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

Author:

Randell Rachel L.12ORCID,Balevic Stephen J.12,Greenberg Rachel G.12,Cohen-Wolkowiez Michael12,Thompson Elizabeth J.12,Venkatachalam Saranya2,Smith Michael J.1,Bendel Catherine3,Bliss Joseph M.4,Chaaban Hala5,Chhabra Rakesh6,Dammann Christiane E. L.7,Downey L. Corbin8,Hornik Chi12,Hussain Naveed9,Laughon Matthew M.10,Lavery Adrian11,Moya Fernando12,Saxonhouse Matthew13,Sokol Gregory M.14,Trembath Andrea15,Weitkamp Joern-Hendrik16,Hornik Christoph P.12ORCID, ,Autmizguine Julie17,Lavoie Julie17,Bendel Catherine18,Wassenaar Jenna18,Ericksen Jensina18,Bliss Joseph M.19,Chandley Jane19,Bloom Barry20,Delmore Paula20,Chaaban Hala21,Benjamin Kimberly21,Chhabra Rakesh22,Riordan Marry Ellen22,Courtney Sherry23,Pierce D. Ann23,Dammann Christiane24,Downey L. Corbin25,Lanier Kristi25,Garland Marianne26,Weindler Marilyn26,Goldstein Stuart27,Kirby Cassie27,Heresi Gloria28,Hornik Chi29,Harward Melissa29,Hudak Mark30,Maddox Ashley30,Hussain Naveed31,Querim Jennifer31,Katheria Anup32,Sauberan Jason32,Kim Roger33,Iwuchukwu Chika33,Laughon Matthew34,Clark Cynthia34,Lavery Adrian35,Rundquist Melissa35,MacGilvray Scott36,Moseley Sherry36,Mendley Susan37,Moya Fernando38,Blanks Tiffony38,Mundakel Gratias39,Limbu Subhatra39,Narvey Michael40,Schellenberg Jeannine40,Perciaccante James41,Rhodes-Ryan Ginger41,Safford Shawn42,Siwach Pradeep42,Saxonhouse Matthew43,Rowden Tobi43,Sokol Gregory M.44,Gunn Susan44,Trembath Andrea45,Goldblatt Eileen45,Weitkamp Joern-Hendrik46,Steele Steven46,Zinkhan Erin47,Rau Carrie47,Cole Laura47

Affiliation:

1. Department of Pediatrics, Duke University, Durham, North Carolina, USA

2. Duke Clinical Research Institute, Durham, North Carolina, USA

3. Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota, USA

4. Department of Pediatrics, University of Rochester Medical Center, Rochester, New York, USA

5. Division of Neonatology, Department of Pediatrics, Oklahoma University Health Sciences Center, Oklahoma City, Oklahoma, USA

6. Division of Neonatology, Department of Pediatrics, Hackensack University Medical Center, Hackensack, New Jersey, USA

7. Department of Pediatrics, Tufts Medical Center, Tufts University, Boston, Massachusetts, USA

8. Department of Pediatrics, Atrium Health Wake Forest Baptist Medical Center, Winston-Salem, North Carolina, USA

9. Division of Neonatology, Department of Pediatrics, Connecticut Children’s, Hartford, Connecticut, USA

10. Department of Pediatrics, Division of Neonatal-Perinatal Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

11. Loma Linda University, Loma Linda, California, USA

12. Division of Wilmington Pediatric Specialties, Department of Pediatrics, UNC School of Medicine, Chapel Hill, North Carolina, USA

13. Division of Neonatology, Department of Pediatrics, Levine Children’s Hospital, Wake Forest School of Medicine, Charlotte campus, Atrium Healthcare, Charlotte, North Carolina, USA

14. Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA

15. Division of Neonatal-Perinatal Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

16. Mildred Stahlman Division of Neonatology, Monroe Carell Jr. Children’s Hospital at Vanderbilt, Vanderbilt University Medical Center, Nashville, Tennessee, USA

17. Hospital Sainte-Justine, Montreal, Quebec, Canada

18. University of Minnesota Fairview University Medical Center, Minneapolis, Minnesota, USA

19. Women and Infants Hospital of Rhode Island, Providence, Rhode Island, USA

20. Wesley Medical Center, Wichita, Kansas, USA

21. University of Oklahoma Health Science Center, Oklahoma City, Oklahoma, USA

22. Hackensack University Medical Center, Hackensack, New Jersey, USA

23. Arkansas Children’s Hospital/Univ of Arkansas for Medical Sciences, Little Rock, Arkansas, USA

24. Floating Hospital for Children at Tufts Medical Center, Boston, Massachusetts, USA

25. Atrium Health Wake Forest Baptist Medical Center, Winston-Salem, North Carolina, USA

26. Columbia University Neonatology, New York, New York, USA

27. Cincinnati Children's Hospital, Cincinnati, Ohio, USA

28. University of Texas Health Science Center at Houston, Houston, Texas, USA

29. Duke University Hospital, Durham, North Carolina, USA

30. Shands Medical Center, Gainesville, Florida, USA

31. Connecticut Children's Medical Center, Hartford, Connecticut, USA

32. Sharp Mary Birch, San Diego, California, USA

33. Brookdale University Hospital, Brooklyn, New York, USA

34. University of North Carolina Hospitals, Chapel Hill, North Carolina, USA

35. Loma Linda University School of Medicine, Loma Linda, California, USA

36. East Carolina University, Greenville, North Carolina, USA

37. University of Maryland, Baltimore, Maryland, USA

38. Division of Wilmington Pediatric Specialties, Wilmington, North Carolina, USA

39. Kings County Hospital, Brooklyn, New York, USA

40. The Children's Hospital Research Institute of Manitoba, Inc., Winnipeg, Manitoba, Canada

41. WakeMed Faculty Neonatology, Raleigh, North Carolina, USA

42. Carilion Roanoke Memorial Hospital, Roanoke, Virginia, USA

43. Levine Children's Hospital, Charlotte, California, USA

44. Riley Hospital for Children at Indiana University Health, Indianapolis, Indiana, USA

45. UH Rainbow Babies and Children's Hospital, Cleveland, Ohio, USA

46. Monroe Carell Jr. Children’s Hospital at Vanderbilt, Vanderbilt University Medical Center, Nashville, Tennessee, USA

47. University of Utah, Salt Lake City, Utah, USA

Abstract

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.

Publisher

American Society for Microbiology

Reference24 articles.

1. External Evaluation of Population Pharmacokinetic Models of Vancomycin in Large Cohorts of Intensive Care Unit Patients

2. External Validation of Model-Based Dosing Guidelines for Vancomycin, Gentamicin, and Tobramycin in Critically Ill Neonates and Children: A Pragmatic Two-Center Study

3. Clinical Pharmacology Studies in Critically Ill Children

4. U.S. Food & Drug Administration Issued by Center for Drug Evaluation and Research. 2022. General clinical pharmacology considerations for neonatal studies for drugs and biological products guidance for industry. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/general-clinical-pharmacology-considerations-neonatal-studies-drugs-and-biological-products-guidance. Retrieved 1 Sep 2023.

5. Medication Use in the Neonatal Intensive Care Unit and Changes from 2010 to 2018

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