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. 2024 Apr 3;68(4):e0153323.
doi: 10.1128/aac.01533-23. Epub 2024 Mar 14.

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

Rachel L Randell  1   2 , Stephen J Balevic  1   2 , Rachel G Greenberg  1   2 , Michael Cohen-Wolkowiez  1   2 , Elizabeth J Thompson  1   2 , Saranya Venkatachalam  2 , Michael J Smith  1 , Catherine Bendel  3 , Joseph M Bliss  4 , Hala Chaaban  5 , Rakesh Chhabra  6 , Christiane E L Dammann  7 , L Corbin Downey  8 , Chi Hornik  1   2 , Naveed Hussain  9 , Matthew M Laughon  10 , Adrian Lavery  11 , Fernando Moya  12 , Matthew Saxonhouse  13 , Gregory M Sokol  14 , Andrea Trembath  15 , Joern-Hendrik Weitkamp  16 , Christoph P Hornik  1   2 ; Best Pharmaceuticals for Children Act – Pediatric Trials Network Steering Committee
Collaborators, Affiliations

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

Rachel L Randell et al. Antimicrob Agents Chemother. .

Erratum in

Abstract

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.

Keywords: metronidazole; pediatric; pharmacokinetics.

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Conflict of interest statement

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.

Figures

Fig 1
Fig 1
Prediction-corrected visual predictive check for external validation of the PTN_METRO population pharmacokinetics model (9) of metronidazole using estimated metronidazole concentrations from critically ill infants in the SCAMP trial (16) with gestational ages ≤ 31 to match the PTN_METRO study demographics. Panel A shows the original PTN_METRO model with fixed parameters, and Panel B shows the original PTN_METRO model with re-estimated parameters. The shaded region denotes the 90% prediction interval of the simulated data. The solid lines from the bottom to the top represent the predicted 5th, 50th, and 95th percentiles. The dashed lines from the bottom to the top represent observed 5th, 50th, and 95th percentiles. Abbreviations: PTN_METRO, Metronidazole Pharmacokinetics in Premature Infants; SCAMP, Antibiotic Safety in Infants with Complicated Intra-Abdominal Infections.
Fig 2
Fig 2
Prediction-corrected visual predictive check for an optimized population pharmacokinetics model of metronidazole in critically ill term and preterm infants. The shaded region and solid lines denote the 90% prediction interval based on 1,000 simulations.
See this image and copyright information in PMC

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