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Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 7/2019

01-07-2019 | Original Research Article

Physiologically Based Pharmacokinetic Modeling for Trimethoprim and Sulfamethoxazole in Children

Authors: Elizabeth J. Thompson, Huali Wu, Anil Maharaj, Andrea N. Edginton, Stephen J. Balevic, Marjan Cobbaert, Anthony P. Cunningham, Christoph P. Hornik, Michael Cohen-Wolkowiez

Published in: Clinical Pharmacokinetics | Issue 7/2019

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Abstract

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.
Appendix
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Metadata
Title
Physiologically Based Pharmacokinetic Modeling for Trimethoprim and Sulfamethoxazole in Children
Authors
Elizabeth J. Thompson
Huali Wu
Anil Maharaj
Andrea N. Edginton
Stephen J. Balevic
Marjan Cobbaert
Anthony P. Cunningham
Christoph P. Hornik
Michael Cohen-Wolkowiez
Publication date
01-07-2019
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 7/2019
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-018-00733-1

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