TY - JOUR
T1 - Physiologically Based Pharmacokinetic Modeling of Meropenem in Preterm and Term Infants
AU - the Best Pharmaceuticals for Children Act-Pediatric Trials Network Steering Committee
AU - Ganguly, Samit
AU - Edginton, Andrea N.
AU - Gerhart, Jacqueline G.
AU - Cohen-Wolkowiez, Michael
AU - Greenberg, Rachel G.
AU - Gonzalez, Daniel
AU - Benjamin, Daniel K.
AU - Hornik, Christoph
AU - Zimmerman, Kanecia
AU - Kennel, Phyllis
AU - Beci, Rose
AU - Hornik, Chi Dang
AU - Kearns, Gregory L.
AU - Laughon, Matthew
AU - Paul, Ian M.
AU - Sullivan, Janice
AU - Wade, Kelly
AU - Delmore, Paula
AU - Taylor-Zapata, Perdita
AU - Lee, June
AU - Anand, Ravinder
AU - Sharma, Gaurav
AU - Simone, Gina
AU - Kaneshige, Kim
AU - Taylor, Lawrence
AU - Green, Thomas
AU - Kantak, Anand
AU - Ohlinger, Judy
AU - Horgan, Mike
AU - Boynton, Susan
AU - Eichenwald, Eric C.
AU - Jones, Karen
AU - Durand, David J.
AU - Asselin, Jeanette
AU - Arrieta, Antonio
AU - Shea, Kathy
AU - Wade, Kelly
AU - Morrison, Tonia
AU - Brozanski, Beverly S.
AU - Baker, Robyn
AU - Weitkamp, Joern Hendrik
AU - Nannie, Millie
AU - Sanchez, Pablo
AU - Montanye, Shirley
AU - van den Anker, John
AU - Williams, Elaine
AU - Smith, P. Brian
AU - Bidegain, Margarita
AU - Benjamin, Daniel K.
AU - Grimes, Sandy
AU - MacKendrick, William
AU - Wolf, Sue
AU - Poindexter, Brenda
AU - Wilson, Leslie Dawn
AU - Castro, Lisa M.
AU - Harris, Ann
AU - Balaraman, Venkataraman
AU - Morse, Robyn
AU - Rasmussen, Maynard
AU - Arnell, Kathy
AU - Valencia, Gloria
AU - Higgerson, Sara
AU - Walsh, Michele
AU - Zadell, Arlene
AU - Roane, Claire M.
AU - Finer, Neil
AU - Capparelli, Edmund V.
AU - Rich, Wade
AU - Burchfield, David
AU - Miller, Cindy
AU - Sullivan, Janice E.
AU - Pierce, Gwendolyn
AU - Bhatt-Mehta, Varsha
AU - Dechert, Ron
AU - Ward, Robert M.
AU - Narus, Jo Ann
AU - Bizzaro, Mathew
AU - Konstantino, Monica
N1 - Funding Information:
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.
Funding Information:
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.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Switzerland AG.
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85122166457&partnerID=8YFLogxK
U2 - 10.1007/s40262-021-01046-6
DO - 10.1007/s40262-021-01046-6
M3 - Article
C2 - 34155614
AN - SCOPUS:85122166457
SN - 0312-5963
VL - 60
SP - 1591
EP - 1604
JO - Clinical Pharmacokinetics
JF - Clinical Pharmacokinetics
IS - 12
ER -