A Study to Describe the Pharmacokinetics of Acyclovir in Infants

Condition(s) targeted: Herpes Simplex Virus; Neonatal Sepsis

Intervention: Acyclovir (Drug)

Phase: Phase 1

Status: Not yet recruiting

Sponsored by: Duke University

Official(s) and/or principal investigator(s):
Robert W Lenfestey, M.D., Principal Investigator, Affiliation: Duke University

Overall contact:
Robert W Lenfestey, M.D., Phone: 919-684-9298, Email: lenfe001@mc.duke.edu

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.

Official title: Phase 1, Prospective An Open Label Study to Describe the Safety and Pharmacokinetics of Acyclovir in Infants

Study design: Treatment, Non-Randomized, Open Label, Uncontrolled, Single Group Assignment, Pharmacokinetics Study

Primary outcome: The appropriate non-compartmental pharmacokinetic parameters will be computed, including AUC, Cmax, CL, Vss, t1/2. Pharmacokinetic parameters will be summarized by patient weight.

Detailed description: Neonatal HSV carries a major risk of death if untreated. Although acyclovir has reduced mortality dramatically, morbidity remains high. The pharmacokinetics of acyclovir have not been adequately studied in neonates less than 48 hours old. The primary objective is to assess the pharmacokinetics of intravenously administered acyclovir at a single institution in infants younger than 120 days of age with suspected Herpes Simplex Virus (HSV) infection.

We plan to enroll 32 infants within the first 2 months of life. We will administer acyclovir every 8 hours for 5-10 days. We will draw levels at 1, 2-4, and 6-8 hours after the initial dose in order to determine first-dose kinetics. In order to determine steady state kinetics, we will also draw levels at immediately prior to, and at 1, 2-4, and 6-8 hours after a steady state dose (Dose 5-15).

Minimum age: N/A. Maximum age: 60 Days. Gender(s): Both.

Criteria:

The investigator or other study site personnel must document in the source documents (e. g., the hospital chart) that the informed consent was obtained. Laboratory tests or non-pharmacologic treatment procedures that were performed and considered "standard of care" within 72 hours may be used for screening procedures required by the protocol and recorded in the CRF. The presence of inclusion criteria and the absence of exclusion criteria will be verified on the CRF.

Inclusion Criteria:

1. Infant < 60 days old at the time of initial study drug administration.

2. Patient must have sufficient venous access to permit administration of study medication.

3. Infant suspected to have systemic infection and appropriate cultures (blood +/- urine/CSF) are obtained within 48 hours of study entry. Urine and CSF cultures will be obtained based on clinical index of suspicion, but are not required for enrollment.

4. Availability and willingness of the parent/legally authorized representative to provide written informed consent.

Exclusion Criteria:

1. Patients with a history of anaphylaxis attributed to acyclovir.

2. Renal dysfunction indicated by serum creatinine >1. 7 mg/dL

3. Previous participation in the study.

4. Any other concomitant condition, which in the opinion of the investigator would preclude a patient's participation in the study.

Robert W Lenfestey, M.D., Phone: 919-684-9298, Email: lenfe001@mc.duke.edu

Duke University, Durham, North Carolina 27713, United States

Related publications:

Whitley RJ. Herpes simplex virus infection. Semin Pediatr Infect Dis. 2002 Jan;13(1):6-11. Review.

Kimberlin DW, Lin CY, Jacobs RF, Powell DA, Corey L, Gruber WC, Rathore M, Bradley JS, Diaz PS, Kumar M, Arvin AM, Gutierrez K, Shelton M, Weiner LB, Sleasman JW, de Sierra TM, Weller S, Soong SJ, Kiell J, Lakeman FD, Whitley RJ; National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group. Safety and efficacy of high-dose intravenous acyclovir in the management of neonatal herpes simplex virus infections. Pediatrics. 2001 Aug;108(2):230-8.

Lietman PS. Acyclovir clinical pharmacology. An overview. Am J Med. 1982 Jul 20;73(1A):193-6. Review.

Englund JA, Fletcher CV, Balfour HH Jr. Acyclovir therapy in neonates. J Pediatr. 1991 Jul;119(1 ( Pt 1)):129-35.

Blum MR, Liao SH, de Miranda P. Overview of acyclovir pharmacokinetic disposition in adults and children. Am J Med. 1982 Jul 20;73(1A):186-92. Review.

Hintz M, Connor JD, Spector SA, Blum MR, Keeney RE, Yeager AS. Neonatal acyclovir pharmacokinetics in patients with herpes virus infections. Am J Med. 1982 Jul 20;73(1A):210-4.

Yeager AS. Use of acyclovir in premature and term neonates. Am J Med. 1982 Jul 20;73(1A):205-9.

Starting date: August 2009
Ending date: August 2010
Last updated: July 17, 2009