Neonatal Herpes Simplex Infection
Conditions
Keywords
valacyclovir
Brief summary
This is an open-label, single center, pharmacokinetic (PK) study to assess valacyclovir pharmacokinetics and pharmacodynamics in neonates and compare to the pharmacokinetics and pharmacodynamics of the standard of care treatment dose of intravenous acyclovir. 6 (up to 10 infants) with virologically confirmed neonatal herpes simplex virus (HSV) disease who meet all inclusion/exclusion criteria will be enrolled in the study. Study duration is 5 years. Primary objective is to define the pharmacokinetics of valacyclovir and assess its safety in neonates 2-12 weeks of age who are ≥ 34 weeks gestation.
Detailed description
This is an open-label, single center, PK study to assess valacyclovir pharmacokinetics and pharmacodynamics in neonates and compare to the pharmacokinetics and pharmacodynamics of the standard of care treatment dose of intravenous acyclovir. Only those babies with virologically confirmed neonatal HSV disease will be enrolled in the study. The decision to initiate valacyclovir for 2 (up to 7) days will be made by a physician based on inclusion/exclusion criteria, and those who meet entry criteria will be eligible for the study. Those enrolled in the study will have daily random parenteral acyclovir PK levels drawn during the first week of treatment (drawn only at times of other lab draws). These infants will also have a pharmacokinetic sampling profile obtained on or after dose 22 and before dose 42 of intravenous acyclovir. The PK samples for the sampling profile will be collected just prior to the next dose of intravenous acyclovir (within 30 minutes prior to the start of the infusion), within 15 minutes of completion of the infusion, and 3-4 hours after infusion. Upon completion of the recommended treatment course duration with intravenous acyclovir determined by disease classification (skin, eye, and mouth; central nervous system; or disseminated disease), the infant will be started on enteral valacyclovir 20 mg/kg every 8 hours. On day 2 and no more than day 7 of valacyclovir 20 mg/kg every 8 hours, a pharmacokinetic sampling profile will be obtained. The PK samples will be collected just prior to the enteral dose of valacyclovir (hour 0; 8 hours after previous dose and immediately before next dose), 1-2 hours after dose, and 3-5 hours after dose. Primary objective is to define the pharmacokinetics of valacyclovir and assess its safety in neonates 2-12 weeks of age who are ≥ 34 weeks gestation. Secondary objectives are to: 1) assess the pharmacokinetics of high-dose parenteral acyclovir in neonates ≥ 34 weeks gestation with virologically confirmed neonatal HSV disease who are receiving acyclovir as standard of care, 2) compare the pharmacokinetics of high-dose parenteral acyclovir to the pharmacokinetics of the proposed study dose of valacyclovir (20 mg/kg every 8 hours).
Interventions
DRUGValacyclovir
Upon completion of standard of care acyclovir for treatment of neonatal HSV disease, valacyclovir oral suspension (per ASHP recipe), 20 mg/kg every 8 hours, to be given for 2 (up to 7) days
Sponsors
University of Alabama at Birmingham
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Weeks to 12 Weeks
Healthy volunteers
No
Inclusion criteria
* Signed informed consent from parent(s) or legal guardian(s) * Confirmation of HSV infection from surface culture/PCR, skin lesion culture/PCR, blood PCR, or CSF PCR (performed at UAB Virology lab) * ≥34 weeks gestational age at birth * Weight at study enrollment is ≥ 2000 grams * Receiving intravenous acyclovir, prescribed by the patient's physician for ≤ 14 days * ≤ 42 days of age at initiation of parenteral acyclovir * Creatinine ≤ 1.2
Exclusion criteria
* Imminent demise * Current receipt of other investigational drugs * Major congenital anomaly that in the site investigator's opinion may impact drug metabolism or the patient's volume of distribution * Creatinine of \> 1.2 prior to initiation of valacyclovir * Evidence of immunosuppression (HIV infected, immune deficiencies, etc.) * Any condition that, in the opinion of the investigator, would place the subject at an unacceptable injury risk or that may interfere with successful study completion * \> 42 days of age at initiation of parenteral acyclovir * Concern for parental/guardian compliance
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve Following Administration of Oral Valacyclovir Suspension 20 mg/kg Every 8 Hours | Between Day 2 and Day 7 of valacyclovir administration: 0, 1-2, 3-5 hours. | Blood will be collected to determine the drug concentration of acyclovir, the metabolite of valacyclovir and will include AUC. |
| Creatinine Clearance Following Administration of Oral Valacyclovir Suspension 20 mg/kg Every 8 Hours | Between Day 2 and Day 7 of valacyclovir administration: 0, 1-2, 3-5 hours. | Blood will be collected to determine the drug concentration of acyclovir, the metabolite of valacyclovir and will include CL/F. |
| Half-life Following Administration of Oral Valacyclovir Suspension 20 mg/kg Every 8 Hours | Between Day 2 and Day 7 of valacyclovir administration: 0, 1-2, 3-5 hours. | Blood will be collected to determine the drug concentration of acyclovir, the metabolite of valacyclovir and will include T1/2. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve Following Administration of Parenteral Acyclovir 20 mg/kg Every 8 Hours | One PK level drawn randomly on days 1-7; in addition, on one day between day 8 -14 of parenteral acyclovir, 3 PK levels to be drawn (drawn 30 minutes prior to infusion, 15 minutes after completion of infusion, and 3-4 hours after infusion) | This study will determine the blood concentrations of acyclovir flowing valacyclovir administration. The goal is to define the valacyclovir dose which will allow a switch from IV to PO medication. In so doing, the potential duration of hospitalization can be decreased. To achieve this end, blood is collected to determine AUC. |
| Comparison of the Area Under the Curve of 20 mg/kg IV Acyclovir to the Area Under the Curve of 20 mg/kg PO Valacyclovir | Random PK levels on days 1-7 of acyclovir administration, PK levels obtained on one day between day 8-14 at specified time intervals, and PK levels obtained one day while on valacyclovir (see outcome 1 and outcome 3 for time intervals) | To determine if the concentration of the active metabolite acyclovir after administration of acyclovir and valacyclovir at specified time intervals produces the same area under the curve |
| Half-life Following Administration of Parenteral Acyclovir 20 mg/kg Every 8 Hours | One PK level drawn randomly on days 1-7; in addition, on one day between day 8 -14 of parenteral acyclovir, 3 PK levels to be drawn (drawn 30 minutes prior to infusion, 15 minutes after completion of infusion, and 3-4 hours after infusion) | This study will determine the blood concentrations of acyclovir flowing valacyclovir administration. The goal is to define the valacyclovir dose which will allow a switch from IV to PO medication. In so doing, the potential duration of hospitalization can be decreased. To achieve this end, blood is collected to determine T1/2 of drug. |
| Creatinine Clearance Following Administration of Parenteral Acyclovir 20 mg/kg Every 8 Hours | One PK level drawn randomly on days 1-7; in addition, on one day between day 8 -14 of parenteral acyclovir, 3 PK levels to be drawn (drawn 30 minutes prior to infusion, 15 minutes after completion of infusion, and 3-4 hours after infusion) | This study will determine the blood concentrations of acyclovir flowing valacyclovir administration. The goal is to define the valacyclovir dose which will allow a switch from IV to PO medication. In so doing, the potential duration of hospitalization can be decreased. To achieve this end, blood is collected to determine creatinine clearance of drug. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Neonatal HSV Disease Requiring Suppressive Therapy All subjects enrolled in the study will receive 2 (up to 7) days of valacyclovir 20 mg/kg every 8 hours after completion of standard of care treatment course with acyclovir. | 7 |
| Total | 7 |
Baseline characteristics
| Characteristic | Neonatal HSV Disease Requiring Suppressive Therapy |
|---|---|
| Age at time of parental acyclovir profile (days) | 30 days |
| Age at time of valacyclovir profile (days) | 35 days |
| Age, Customized 0-20 days | 4 Participants |
| Age, Customized 21-42 days | 3 Participants |
| Interval between parental acyclovir and valacyclovir profile (days) | 6 days |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 6 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 7 |
| other Total, other adverse events | 0 / 7 |
| serious Total, serious adverse events | 0 / 7 |
Outcome results
Primary
Area Under the Curve Following Administration of Oral Valacyclovir Suspension 20 mg/kg Every 8 Hours
Blood will be collected to determine the drug concentration of acyclovir, the metabolite of valacyclovir and will include AUC.
Time frame: Between Day 2 and Day 7 of valacyclovir administration: 0, 1-2, 3-5 hours.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Neonatal HSV Disease Requiring Suppressive Therapy | Area Under the Curve Following Administration of Oral Valacyclovir Suspension 20 mg/kg Every 8 Hours | 28.8 mgxh/l | Standard Deviation 16.8 |
Primary
Creatinine Clearance Following Administration of Oral Valacyclovir Suspension 20 mg/kg Every 8 Hours
Blood will be collected to determine the drug concentration of acyclovir, the metabolite of valacyclovir and will include CL/F.
Time frame: Between Day 2 and Day 7 of valacyclovir administration: 0, 1-2, 3-5 hours.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Neonatal HSV Disease Requiring Suppressive Therapy | Creatinine Clearance Following Administration of Oral Valacyclovir Suspension 20 mg/kg Every 8 Hours | 3.1 L/h | Standard Deviation 1.8 |
Primary
Half-life Following Administration of Oral Valacyclovir Suspension 20 mg/kg Every 8 Hours
Blood will be collected to determine the drug concentration of acyclovir, the metabolite of valacyclovir and will include T1/2.
Time frame: Between Day 2 and Day 7 of valacyclovir administration: 0, 1-2, 3-5 hours.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Neonatal HSV Disease Requiring Suppressive Therapy | Half-life Following Administration of Oral Valacyclovir Suspension 20 mg/kg Every 8 Hours | 2.7 hrs. | Standard Deviation 1.2 |
Secondary
Area Under the Curve Following Administration of Parenteral Acyclovir 20 mg/kg Every 8 Hours
This study will determine the blood concentrations of acyclovir flowing valacyclovir administration. The goal is to define the valacyclovir dose which will allow a switch from IV to PO medication. In so doing, the potential duration of hospitalization can be decreased. To achieve this end, blood is collected to determine AUC.
Time frame: One PK level drawn randomly on days 1-7; in addition, on one day between day 8 -14 of parenteral acyclovir, 3 PK levels to be drawn (drawn 30 minutes prior to infusion, 15 minutes after completion of infusion, and 3-4 hours after infusion)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Neonatal HSV Disease Requiring Suppressive Therapy | Area Under the Curve Following Administration of Parenteral Acyclovir 20 mg/kg Every 8 Hours | 70.1 mgxh/L | Standard Deviation 41 |
Secondary
Comparison of the Area Under the Curve of 20 mg/kg IV Acyclovir to the Area Under the Curve of 20 mg/kg PO Valacyclovir
To determine if the concentration of the active metabolite acyclovir after administration of acyclovir and valacyclovir at specified time intervals produces the same area under the curve
Time frame: Random PK levels on days 1-7 of acyclovir administration, PK levels obtained on one day between day 8-14 at specified time intervals, and PK levels obtained one day while on valacyclovir (see outcome 1 and outcome 3 for time intervals)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Neonatal HSV Disease Requiring Suppressive Therapy | Comparison of the Area Under the Curve of 20 mg/kg IV Acyclovir to the Area Under the Curve of 20 mg/kg PO Valacyclovir | PO valacyclovir AUC | 28.8 AUC- mgxh/l | Standard Deviation 16.8 |
| Neonatal HSV Disease Requiring Suppressive Therapy | Comparison of the Area Under the Curve of 20 mg/kg IV Acyclovir to the Area Under the Curve of 20 mg/kg PO Valacyclovir | IV acyclovir AUC (linear adjustment) | 74 AUC- mgxh/l | Standard Deviation 41 |
Secondary
Creatinine Clearance Following Administration of Parenteral Acyclovir 20 mg/kg Every 8 Hours
This study will determine the blood concentrations of acyclovir flowing valacyclovir administration. The goal is to define the valacyclovir dose which will allow a switch from IV to PO medication. In so doing, the potential duration of hospitalization can be decreased. To achieve this end, blood is collected to determine creatinine clearance of drug.
Time frame: One PK level drawn randomly on days 1-7; in addition, on one day between day 8 -14 of parenteral acyclovir, 3 PK levels to be drawn (drawn 30 minutes prior to infusion, 15 minutes after completion of infusion, and 3-4 hours after infusion)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Neonatal HSV Disease Requiring Suppressive Therapy | Creatinine Clearance Following Administration of Parenteral Acyclovir 20 mg/kg Every 8 Hours | 1.1 L/h | Standard Deviation 0.4 |
Secondary
Half-life Following Administration of Parenteral Acyclovir 20 mg/kg Every 8 Hours
This study will determine the blood concentrations of acyclovir flowing valacyclovir administration. The goal is to define the valacyclovir dose which will allow a switch from IV to PO medication. In so doing, the potential duration of hospitalization can be decreased. To achieve this end, blood is collected to determine T1/2 of drug.
Time frame: One PK level drawn randomly on days 1-7; in addition, on one day between day 8 -14 of parenteral acyclovir, 3 PK levels to be drawn (drawn 30 minutes prior to infusion, 15 minutes after completion of infusion, and 3-4 hours after infusion)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Neonatal HSV Disease Requiring Suppressive Therapy | Half-life Following Administration of Parenteral Acyclovir 20 mg/kg Every 8 Hours | 2.5 hrs | Standard Deviation 1.3 |