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

Publication ,  Journal Article
Randell, RL; Balevic, SJ; Greenberg, RG; Cohen-Wolkowiez, M; Thompson, EJ; Venkatachalam, S; Smith, MJ; Bendel, C; Bliss, JM; Chaaban, H ...
Published in: Antimicrob Agents Chemother
April 3, 2024

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.

Duke Scholars

Published In

Antimicrob Agents Chemother

DOI

EISSN

1098-6596

Publication Date

April 3, 2024

Volume

68

Issue

4

Start / End Page

e0153323

Location

United States

Related Subject Headings

  • Microbiology
  • Metronidazole
  • Infant, Premature
  • Infant, Newborn
  • Infant
  • Humans
  • Gestational Age
  • Critical Illness
  • Anti-Bacterial Agents
  • 3214 Pharmacology and pharmaceutical sciences
 

Citation

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MLA
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Randell, R. L., Balevic, S. J., Greenberg, R. G., Cohen-Wolkowiez, M., Thompson, E. J., Venkatachalam, S., … Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee. (2024). Opportunistic dried blood spot sampling validates and optimizes a pediatric population pharmacokinetic model of metronidazole. Antimicrob Agents Chemother, 68(4), e0153323. https://doi.org/10.1128/aac.01533-23
Randell, Rachel L., Stephen J. Balevic, Rachel G. Greenberg, Michael Cohen-Wolkowiez, Elizabeth J. Thompson, Saranya Venkatachalam, Michael J. Smith, et al. “Opportunistic dried blood spot sampling validates and optimizes a pediatric population pharmacokinetic model of metronidazole.Antimicrob Agents Chemother 68, no. 4 (April 3, 2024): e0153323. https://doi.org/10.1128/aac.01533-23.
Randell RL, Balevic SJ, Greenberg RG, Cohen-Wolkowiez M, Thompson EJ, Venkatachalam S, et al. Opportunistic dried blood spot sampling validates and optimizes a pediatric population pharmacokinetic model of metronidazole. Antimicrob Agents Chemother. 2024 Apr 3;68(4):e0153323.
Randell, Rachel L., et al. “Opportunistic dried blood spot sampling validates and optimizes a pediatric population pharmacokinetic model of metronidazole.Antimicrob Agents Chemother, vol. 68, no. 4, Apr. 2024, p. e0153323. Pubmed, doi:10.1128/aac.01533-23.
Randell RL, Balevic SJ, Greenberg RG, Cohen-Wolkowiez M, Thompson EJ, Venkatachalam S, Smith MJ, Bendel C, Bliss JM, Chaaban H, Chhabra R, Dammann CEL, Downey LC, Hornik C, Hussain N, Laughon MM, Lavery A, Moya F, Saxonhouse M, Sokol GM, Trembath A, Weitkamp J-H, Hornik CP, Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee. Opportunistic dried blood spot sampling validates and optimizes a pediatric population pharmacokinetic model of metronidazole. Antimicrob Agents Chemother. 2024 Apr 3;68(4):e0153323.

Published In

Antimicrob Agents Chemother

DOI

EISSN

1098-6596

Publication Date

April 3, 2024

Volume

68

Issue

4

Start / End Page

e0153323

Location

United States

Related Subject Headings

  • Microbiology
  • Metronidazole
  • Infant, Premature
  • Infant, Newborn
  • Infant
  • Humans
  • Gestational Age
  • Critical Illness
  • Anti-Bacterial Agents
  • 3214 Pharmacology and pharmaceutical sciences