A Study to Describe the Pharmacokinetics of Acyclovir in Premature Infants (PTN_Acyclo)
NCT ID: NCT00942084
Last Updated: 2019-01-08
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE1
32 participants
INTERVENTIONAL
2011-09-30
2012-06-30
Brief Summary
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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.
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Detailed Description
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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)
Conditions
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Study Design
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NON_RANDOMIZED
SINGLE_GROUP
TREATMENT
NONE
Study Groups
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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
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 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
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 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
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
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).
Interventions
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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).
Eligibility Criteria
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Inclusion Criteria
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
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
45 Days
ALL
No
Sponsors
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Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
NIH
Phillip Brian Smith
OTHER
Responsible Party
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Phillip Brian Smith
Associate Professor of Pediatrics
Principal Investigators
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Phillip B Smith, M.D.
Role: PRINCIPAL_INVESTIGATOR
Duke University
Locations
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Wesely Medical Center
Wichita, Kansas, United States
Tulane School of Medicine
New Orleans, Louisiana, United States
Duke University
Durham, North Carolina, United States
Countries
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References
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Whitley RJ. Herpes simplex virus infection. Semin Pediatr Infect Dis. 2002 Jan;13(1):6-11. doi: 10.1053/spid.2002.29752.
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.
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.
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.
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.
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.
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.
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. No abstract available.
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.
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.
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 Identifiers
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Pro00028772
Identifier Type: -
Identifier Source: org_study_id
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