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

• ClinicalTrials.gov Identifier: NCT00942084
• Recruitment Status: Completed
• First Posted: July 20, 2009
• Results First Posted: January 8, 2014
• Last Update Posted: January 8, 2019
• Sponsor: Phillip Brian Smith
• Collaborator: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Information provided by (Responsible Party): Phillip Brian Smith, Duke University

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Herpes Simplex Virus; Neonatal Sepsis	Drug: Acyclovir	Phase 1

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)

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 32 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open Label Study to Describe the Pharmacokinetics of Acyclovir in Premature Infants
• Study Start Date: September 2011
• Actual Primary Completion Date: June 2012
• Actual Study Completion Date: June 2012

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Protocol V2&up-Grp1-Acyclo10 mg/kg IVq12; Gestational Age 23-29 weeks Postnatal Age < 14 days Dosage 10 mg/kg IV q12 Number of Infants 8	Drug: Acyclovir; 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).
Active Comparator: Protocol V2&up-Grp2_Acyclo20 mg/kg IVq12; 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: 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).
Active Comparator: Protocol V2&up-Grp3-Acyclo20 mg/kg IVq8; Gestational Age 30-34 weeks Postnatal Age <45 days Dosage 20 mg/kg IV q8 Number of Infants 4	Drug: Acyclovir; 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; 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; 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).

Outcome Measures

Primary Outcome Measures :

1. Clearance (CL) [ Time Frame: 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 ]

   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

2. Volume of Distribution (V) [ Time Frame: up to 3 days of study drug administration and 10 days of safety monitoring ]
3. Half-life (T1/2) [ Time Frame: up to 3 days of study drug administration and 10 days of safety monitoring ]
4. Maximum Steady State Concentration (Cmaxss) [ Time Frame: up to 3 dasy of study drug administration and 10 days of safety monitoring ]
5. Steady State Concentration at 50% of the Dosing Interval (C50ss) [ Time Frame: up to 3 days of study drug administration and 10 days of safety monitoring ]
6. Minimum Steady State Concentration (Cminss) [ Time Frame: up to 3 days of study drug administration and 10 days of safety monitoring ]

Eligibility Criteria

• Ages Eligible for Study: up to 45 Days (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, Kansas

Wesely Medical Center

Wichita, Kansas, United States, 67214-4976

United States, Louisiana

Tulane School of Medicine

New Orleans, Louisiana, United States, 70112

United States, North Carolina

Duke University

Durham, North Carolina, United States, 27713

Sponsors and Collaborators

Phillip Brian Smith

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

• Principal Investigator: Phillip B Smith, M.D.; Duke University

More Information

Publications of Results:

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.

Other 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.

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

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.

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.

Feldman S, Rodman J, Gregory B. Excessive serum concentrations of acyclovir and neurotoxicity. J Infect Dis. 1988 Feb;157(2):385-8.

• Responsible Party: Phillip Brian Smith, Associate Professor of Pediatrics, Duke University
• ClinicalTrials.gov Identifier: NCT00942084
• Other Study ID Numbers: Pro00028772
• First Posted: July 20, 2009
• Results First Posted: January 8, 2014
• Last Update Posted: January 8, 2019
• Last Verified: December 2018

Keywords provided by Phillip Brian Smith, Duke University:

HSV; Acyclovir; Pharmacokinetics; Neonate; Premature; Sepsis

Additional relevant MeSH terms:

Herpes Simplex; Neonatal Sepsis; Premature Birth; Sepsis; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Obstetric Labor, Premature; Obstetric Labor Complications; Pregnancy Complications; Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Skin Diseases, Viral; Skin Diseases, Infectious; Skin Diseases; Infant, Newborn, Diseases; Acyclovir; Antiviral Agents; Anti-Infective Agents