Clinical trial NCT00942084: A Study to Describe the Pharmacokinetics of Acyclovir in Premature Infants (PTN_Acyclo)
Official title: An Open Label Study to Describe the Pharmacokinetics of Acyclovir in Premature Infants
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Herpes Simplex Virus
Neonatal Sepsis
Keywords: HSV
Acyclovir
Pharmacokinetics
Neonate
Premature
Sepsis
Lead sponsor: Duke University
Sponsor class: OTHER
Collaborators: name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2009-07-20
Enrollment: 32
Sex: ALL
Maximum age (years): 45
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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)

Eligibility criteria: 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

Primary outcomes:
measure: Clearance (CL)
timeFrame: 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
measure: Volume of Distribution (V)
timeFrame: up to 3 days of study drug administration and 10 days of safety monitoring
measure: Half-life (T1/2)
timeFrame: up to 3 days of study drug administration and 10 days of safety monitoring
measure: Maximum Steady State Concentration (Cmaxss)
timeFrame: up to 3 dasy of study drug administration and 10 days of safety monitoring
measure: Steady State Concentration at 50% of the Dosing Interval (C50ss)
timeFrame: up to 3 days of study drug administration and 10 days of safety monitoring
measure: Minimum Steady State Concentration (Cminss)
timeFrame: up to 3 days of study drug administration and 10 days of safety monitoring
Secondary outcomes:
Other outcomes:
Locations:
city: Wichita
country: United States
facility: Wesely Medical Center
state: Kansas
city: New Orleans
country: United States
facility: Tulane School of Medicine
state: Louisiana
city: Durham
country: United States
facility: Duke University
state: North Carolina
Study officials:
affiliation: Duke University
name: Phillip B Smith, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Whitley RJ. Herpes simplex virus infection. Semin Pediatr Infect Dis. 2002 Jan;13(1):6-11. doi: 10.1053/spid.2002.29752.
citation: 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. doi: 10.1542/peds.108.2.230.
citation: Lietman PS. Acyclovir clinical pharmacology. An overview. Am J Med. 1982 Jul 20;73(1A):193-6. doi: 10.1016/0002-9343(82)90089-4.
citation: Englund JA, Fletcher CV, Balfour HH Jr. Acyclovir therapy in neonates. J Pediatr. 1991 Jul;119(1 Pt 1):129-35. doi: 10.1016/s0022-3476(05)81053-4.
citation: 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. doi: 10.1016/0002-9343(82)90088-2.
citation: 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. doi: 10.1016/0002-9343(82)90093-6.
citation: Yeager AS. Use of acyclovir in premature and term neonates. Am J Med. 1982 Jul 20;73(1A):205-9. doi: 10.1016/0002-9343(82)90092-4.
citation: Pickering LK. Red Book. 28th ed. Elk Grove Village, Illinois: American Academy of Pediatrics; 2009.
citation: Kimberlin DW. When should you initiate acyclovir therapy in a neonate? J Pediatr. 2008 Aug;153(2):155-6. doi: 10.1016/j.jpeds.2008.04.027. No abstract available.
citation: Brigden D, Bye A, Fowle AS, Rogers H. Human pharmacokinetics of acyclovir (an antiviral agent) following rapid intravenous injection. J Antimicrob Chemother. 1981 Apr;7(4):399-404. doi: 10.1093/jac/7.4.399. No abstract available.
citation: Feldman S, Rodman J, Gregory B. Excessive serum concentrations of acyclovir and neurotoxicity. J Infect Dis. 1988 Feb;157(2):385-8. doi: 10.1093/infdis/157.2.385. No abstract available.
citation: Rhodin MM, Anderson BJ, Peters AM, Coulthard MG, Wilkins B, Cole M, Chatelut E, Grubb A, Veal GJ, Keir MJ, Holford NH. Human renal function maturation: a quantitative description using weight and postmenstrual age. Pediatr Nephrol. 2009 Jan;24(1):67-76. doi: 10.1007/s00467-008-0997-5. Epub 2008 Oct 10.