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Pediatric Infectious Disease Journal:
doi: 10.1097/INF.0b013e3182947cf8
Antimicrobial Reviews

Determining Population and Developmental Pharmacokinetics of Metronidazole Using Plasma and Dried Blood Spot Samples From Premature Infants

Cohen-Wolkowiez, Michael MD, PhD*†; Sampson, Mario PharmD; Bloom, Barry T. MD; Arrieta, Antonio MD§; Wynn, James L. MD; Martz, Karen MS; Harper, Barrie BSMT (ASCP); Kearns, Gregory L. PharmD, PhD**; Capparelli, Edmund V. PharmD††; Siegel, David MD‡‡; Benjamin, Daniel K. Jr MD, PhD, MPH*†; Smith, P. Brian MD, MPH, MHS*†; on behalf of the Best Pharmaceuticals for Children Act–Pediatric Trials Network

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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)2.45 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.

Conclusion: Simulations suggested the majority of infants in the neonatal intensive care unit (>80%) would meet the surrogate efficacy target using postmenstrual age–based dosing.

© 2013 by Lippincott Williams & Wilkins, Inc.

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