Precision sirolimus dosing in children: The potential for model-informed dosing and novel drug monitoring
Abstract
The mTOR inhibitor sirolimus is prescribed to treat children with varying diseases, ranging from vascular anomalies to sporadic lymphangioleiomyomatosis to transplantation (solid organ or hematopoietic cell). Precision dosing of sirolimus using therapeutic drug monitoring (TDM) of sirolimus concentrations in whole blood drawn at the trough (before the next dose) time-point is the current standard of care. For sirolimus, trough concentrations are only modestly correlated with the area under the curve, with R² values ranging from 0.52 to 0.84. Thus, it should not be surprising, even with the use of sirolimus TDM, that patients treated with sirolimus have variable pharmacokinetics, toxicity, and effectiveness. Model-informed precision dosing (MIPD) will be beneficial and should be implemented. The data do not suggest dried blood spots point-of-care sampling of sirolimus concentrations for precision dosing of sirolimus. Future research on precision dosing of sirolimus should focus on pharmacogenomic and pharmacometabolomic tools to predict sirolimus pharmacokinetics and wearables for point-of-care quantitation and MIPD.
Additional Information
© 2023 Shen, Moua, Perkins, Johnson, Li, Curtin, Gao and McCune. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. This work was supported by the Caltech–City of Hope Biomedical Research Initiative Pilot Grants, the Office of the Chief Medical Information Officer at City of Hope National Medical Center, the American Cancer Society RSG-21-181-01-CTPS, U01CA237393, R01GM129863, and P30CA033572 (Analytical Pharmacology Core, Biostatistics, and Hematopoietic Tissue Biorepository). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We are grateful to the participants, their families, and the healthcare providers caring for them. We are also grateful to the research faculty and staff (Paul Fu Jr., Tinisha McDonald, Elena Pulkinen, Kelly Synold, Timothy Synold) involved in sample acquisition, transport, sample quantitation, and quality assurance, and data management. Finally, the authors would like to acknowledge the City of Hope Center for Informatics and the utilization of the POSEIDON platforms for data exploration, visualization, analysis, and discovery. Author contributions. GS, KM, KP, and JM, wrote the manuscript; DJ and JM designed the research; GS, DJ, PC, WG, and JM performed the research; DJ, AL, and JM analyzed the data. All authors edited the manuscript. Conflict of interest. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.Attached Files
Published - fphar-14-1126981.pdf
Supplemental Material - Data_Sheet_1.docx
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Additional details
- PMCID
- PMC10069443
- Eprint ID
- 121172
- Resolver ID
- CaltechAUTHORS:20230425-250392700.6
- Caltech-City of Hope Biomedical Initiative
- RSG-21-181-01-CTPS
- American Cancer Society
- U01CA237393
- NIH
- R01GM129863
- NIH
- P30CA033572
- NIH
- Created
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2023-04-27Created from EPrint's datestamp field
- Updated
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2023-04-27Created from EPrint's last_modified field