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Physiologically Based Pharmacokinetic Modeling of Meropenem in Preterm and Term Infants

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Abstract

Background

Meropenem is a broad-spectrum carbapenem antibiotic approved by the US Food and Drug Administration for use in pediatric patients, including treating complicated intra-abdominal infections in infants < 3 months of age. The impact of maturation in glomerular filtration rate and tubular secretion by renal transporters on meropenem pharmacokinetics, and the effect on meropenem dosing, remains unknown. We applied physiologically based pharmacokinetic (PBPK) modeling to characterize the disposition of meropenem in preterm and term infants.

Methods

An adult meropenem PBPK model was developed in PK-Sim® (Version 8) and scaled to infants accounting for renal transporter ontogeny and glomerular filtration rate maturation. The PBPK model was evaluated using 645 plasma concentrations from 181 infants (gestational age 23–40 weeks; postnatal age 1–95 days). The PBPK model-based simulations were performed to evaluate meropenem dosing in the product label for infants < 3 months of age treated for complicated intra-abdominal infections.

Results

Our model predicted plasma concentrations in infants in agreement with the observed data (average fold error of 0.90). The PBPK model-predicted clearance in a virtual infant population was successfully able to capture the post hoc estimated clearance of meropenem in this population, estimated by a previously published model. For 90% of virtual infants, a 4-mg/L target plasma concentration was achieved for > 50% of the dosing interval following product label-recommended dosing.

Conclusions

Our PBPK model supports the meropenem dosing regimens recommended in the product label for infants <3 months of age.

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Acknowledgements

Pediatric Trials Network (PTN) Steering Committee Members: Daniel K. Benjamin Jr, Christoph Hornik, Kanecia Zimmerman, Phyllis Kennel, and Rose Beci, Duke Clinical Research Institute, Durham, NC; Chi Dang Hornik, Duke University Medical Center, Durham, NC; Gregory L. Kearns, Scottsdale, AZ; Matthew Laughon, University of North Carolina at Chapel Hill, Chapel Hill, NC; Ian M. Paul, Penn State College of Medicine, Hershey, PA; Janice Sullivan, University of Louisville, Louisville, KY; Kelly Wade, Children’s Hospital of Philadelphia, Philadelphia, PA; Paula Delmore, Wichita Medical Research and Education Foundation, Wichita, KS. The Eunice Kennedy Shriver National Institute of Child Health and Human Development: Perdita Taylor-Zapata and June Lee. The Emmes Company, LLC (Data Coordinating Center): Ravinder Anand, Gaurav Sharma, Gina Simone, Kim Kaneshige, and Lawrence Taylor. PTN Publications Committee: chaired by Thomas Green, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL. Pediatric Trials Network Meropenem Study Team: Akron Children’s Hospital: Anand Kantak, MD and Judy Ohlinger, RN; Albany Medical Center: Mike Horgan, MD and Susan Boynton, RN, BSN; Baylor College of Medicine: Eric C. Eichenwald, MD and Karen Jones, RN, CCRC; Children’s Hospital of Oakland: David J. Durand, MD and Jeanette Asselin, RRT, MS; Children’s Hospital of Orange County: Antonio Arrieta, MD and Kathy Shea, BA; Children’s Hospital of Philadelphia: Kelly Wade, MD, PhD, MSCE and Tonia Morrison, BA, CCRC; Children’s Hospital of Pittsburgh of UPMC: Beverly S. Brozanski, MD and Robyn Baker, BSN, NNP; Children’s Hospital at Vanderbilt: Joern-Hendrik Weitkamp, MD and Millie Nannie, RN, BA, BS, CCRN, CLNC; Children’s Medical Center of Dallas: Pablo Sanchez, MD and Shirley Montanye, RN, ADN, CCRC; Children’s National Medical Center: John van den Anker, MD and Elaine Williams, RN, MSN; Duke University: P. Brian Smith, MD, MPH, MHS, Michael Cohen-Wolkowiez, MD, PhD, Margarita Bidegain, MD, MHS, Daniel K. Benjamin Jr, MD, PhD, MPH, and Sandy Grimes, RN, BSN; Evanston Northwestern Healthcare: William MacKendrick, MD and Sue Wolf, RNC-NIC, CCRP; Indiana University, James W. Riley Hospital for Children: Brenda Poindexter, MD, MS and Leslie Dawn Wilson, BSN, CCRC; Kansas City Children’s Mercy Hospital: Lisa M. Castro, MD and Ann Harris, RN, BSN, MBA; Kapiolani Medical Center for Women and Children: Venkataraman Balaraman, MD and Robyn Morse, BA, CCRC; Sharp Mary Birch Hospital for Women: Maynard Rasmussen, MD and Kathy Arnell, RNC; SUNY Downstate Medical Center: Gloria Valencia, MD and Sara Higgerson, BA; University Hospitals (Cleveland, OH): Michele Walsh, MD and Arlene Zadell, RN, BSN; University of Alabama at Birmingham: Claire M. Roane, RN, MSN; University of California–San Diego: Neil Finer, MD, Edmund V. Capparelli, PharmD, and Wade Rich, BSHS, RRT, CCRC; University of Florida: David Burchfield, MD and Cindy Miller, RN; University of Louisville and Kosair Children’s Hospital: Janice E. Sullivan, MD and Gwendolyn Pierce, RN, CCRC; University of Michigan–Ann Arbor: Varsha Bhatt-Mehta, MS, PharmD, FCCP and Ron Dechert, DPH, MS, RRT, FAARC; University of Utah, Primary Children’s Medical Center: Robert M. Ward, MD and JoAnn Narus, MS, JD, MD; Yale University: Mathew Bizzaro, MD and Monica Konstantino, RN, BSN. Certara Academic Center of Excellence Program: Phoenix® WinNonlin® is generously provided to the authors by Certara through the Academic Center of Excellence Program.

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Authors and Affiliations

  1. Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, 301 Pharmacy Lane, Campus Box #7569, Chapel Hill, NC, 27599-7569, USA

    Samit Ganguly, Jacqueline G. Gerhart & Daniel Gonzalez

  2. Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA

    Samit Ganguly

  3. School of Pharmacy, University of Waterloo, Kitchener, ON, Canada

    Andrea N. Edginton

  4. Duke Clinical Research Institute, Durham, NC, USA

    Michael Cohen-Wolkowiez & Rachel G. Greenberg

  5. Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA

    Michael Cohen-Wolkowiez & Rachel G. Greenberg

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  1. Samit Ganguly
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  2. Andrea N. Edginton
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  4. Michael Cohen-Wolkowiez
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  5. Rachel G. Greenberg
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  6. Daniel Gonzalez
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Consortia

the Best Pharmaceuticals for Children Act-Pediatric Trials Network Steering Committee

  • Daniel K. Benjamin Jr
  • , Christoph Hornik
  • , Kanecia Zimmerman
  • , Phyllis Kennel
  • , Rose Beci
  • , Chi Dang Hornik
  • , Gregory L. Kearns
  • , Matthew Laughon
  • , Ian M. Paul
  • , Janice Sullivan
  • , Kelly Wade
  • , Paula Delmore
  • , Perdita Taylor-Zapata
  • , June Lee
  • , Ravinder Anand
  • , Gaurav Sharma
  • , Gina Simone
  • , Kim Kaneshige
  • , Lawrence Taylor
  • , Thomas Green
  • , Anand Kantak
  • , Judy Ohlinger
  • , Mike Horgan
  • , Susan Boynton
  • , Eric C. Eichenwald
  • , Karen Jones
  • , David J. Durand
  • , Jeanette Asselin
  • , Antonio Arrieta
  • , Kathy Shea
  • , Kelly Wade
  • , Tonia Morrison
  • , Beverly S. Brozanski
  • , Robyn Baker
  • , Joern-Hendrik Weitkamp
  • , Millie Nannie
  • , Pablo Sanchez
  • , Shirley Montanye
  • , John van den Anker
  • , Elaine Williams
  • , P. Brian Smith
  • , Michael Cohen-Wolkowiez
  • , Margarita Bidegain
  • , Daniel K. Benjamin Jr
  • , Sandy Grimes
  • , William MacKendrick
  • , Sue Wolf
  • , Brenda Poindexter
  • , Leslie Dawn Wilson
  • , Lisa M. Castro
  • , Ann Harris
  • , Venkataraman Balaraman
  • , Robyn Morse
  • , Maynard Rasmussen
  • , Kathy Arnell
  • , Gloria Valencia
  • , Sara Higgerson
  • , Michele Walsh
  • , Arlene Zadell
  • , Claire M. Roane
  • , Neil Finer
  • , Edmund V. Capparelli
  • , Wade Rich
  • , David Burchfield
  • , Cindy Miller
  • , Janice E. Sullivan
  • , Gwendolyn Pierce
  • , Varsha Bhatt-Mehta
  • , Ron Dechert
  • , Robert M. Ward
  • , JoAnn Narus
  • , Mathew Bizzaro
  •  & Monica Konstantino

Corresponding author

Correspondence to Daniel Gonzalez.

Ethics declarations

Funding

This work was funded under the National Institute of Child Health and Human Development contract (HHSN275201000003I) for the Pediatric Trials Network (principal investigator Danny Benjamin). JGG received research support from a National Institute of General Medical Sciences funded T32 program (T32GM122741), as well as the American Foundation for Pharmaceutical Education. DG received research support from the National Institute of Child Health and Human Development (K23HD083465, R01HD096435, and HHSN275201000003I). The Best Pharmaceuticals for Children Act Data Coordinating Center was funded under HHSN275201700002C (principal investigator: Ravinder Anand). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Conflict of interest

Michael Cohen-Wolkowiez receives support for research from the National Institutes of Health (1U24-MD016258), National Institute of Allergy and Infectious Diseases (HHSN272201500006I, HHSN272201300017I, 1K24-AI143971), National Institute of Child Health and Human Development (HHSN275201000003I), US Food and Drug Administration (5U18-FD006298), and industry for drug development in adults and children. Samit Ganguly, Andrea N. Edginton, Jacqueline G. Gerhart, Rachel G. Greenberg, and Daniel Gonzalez have no conflicts of interest that are directly relevant to the content of this article.

Ethics approval

For the study protocol that allowed the collection of the PK data from infants with a suspected or confirmed intra-abdominal infection (ClinicalTrials.gov #NCT00621192), institutional review board approval was obtained at each participating site. For the PBPK analyses described in this publication, the Office of Human Research Ethics at the University of North Carolina at Chapel Hill determined that the research did not constitute human subjects research as defined under federal regulations [45 CFR 46.102 (d or f) and 21 CFR 56.102(c)(e)(l)] and did not require institutional review board approval.

Consent to participate

For the original study in infants with a suspected or confirmed intra-abdominal infection (ClinicalTrials.gov #NCT00621192), written permission (informed consent) was obtained from the parent or legal guardian.

Consent for publication

Not applicable.

Availability of data and material

Meropenem infant PK data were accessed through the Eunice Kennedy Shriver National Institute of Child Health and Human Development Data and Specimen Hub (https://dash.nichd.nih.gov/).

Code availability

Not applicable.

Author contributions

SG and DG designed and performed the research; SG and JGG analyzed the data; SG, ANE, JGG, MC-W, RGG, and DG wrote or contributed to the writing of the manuscript.

Additional information

The members of on behalf of the Best Pharmaceuticals for Children Act-Pediatric Trials Network Steering Committee is present in the Acknowledgements section.

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Ganguly, S., Edginton, A.N., Gerhart, J.G. et al. Physiologically Based Pharmacokinetic Modeling of Meropenem in Preterm and Term Infants. Clin Pharmacokinet 60, 1591–1604 (2021). https://doi.org/10.1007/s40262-021-01046-6

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