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Physiologically Based Pharmacokinetic Modeling for Trimethoprim and Sulfamethoxazole in Children

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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.

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Authors and Affiliations

  1. Department of Pediatrics, Duke University Medical Center, Durham, NC, USA

    Elizabeth J. Thompson, Stephen J. Balevic, Christoph P. Hornik & Michael Cohen-Wolkowiez

  2. Duke Clinical Research Institute, 300 West Morgan Street, Suite 800, Durham, NC, 27701, USA

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

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  1. Elizabeth J. Thompson
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Correspondence to Michael Cohen-Wolkowiez.

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Funding

This work was funded by the National Institutes of Health (1R01-HD076676-01A1; M.C.W.). Funding acknowledgements: NIGMS/NICHD (National Institute of General Medical Sciences/National Institute of Child Health and Human Development) 2T32GM086330-06; Clinical and Translational Science Awards (CTSA).

Conflict of interest

Stephen J. Balevic receives salary and research support from the National Institutes of Health (5R01-HD076676-04, HHSN275201000003I, the Rheumatology Research Foundation’s Scientist Development Award, and the Thrasher Research Fund. Andrea N. Edginton receives support for research from the National Institutes of Health (1R01-HD076676-01A1 [PI: Cohen-Wolkowiez]). Elizabeth J. Thompson, Huali Wu, Anil Maharaj, Marjan Cobbaert, Anthony P. Cunningham, Christoph P. Hornik, and Michael Cohen-Wolkowiez have nothing to disclose.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Thompson, E.J., Wu, H., Maharaj, A. et al. Physiologically Based Pharmacokinetic Modeling for Trimethoprim and Sulfamethoxazole in Children. Clin Pharmacokinet 58, 887–898 (2019). https://doi.org/10.1007/s40262-018-00733-1

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