Opportunistic dried blood spot sampling validates and optimizes a pediatric population pharmacokinetic model of metronidazole.

Autor:	Randell RL; Department of Pediatrics, Duke University, Durham, North Carolina, USA.; Duke Clinical Research Institute, Durham, North Carolina, USA., Balevic SJ; Department of Pediatrics, Duke University, Durham, North Carolina, USA.; Duke Clinical Research Institute, Durham, North Carolina, USA., Greenberg RG; Department of Pediatrics, Duke University, Durham, North Carolina, USA.; Duke Clinical Research Institute, Durham, North Carolina, USA., Cohen-Wolkowiez M; Department of Pediatrics, Duke University, Durham, North Carolina, USA.; Duke Clinical Research Institute, Durham, North Carolina, USA., Thompson EJ; Department of Pediatrics, Duke University, Durham, North Carolina, USA.; Duke Clinical Research Institute, Durham, North Carolina, USA., Venkatachalam S; Duke Clinical Research Institute, Durham, North Carolina, USA., Smith MJ; Department of Pediatrics, Duke University, Durham, North Carolina, USA., Bendel C; Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota, USA., Bliss JM; Department of Pediatrics, University of Rochester Medical Center, Rochester, New York, USA., Chaaban H; Division of Neonatology, Department of Pediatrics, Oklahoma University Health Sciences Center, Oklahoma City, Oklahoma, USA., Chhabra R; Division of Neonatology, Department of Pediatrics, Hackensack University Medical Center, Hackensack, New Jersey, USA., Dammann CEL; Department of Pediatrics, Tufts Medical Center, Tufts University, Boston, Massachusetts, USA., Downey LC; Department of Pediatrics, Atrium Health Wake Forest Baptist Medical Center, Winston-Salem, North Carolina, USA., Hornik C; Department of Pediatrics, Duke University, Durham, North Carolina, USA.; Duke Clinical Research Institute, Durham, North Carolina, USA., Hussain N; Division of Neonatology, Department of Pediatrics, Connecticut Children's, Hartford, Connecticut, USA., Laughon MM; Department of Pediatrics, Division of Neonatal-Perinatal Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA., Lavery A; Loma Linda University, Loma Linda, California, USA., Moya F; Division of Wilmington Pediatric Specialties, Department of Pediatrics, UNC School of Medicine, Chapel Hill, North Carolina, USA., Saxonhouse M; Division of Neonatology, Department of Pediatrics, Levine Children's Hospital, Wake Forest School of Medicine, Charlotte campus, Atrium Healthcare, Charlotte, North Carolina, USA., Sokol GM; Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA., Trembath A; Division of Neonatal-Perinatal Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA., Weitkamp J-H; Mildred Stahlman Division of Neonatology, Monroe Carell Jr. Children's Hospital at Vanderbilt, Vanderbilt University Medical Center, Nashville, Tennessee, USA., Hornik CP; Department of Pediatrics, Duke University, Durham, North Carolina, USA.; Duke Clinical Research Institute, Durham, North Carolina, USA.
Jazyk:	angličtina
Zdroj:	Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2024 Apr 03; Vol. 68 (4), pp. e0153323. Date of Electronic Publication: 2024 Mar 14.
DOI:	10.1128/aac.01533-23
Abstrakt:	Pharmacokinetic models rarely undergo external validation in vulnerable populations such as critically ill infants, thereby limiting the accuracy, efficacy, and safety of model-informed dosing in real-world settings. Here, we describe an opportunistic approach using dried blood spots (DBS) to evaluate a population pharmacokinetic model of metronidazole in critically ill preterm infants of gestational age (GA) ≤31 weeks from the Metronidazole Pharmacokinetics in Premature Infants (PTN_METRO, NCT01222585) study. First, we used linear correlation to compare 42 paired DBS and plasma metronidazole concentrations from 21 preterm infants [mean (SD): post natal age 28.0 (21.7) days, GA 26.3 (2.4) weeks]. Using the resulting predictive equation, we estimated plasma metronidazole concentrations (ePlasma) from 399 DBS collected from 122 preterm and term infants [mean (SD): post natal age 16.7 (15.8) days, GA 31.4 (5.1) weeks] from the Antibiotic Safety in Infants with Complicated Intra-Abdominal Infections (SCAMP, NCT01994993) trial. When evaluating the PTN_METRO model using ePlasma from the SCAMP trial, we found that the model generally predicted ePlasma well in preterm infants with GA ≤31 weeks. When including ePlasma from term and preterm infants with GA >31 weeks, the model was optimized using a sigmoidal Emax maturation function of postmenstrual age on clearance and estimated the exponent of weight on volume of distribution. The optimized model supports existing dosing guidelines and adds new data to support a 6-hour dosing interval for infants with postmenstrual age >40 weeks. Using an opportunistic DBS to externally validate and optimize a metronidazole population pharmacokinetic model was feasible and useful in this vulnerable population. Competing Interests: R.L.R. and E.J.T. are supported by the NICHD under Award Number T32HD104576. The spouse of R.L.R. has financial relationships with Merck & Co, Inc. and Biogen. S.J.B. receives support from the National Institutes of Health, the US Food and Drug Administration, the Childhood Arthritis and Rheumatology Research Alliance, Purdue Pharma, consulting for UCB and Rutgers, and serves on an NIH Data Safety Monitoring Board. M.C.W. receives support for research from the NIH [1U24-MD016258], National Institute of Allergy and Infectious Diseases [HHSN272201500006I, 1K24-AI143971], FDA [5U18-FD006298], and industry for drug development in adults and children. M.J.S. reports research support from Pfizer and Merck. C.P.H. receives salary support for research from NIH, FDA, the Burroughs Wellcome Fund, and other sponsors for drug development in adults and children (https://dcri.org/about-us/conflict-of-interest/). R.G.G. has received support from the NIH, the FDA, the Centers for Disease Control, and industry for research services (https://dcri.org/about-us/conflict-of-interest/). C.B. receives research support from the NIH and Aerogen. J.M.B. receives research support from NICHD (R01HD097081). H.C. receives support for research from the NIH (1R01HD109784). M.M.L. receives support from grant K24 HL143283. G.M.S. receives research support from NIH, Thrasher Research Fund, Airway Therapeutics, and ICON Clinical Research. J.H.W. is consulting for Roche Diagnostics, Inc. R.C., L.C.D., N.H., A.L., F.M., M.S., A.T., S.V., C.E.L.D., and C.H. report no funding.
Databáze:	MEDLINE
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