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Determining population and developmental pharmacokinetics of metronidazole using plasma and dried blood spot samples

Michael Cohen-Wolkowiez1, Mario Sampson, Barry T Bloom

  • 1From 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.

The Pediatric Infectious Disease Journal
|April 17, 2013
PubMed

Insights

This study on metronidazole pharmacokinetics in premature infants suggests postmenstrual age-based dosing can help achieve efficacy targets in neonates.

Area of Science:

  • Neonatal Pharmacology
  • Pediatric Infectious Diseases
  • Clinical Pharmacy

Background:

  • Limited pharmacokinetic data for metronidazole in premature infants necessitates optimized dosing strategies.
  • Current metronidazole dosing recommendations vary due to insufficient pharmacokinetic information.
  • Efficacy targets for metronidazole are not well-defined, aiming to exceed minimum inhibitory concentrations for intra-abdominal infections.

Purpose of the Study:

  • To evaluate the pharmacokinetics (PK) of metronidazole in premature infants.
  • To assess the achievement of surrogate efficacy targets using population PK modeling.
  • To compare plasma and dried blood spot sampling for metronidazole PK analysis.

Main Methods:

  • An open-label, multicenter pharmacokinetic study involving infants ≤32 weeks gestational age.
  • Population pharmacokinetic modeling using NONMEM and Monte Carlo simulations for efficacy target evaluation.
  • Analysis of plasma and dried blood spot samples, including calculation of metabolic ratios.

Main Results:

  • Twenty-four premature infants were enrolled, with detailed demographic and sample data provided.
  • Population pharmacokinetic parameters for metronidazole were determined: clearance and volume of distribution.
  • Pharmacokinetic parameter estimates were comparable between plasma and dried blood spot samples, with metabolic ratios correlating with clearance.

Conclusions:

  • Postmenstrual age-based dosing is predicted to enable over 80% of neonatal intensive care unit infants to meet the surrogate efficacy target for metronidazole.
  • Dried blood spot sampling offers a viable alternative to plasma sampling for metronidazole pharmacokinetic assessments in neonates.
  • The study provides valuable data to inform metronidazole dosing guidelines for premature infants.
Abstract

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