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Physiologically Based Pharmacokinetic Modeling for Trimethoprim and Sulfamethoxazole in Children.

Publication ,  Journal Article
Thompson, EJ; Wu, H; Maharaj, A; Edginton, AN; Balevic, SJ; Cobbaert, M; Cunningham, AP; Hornik, CP; Cohen-Wolkowiez, M
Published in: Clin Pharmacokinet
July 2019

OBJECTIVE: The aims of this study were to (1) determine whether opportunistically collected data can be used to develop physiologically based pharmacokinetic (PBPK) models in pediatric patients; and (2) characterize age-related maturational changes in drug disposition for the renally eliminated and hepatically metabolized antibiotic trimethoprim (TMP)-sulfamethoxazole (SMX). METHODS: We developed separate population PBPK models for TMP and SMX in children after oral administration of the combined TMP-SMX product and used sparse and opportunistically collected plasma concentration samples to validate our pediatric model. We evaluated predictability of the pediatric PBPK model based on the number of observed pediatric data out of the 90% prediction interval. We performed dosing simulations to target organ and tissue (skin) concentrations greater than the methicillin-resistant Staphylococcus aureus (MRSA) minimum inhibitory concentration (TMP 2 mg/L; SMX 9.5 mg/L) for at least 50% of the dosing interval. RESULTS: We found 67-87% and 71-91% of the observed data for TMP and SMX, respectively, were captured within the 90% prediction interval across five age groups, suggesting adequate fit of our model. Our model-rederived optimal dosing of TMP at the target tissue was in the range of recommended dosing for TMP-SMX in children in all age groups by current guidelines for the treatment of MRSA. CONCLUSION: We successfully developed a pediatric PBPK model of the combination antibiotic TMP-SMX using sparse and opportunistic pediatric pharmacokinetic samples. This novel and efficient approach has the potential to expand the use of PBPK modeling in pediatric drug development.

Duke Scholars

Published In

Clin Pharmacokinet

DOI

EISSN

1179-1926

Publication Date

July 2019

Volume

58

Issue

7

Start / End Page

887 / 898

Location

Switzerland

Related Subject Headings

  • Trimethoprim, Sulfamethoxazole Drug Combination
  • Pharmacology & Pharmacy
  • Models, Biological
  • Male
  • Infant
  • Humans
  • Female
  • Child, Preschool
  • Child
  • Anti-Bacterial Agents
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Thompson, E. J., Wu, H., Maharaj, A., Edginton, A. N., Balevic, S. J., Cobbaert, M., … Cohen-Wolkowiez, M. (2019). Physiologically Based Pharmacokinetic Modeling for Trimethoprim and Sulfamethoxazole in Children. Clin Pharmacokinet, 58(7), 887–898. https://doi.org/10.1007/s40262-018-00733-1
Thompson, Elizabeth J., Huali Wu, Anil Maharaj, Andrea N. Edginton, Stephen J. Balevic, Marjan Cobbaert, Anthony P. Cunningham, Christoph P. Hornik, and Michael Cohen-Wolkowiez. “Physiologically Based Pharmacokinetic Modeling for Trimethoprim and Sulfamethoxazole in Children.Clin Pharmacokinet 58, no. 7 (July 2019): 887–98. https://doi.org/10.1007/s40262-018-00733-1.
Thompson EJ, Wu H, Maharaj A, Edginton AN, Balevic SJ, Cobbaert M, et al. Physiologically Based Pharmacokinetic Modeling for Trimethoprim and Sulfamethoxazole in Children. Clin Pharmacokinet. 2019 Jul;58(7):887–98.
Thompson, Elizabeth J., et al. “Physiologically Based Pharmacokinetic Modeling for Trimethoprim and Sulfamethoxazole in Children.Clin Pharmacokinet, vol. 58, no. 7, July 2019, pp. 887–98. Pubmed, doi:10.1007/s40262-018-00733-1.
Thompson EJ, Wu H, Maharaj A, Edginton AN, Balevic SJ, Cobbaert M, Cunningham AP, Hornik CP, Cohen-Wolkowiez M. Physiologically Based Pharmacokinetic Modeling for Trimethoprim and Sulfamethoxazole in Children. Clin Pharmacokinet. 2019 Jul;58(7):887–898.
Journal cover image

Published In

Clin Pharmacokinet

DOI

EISSN

1179-1926

Publication Date

July 2019

Volume

58

Issue

7

Start / End Page

887 / 898

Location

Switzerland

Related Subject Headings

  • Trimethoprim, Sulfamethoxazole Drug Combination
  • Pharmacology & Pharmacy
  • Models, Biological
  • Male
  • Infant
  • Humans
  • Female
  • Child, Preschool
  • Child
  • Anti-Bacterial Agents