title: Determining population and developmental pharmacokinetics of metronidazole using plasma and dried blood spot samples from premature infants.
abstract: BACKGROUND
  Limited pharmacokinetic (PK) data of metronidazole in premature infants have led to various dosing recommendations. Surrogate efficacy targets for metronidazole are ill-defined and therefore aimed to exceed minimum inhibitory concentration of organisms responsible for intra-abdominal infections.
  
  
  METHODS
  We evaluated the PK of metronidazole using plasma and dried blood spot samples from infants ≤32 weeks gestational age in an open-label, PK, multicenter (N = 3) study using population PK modeling (NONMEM). Monte Carlo simulations (N = 1000 virtual subjects) were used to evaluate the surrogate efficacy target. Metabolic ratios of parent and metabolite were calculated.
  
  
  RESULTS
  Twenty-four premature infants (111 plasma and 51 dried blood spot samples) were enrolled: median (range) gestational age at birth 25 (23-31) weeks, postnatal age 27 (1-82) days, postmenstrual age 31 (24-39) weeks and weight 740 (431-1466) g. Population clearance (L/h/kg) was 0.038 × (postmenstrual age/30) and volume of distribution (L/kg) of 0.93. PK parameter estimates and precision were similar between plasma and dried blood spot samples. Metabolic ratios correlated with clearance.
  
  
  CONCLUSIONS
  Simulations suggested the majority of infants in the neonatal intensive care unit (>80%) would meet the surrogate efficacy target using postmenstrual age-based dosing.
authors.affiliation: From the *Department of Pediatrics, Duke University; †Duke Clinical Research Institute, Durham, NC; ‡Wichita Medical Research and Education Foundation, Wichita, KS; §Division of Infectious Diseases, CHOC-Children's Hospital of Orange County, Orange, CA; ¶Department of Pediatrics, Division of Neonatal-Perinatal Medicine, Vanderbilt University Medical Center, Nashville, TN; ‖EMMES Corporation, Rockville, MD; **Department of Pediatrics, University of Missouri-Kansas City School of Medicine and the Division of Pediatric Pharmacology and Therapeutic Innovation, The Children's Mercy Hospital, Kansas City, MO; ††Department of Pediatric Pharmacology, University of California, San Diego, CA; and ‡‡Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD.
authors.forename: Michael
authors.initials: M
authors.lastname: Cohen-Wolkowiez
authors.forename: Mario
authors.initials: M
authors.lastname: Sampson
authors.forename: Barry T
authors.initials: BT
authors.lastname: Bloom
authors.forename: Antonio
authors.initials: A
authors.lastname: Arrieta
authors.forename: James L
authors.initials: JL
authors.lastname: Wynn
authors.forename: Karen
authors.initials: K
authors.lastname: Martz
authors.forename: Barrie
authors.initials: B
authors.lastname: Harper
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Kearns
authors.forename: Edmund V
authors.initials: EV
authors.lastname: Capparelli
authors.forename: David
authors.initials: D
authors.lastname: Siegel
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Benjamin
authors.forename: P Brian
authors.initials: PB
authors.lastname: Smith
mesh_terms: D000890:Anti-Infective Agents / Q000493:pharmacokinetics*; D001774:Blood Chemical Analysis; D003890:Desiccation; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007234:Infant, Premature; D008297:Male; D008795:Metronidazole / Q000493:pharmacokinetics*; D008962:Models, Theoretical; D011446:Prospective Studies; D013048:Specimen Handling / Q000379:methods
chemical_list: D000890:Anti-Infective Agents; D008795:Metronidazole