Opportunistic dried blood spot sampling validates and optimizes a pediatric population pharmacokinetic model of metronidazole
Authors: Randell Rachel L. , Balevic Stephen J. , Greenberg Rachel G. , Cohen-Wolkowiez Michael , Thompson Elizabeth J. , Venkatachalam Saranya , Smith Michael J. , Bendel Catherine , Bliss Joseph M. , Chaaban Hala , Chhabra Rakesh , Dammann Christiane E. L. , Downey L. Corbin , Hornik Chi , Hussain Naveed , Laughon Matthew M. , Lavery Adrian , Moya Fernando , Saxonhouse Matthew , Sokol Gregory M. , Trembath Andrea , Weitkamp Joern-Hendrik , Hornik Christoph P. ,   Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee, Autmizguine Julie , Lavoie Julie , Bendel Catherine , Wassenaar Jenna , Ericksen Jensina , Bliss Joseph M. , Chandley Jane , Bloom Barry , Delmore Paula , Chaaban Hala , Benjamin Kimberly , Chhabra Rakesh , Riordan Marry Ellen , Courtney Sherry , Pierce D. Ann , Dammann Christiane , Downey L. Corbin , Lanier Kristi , Garland Marianne , Weindler Marilyn , Goldstein Stuart , Kirby Cassie , Heresi Gloria , Hornik Chi , Harward Melissa , Hudak Mark , Maddox Ashley , Hussain Naveed , Querim Jennifer , Katheria Anup , Sauberan Jason , Kim Roger , Iwuchukwu Chika , Laughon Matthew , Clark Cynthia , Lavery Adrian , Rundquist Melissa , MacGilvray Scott , Moseley Sherry , Mendley Susan , Moya Fernando , Blanks Tiffony , Mundakel Gratias , Limbu Subhatra , Narvey Michael , Schellenberg Jeannine , Perciaccante James , Rhodes-Ryan Ginger , Safford Shawn , Siwach Pradeep , Saxonhouse Matthew , Rowden Tobi , Sokol Gregory M. , Gunn Susan , Trembath Andrea , Goldblatt Eileen , Weitkamp Joern-Hendrik , Steele Steven , Zinkhan Erin , Rau Carrie , Cole Laura 
Published: April 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.