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

NCT00942084 | Completed Phase 1 Results DMC

• 1 other identifier: Pro00028772
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 3

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.

Conditions

Herpes Simplex Virus; Neonatal Sepsis

Keywords

HSV; Acyclovir; Pharmacokinetics; Neonate; Premature; Sepsis

Outcome Measures

Primary Outcomes (6)

• 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

Study Arms (4)

Protocol V2&up-Grp1-Acyclo10 mg/kg IVq12

ACTIVE COMPARATOR

Gestational Age 23-29 weeks Postnatal Age \< 14 days Dosage 10 mg/kg IV q12 Number of Infants 8

Drug: Acyclovir

Protocol V2&up-Grp2_Acyclo20 mg/kg IVq12

ACTIVE COMPARATOR

Gestational Age 23-29 weeks Postnatal Age 14-44 days Dosage 20 mg/kg IV q12 Number of Infants 8

Drug: Acyclovir

Protocol V2&up-Grp3-Acyclo20 mg/kg IVq8

ACTIVE COMPARATOR

Gestational Age 30-34 weeks Postnatal Age \<45 days Dosage 20 mg/kg IV q8 Number of Infants 4

Drug: Acyclovir

Protocol V1-Grps1-4-Acyclo 500 mg/m2 IVq8h

OTHER

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

Interventions

Acyclovir DRUG

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).

Protocol V1-Grps1-4-Acyclo 500 mg/m2 IVq8h; Protocol V2&up-Grp1-Acyclo10 mg/kg IVq12; Protocol V2&up-Grp2_Acyclo20 mg/kg IVq12; Protocol V2&up-Grp3-Acyclo20 mg/kg IVq8

Eligibility Criteria

• Age: Up to 45 Days
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• \< 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Phillip Brian Smith: lead
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Study Sites (3)

Wesely Medical Center

Wichita, Kansas, 67214-4976, United States

Location

Tulane School of Medicine

New Orleans, Louisiana, 70112, United States

Location

Duke University

Durham, North Carolina, 27713, United States

Location

Related Publications (12)

• Whitley RJ. Herpes simplex virus infection. Semin Pediatr Infect Dis. 2002 Jan;13(1):6-11. doi: 10.1053/spid.2002.29752.

  PMID: 12118847 BACKGROUND

• 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.

  PMID: 11483782 BACKGROUND

• 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.

  PMID: 7048912 BACKGROUND

• 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.

  PMID: 2066845 BACKGROUND

• 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.

  PMID: 7048911 BACKGROUND

• 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.

  PMID: 6285713 BACKGROUND

• 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.

  PMID: 6285712 BACKGROUND

• Pickering LK. Red Book. 28th ed. Elk Grove Village, Illinois: American Academy of Pediatrics; 2009.

  BACKGROUND

• 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.

  PMID: 18639724 BACKGROUND

• 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.

  PMID: 7251524 BACKGROUND

• 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.

  PMID: 3335815 BACKGROUND

• 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.

  PMID: 18846389 RESULT

MeSH Terms

Conditions

Herpes Simplex; Neonatal Sepsis; Premature Birth; Sepsis

Interventions

Acyclovir

Condition Hierarchy (Ancestors)

Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Infections; Skin Diseases, Viral; Skin Diseases, Infectious; Skin Diseases; Skin and Connective Tissue Diseases; Infant, Newborn, Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases

Intervention Hierarchy (Ancestors)

Guanine; Hypoxanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: P. Brian Smith, MD MPH MHS
• Organization: Duke Clinical Research Institute

brian.smith@duke.edu

919-668-8951

Study Officials

• Phillip B Smith, M.D.

  Duke University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor of Pediatrics

Study Record Dates

• First Submitted: July 17, 2009
• First Posted: July 20, 2009
• Study Start: September 1, 2011
• Primary Completion: June 1, 2012
• Study Completion: June 1, 2012
• Last Updated: January 8, 2019
• Results First Posted: January 8, 2014

Record last verified: 2018-12

Locations

US (3)