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

Study Overview
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Brief Summary
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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.

Detailed Description
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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)

Official Title
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An Open Label Study to Describe the Pharmacokinetics of Acyclovir in Premature Infants

Conditions
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Herpes Simplex Virus, Neonatal Sepsis

Intervention / Treatment
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* Drug: Acyclovir


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Maximum Age: 45 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Protocol V2&up-Grp1-Acyclo10 mg/kg IVq12<br>Gestational Age 23-29 weeks Postnatal Age < 14 days Dosage 10 mg/kg IV q12 Number of Infants 8 | Drug: Acyclovir<br>* Protocol V2 & up: Acyclovir 7mg/ml to be administered IV at 10 mg/kg IV q12 or 20 mg/kg IV q12 or 20 mg/kg IV q8 for a total of 6-9 doses(3 days). Protocol V1: Acyclovir 5 mg/mL to be administered IV at 500 mg/m2 IV q8h for a total of approximately 15 doses (10 days).<br>|
| Active Comparator: Protocol V2&up-Grp2_Acyclo20 mg/kg IVq12<br>Gestational Age 23-29 weeks Postnatal Age 14-44 days Dosage 20 mg/kg IV q12 Number of Infants 8 | Drug: Acyclovir<br>* Protocol V2 & up: Acyclovir 7mg/ml to be administered IV at 10 mg/kg IV q12 or 20 mg/kg IV q12 or 20 mg/kg IV q8 for a total of 6-9 doses(3 days). Protocol V1: Acyclovir 5 mg/mL to be administered IV at 500 mg/m2 IV q8h for a total of approximately 15 doses (10 days).<br>|
| Active Comparator: Protocol V2&up-Grp3-Acyclo20 mg/kg IVq8<br>Gestational Age 30-34 weeks Postnatal Age <45 days Dosage 20 mg/kg IV q8 Number of Infants 4 | Drug: Acyclovir<br>* Protocol V2 & up: Acyclovir 7mg/ml to be administered IV at 10 mg/kg IV q12 or 20 mg/kg IV q12 or 20 mg/kg IV q8 for a total of 6-9 doses(3 days). Protocol V1: Acyclovir 5 mg/mL to be administered IV at 500 mg/m2 IV q8h for a total of approximately 15 doses (10 days).<br>|
| Other: Protocol V1-Grps1-4-Acyclo 500 mg/m2 IVq8h<br>All patients in protocol V1 were to be dosed with 500 mg/m2 IV q8h. Protocol V1 Group 1: Gestational Age: 23-29 Weeks; PNA: <14 days; Protocol V1 Group 2: Gestational Age: 30-42 Weeks; PNA: <14 days; Protocol V1 Group 3: Gestational Age: 23-29 Weeks; PNA: 14-60 days; Protocol V1 Group 4: Gestational Age: 30-42 Weeks; PNA: 14-60 days | Drug: Acyclovir<br>* Protocol V2 & up: Acyclovir 7mg/ml to be administered IV at 10 mg/kg IV q12 or 20 mg/kg IV q12 or 20 mg/kg IV q8 for a total of 6-9 doses(3 days). Protocol V1: Acyclovir 5 mg/mL to be administered IV at 500 mg/m2 IV q8h for a total of approximately 15 doses (10 days).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clearance (CL) | Timeframe: Version 1:0-5 min,2-4 hrs,6-8 hrs post doses 1 and 5-15; prior to doses 5-15 Version 2:0-15 min post doses 1 and 5-15; within 30 min prior to doses 2 and 5-15; 2-3 hrs post doses 5-15; 15-18 hrs post last dose | V1:0-5 min,2-4 hrs,6-8 hrs post Doses 1&5-15;prior to doses 5-15; V2:0-15 min post doses 1&5-15; within 30 min prior to doses 2&5-15; 2-3 hrs post doses 5-15; 15-18 hrs post last dose | 
| Volume of Distribution (V) |  | up to 3 days of study drug administration and 10 days of safety monitoring | 
| Half-life (T1/2) |  | up to 3 days of study drug administration and 10 days of safety monitoring | 
| Maximum Steady State Concentration (Cmaxss) |  | up to 3 dasy of study drug administration and 10 days of safety monitoring | 
| Steady State Concentration at 50% of the Dosing Interval (C50ss) |  | up to 3 days of study drug administration and 10 days of safety monitoring | 
| Minimum Steady State Concentration (Cminss) |  | up to 3 days of study drug administration and 10 days of safety monitoring | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HSV, Acyclovir, Pharmacokinetics, Neonate, Premature, Sepsis