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Population Pharmacokinetics of Intravenous Acyclovir in Preterm and Term Infants

Sampson, Mario R. PharmD*†; Bloom, Barry T. MD; Lenfestey, Robert W. MD, MHS*; Harper, Barrie BSMT (ASCP)*; Kashuba, Angela D. PharmD; Anand, Ravinder PhD§; Benjamin, Daniel K. Jr MD, PhD, MPH*; Capparelli, Edmund PharmD; Cohen-Wolkowiez, Michael MD, PhD*; Smith, P. Brian MD, MPH, MHS*; on behalf of the Best Pharmaceuticals for Children Act–Pediatric Trials Network

Pediatric Infectious Disease Journal: January 2014 - Volume 33 - Issue 1 - p 42–49
doi: 10.1097/01.inf.0000435509.75114.3d
Antimicrobial Reviews

Background: Acyclovir is used to treat herpes infections in preterm and term infants; however, the influence of maturation on drug disposition and dosing requirements is poorly characterized in this population.

Methods: We administered intravenous acyclovir to preterm and term infants <31 days postnatal age and collected plasma samples. We performed a population pharmacokinetic analysis. The primary pharmacodynamic target was acyclovir concentration ≥3 mg/L for ≥50% of the dosing interval. The final model was simulated using infant data from a clinical database.

Results: The analysis included 28 infants (median 30 weeks gestation). Acyclovir pharmacokinetics was described by a 1-compartment model: clearance (L/h/kg) = 0.305 × [postmenstrual age (PMA)/31.3 weeks]3.02. This equation predicts a 4.5-fold increase in clearance from 25 to 41 weeks PMA. With proposed dosing, the pharmacodynamic target was achieved in 91% of infants: 20 mg/kg every 12 hours in infants <30 weeks PMA; 20 mg/kg every 8 hours in infants 30 to <36 weeks PMA and 20 mg/kg every 6 hours in infants 36–41 weeks PMA.

Conclusions: Acyclovir clearance increased with infant maturation. A dosing strategy based on PMA accounted for developmental changes in acyclovir disposition to achieve the surrogate pharmacodynamic target in many infants.

From the *Duke Clinical Research Institute, Durham; University of North Carolina, Eshelman School of Pharmacy, Chapel Hill, NC; Wichita Medical Research and Education Foundation, Wichita, KS; §EMMES Corporation, Rockville, MD; and University of California–San Diego, Schools of Medicine and Pharmacy, La Jolla, CA.

Accepted for publication July 30, 2013.

This work was funded under NICHD contract HHSN2752010000031 for the Pediatric Trials Network. Dr. Sampson was supported by training grant T32GM086330 from the National Institute of General Medical Sciences. Dr. Lenfestey has received grant support from the Children’s Miracle Network. Dr. Kashuba has received support from Bristol-Myers Squibb, Boehringer Ingelheim, Merck and GlaxoSmithKline. Dr. Anand received support from Government Contract HHSN267200700051C (PI: Benjamin). Dr. Benjamin received support from the United States government for his work in pediatric and neonatal clinical pharmacology (1R01HD057956-05, 1K24HD058735-05, and NICHD contract HHSN275201000003I) and the nonprofit organization Thrasher Research Fund for his work in neonatal candidiasis (www.thrasherresearch.org); he also received research support from industry for neonatal and pediatric drug development (www.dcri.duke.edu/research/coi.jsp). Dr. Capparelli received salary support from the United States government (U54 HD071600-01) and research support from Trius, Cerexa Pharmaceuticals, Abbott and Theravance. Dr. Cohen-Wolkowiez received support for research from the National Institutes of Health (1K23HD064814); the Food and Drug Administration (1U01FD004858-01), the nonprofit organization Thrasher Research Fund (www.thrasherresearch.org), and from industry for drug development in adults and children (www.dcri.duke.edu/research/coi.jsp). Dr. Smith received salary support for research from the National Institutes of Health and the U.S. Department of Health and Human Services (NICHD 1K23HD060040-01, DHHS-1R18AE000028-01 and HHSN267200700051C); he also received research support from industry for neonatal and pediatric drug development (www.dcri.duke.edu/research/coi.jsp). The authors have no other funding or conflicts of interest to disclose.

Address for correspondence: P. Brian Smith, MD, MPH, MHS, Duke Clinical Research Institute, Box 17969, Durham, NC 27715. E-mail: brian.smith@duke.edu.

© 2014 by Lippincott Williams & Wilkins, Inc.