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.
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.
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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: firstname.lastname@example.org.