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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

The Pediatric Infectious Disease Journal: September 2013 - Volume 32 - Issue 9 - p 956–961
doi: 10.1097/INF.0b013e3182947cf8
Antimicrobial Reviews

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.

Supplemental Digital Content is available in the text.

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.

Accepted for publication March 18, 2013.

This work was supported by US government contract HHSN267200700051C (PI: D.K.B.), DHHS-1R18AE000028-01 (PI: P.B.S.), T32GM086330 (M.S.) from the National Institutes of Health/National Institute of General Medical Sciences, the Best Pharmaceuticals for Children Act and the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

M.C.-W. receives support from the nonprofit organization Thrasher Research Foundation (www.thrasherresearch.org) and from industry for neonatal and pediatric drug development (www.dcri.duke.edu/research/coi.jsp). D.K.B. has received research grants from Astellas Pharma US, AstraZeneca and UCB Pharma; he has also served as a consultant for Astellas Pharma US, Biosynexus, Cubist Pharmaceuticals, Johnson & Johnson Pharmaceutical Research & Development, Merck & Co., Pfizer and The Medicines Company. P.B.S. has received a research grant from CV Therapeutics Inc.; he has also served as consultant for Astellas Pharma US, CV Therapeutics Inc., Johnson & Johnson, Pangen, Biostystems Inc. and Pfizer. The authors have no other funding or conflicts of interest to disclose.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.pidj.com).

Address for correspondence: Michael Cohen-Wolkowiez, MD, PhD, Assistant Professor, Duke University, Pediatrics, Duke Clinical Research Institute, P.O. Box 17969, Durham, NC 27715. E-mail: michael.cohenwolkowiez@duke.edu.

© 2013 by Lippincott Williams & Wilkins, Inc.