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Sirolimus exposure\u2013response association studies in HCT patients (i.e., the association of trough concentration with clinical outcomes) have been conflicting. Sirolimus has important effects on T\u2010cells, including conventional (Tcons) and regulatory T\u2010cells (Tregs), both of which have been implicated in the mechanisms by which PTCy prevents GVHD, but there is an absence of validated biomarkers of sirolimus effects on these cell subsets. Considering the paucity of existing biomarkers and the complexities of the immune system, we conducted a literature review to inform a quantitative systems pharmacology (QSP) model of GVHD. The published literature presented multiple challenges. The sirolimus pharmacokinetic models insufficiently describe sirolimus distribution to relevant physiological compartments. Despite multiple publications describing sirolimus effects on Tcons and Tregs in preclinical and human ex\u00a0vivo models, consistent parameters relating sirolimus concentrations to circulating Tcons and Tregs could not be found. Each aspect presents a challenge in building a QSP model of sirolimus and its temporal effects on T\u2010cell subsets and GVHD prevention. To optimize GVHD prevention regimens, phase I studies and systematic studies of immunosuppressant concentration\u2013effect association are needed for QSP modeling.<\/jats:p>","DOI":"10.1111\/cts.70014","type":"journal-article","created":{"date-parts":[[2024,8,20]],"date-time":"2024-08-20T13:08:36Z","timestamp":1724159316000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Challenges with sirolimus experimental data to inform <scp>QSP<\/scp> model of post\u2010transplantation cyclophosphamide regimens"],"prefix":"10.1111","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6490-4477","authenticated-orcid":false,"given":"Ezhilpavai","family":"Mohanan","sequence":"first","affiliation":[{"name":"Department of Hematologic Malignancies Translational Sciences City of Hope  Duarte California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6653-0440","authenticated-orcid":false,"given":"Guofang","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Hematologic Malignancies Translational Sciences City of Hope  Duarte California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7673-7138","authenticated-orcid":false,"given":"Suping","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Hematologic Malignancies Translational Sciences City of Hope  Duarte California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7428-1349","authenticated-orcid":false,"given":"Hsuan\u2010Hao","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences University at Buffalo, SUNY  Buffalo New York USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9779-3817","authenticated-orcid":false,"given":"Kao Tang Ying","family":"Moua","sequence":"additional","affiliation":[{"name":"Alfred E. 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