir in Premature Infants
Acyclovir is a drug used to treat herpes simplex virus (HSV) infections in babies.
Appropriate dosing of acyclovir is known for adults and children but acyclovir has not been
adequately studied in full-term or premature neonates. HSV is a very serious infection in
babies <6 months of age and often results in death or profound mental retardation. HSV leads
to profound mental retardation in young infants because the virus attacks the central nervous
system.
The investigators hypothesize that the currently recommended dose of acyclovir is inadequate
to produce adequate blood levels to combat herpes simplex infection. The investigators
propose to study acyclovir levels in the blood of babies who are placed on acyclovir to treat
a suspected HSV infection. This will allow them to determine the appropriate dose in
premature infants. This is an unmet public health need because it is likely that the drug
behaves differently in premature infants than it does in term infants and older children.
Premature babies have more body water and less body tissue. Their kidneys are more immature
and do not function as well as full term infants. Premature neonates are also at the greatest
risk from herpes infection because they have poorly functioning immature immune systems.
Early and appropriate treatment with acyclovir has resulted in improved outcome in term
infants.
Appropriate dosing of acyclovir is known for adults and children but acyclovir has not been
adequately studied in full-term or premature neonates. HSV is a very serious infection in
babies <6 months of age and often results in death or profound mental retardation. HSV leads
to profound mental retardation in young infants because the virus attacks the central nervous
system.
The investigators hypothesize that the currently recommended dose of acyclovir is inadequate
to produce adequate blood levels to combat herpes simplex infection. The investigators
propose to study acyclovir levels in the blood of babies who are placed on acyclovir to treat
a suspected HSV infection. This will allow them to determine the appropriate dose in
premature infants. This is an unmet public health need because it is likely that the drug
behaves differently in premature infants than it does in term infants and older children.
Premature babies have more body water and less body tissue. Their kidneys are more immature
and do not function as well as full term infants. Premature neonates are also at the greatest
risk from herpes infection because they have poorly functioning immature immune systems.
Early and appropriate treatment with acyclovir has resulted in improved outcome in term
infants.
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)
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
1. < 45 days of age at the time of initial study drug administration.
2. Sufficient venous access to permit administration of study medication.
3. Availability and willingness of the parent/legal guardian to provide written informed
consent.
4. 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
1. History of anaphylaxis attributed to acyclovir.
2. Serum creatinine >1.7 mg/dL.
3. Urine output <0.5 mL/kg/hour over the previous 12 hours
4. Previous participation in the study.
5. Concomitant condition, which in the opinion of the investigator would preclude a
participant's participation in the study
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