{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T05:15:09Z","timestamp":1788671709855,"version":"build-2803163510"},"reference-count":41,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:00:00Z","timestamp":1788480000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004731","name":"Natural Science Foundation of Zhejiang Province","doi-asserted-by":"crossref","award":["LZYQ25H270001"],"award-info":[{"award-number":["LZYQ25H270001"]}],"id":[{"id":"10.13039\/501100004731","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004731","name":"Natural Science Foundation of Zhejiang Province","doi-asserted-by":"crossref","award":["LY24H270007"],"award-info":[{"award-number":["LY24H270007"]}],"id":[{"id":"10.13039\/501100004731","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Zhejiang Province Traditional Chinese Medicine Science and Technology Plan Project","award":["2026ZF41"],"award-info":[{"award-number":["2026ZF41"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>To quantitatively characterize the pharmacokinetic and pharmacodynamic interactions between Hydroxysafflor Yellow A (HSYA) and Calycosin (CA) in cerebral ischemia\u2013reperfusion injury (CIRI), a factorial experimental design was combined with a hierarchical coupled PK-PD modeling framework. The coupled PK model adequately described the concentration-time profiles of HSYA and CA under co-administration, with R2 values of 0.83 and 0.86, respectively, while the PK-PD model showed good fitting performance for Caspase-3 and HIF-1\u03b1, with all R2 values exceeding 0.97. Structural identifiability analysis showed that the newly introduced PK and PD coupling parameters were globally identifiable, and their Bootstrap 95% confidence intervals excluded zero. After Holm-Bonferroni correction, AUC0-t, AUC0-\u221e and CL differed significantly between single and combined administration, whereas MRT did not. The model-derived relative contribution weights of HSYA and CA were quantified for both Caspase-3 and HIF-1\u03b1, with uncertainty assessed using Bootstrap 95% confidence intervals. Overall, the proposed coupled PK-PD framework provides a quantitative approach for characterizing component interactions and relative pharmacodynamic contributions in multi-component systems.<\/jats:p>","DOI":"10.3390\/biology15171543","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T13:50:44Z","timestamp":1788529844000},"page":"1543","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Deciphering the Combined Effects of Hydroxysafflor Yellow A and Calycosin Through Coupled PK\u2013PD Modeling"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-4760-8570","authenticated-orcid":false,"given":"Yanxuan","family":"Hu","sequence":"first","affiliation":[{"name":"The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou 310053, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Xixi","family":"Zhao","sequence":"additional","affiliation":[{"name":"Laboratory Animal Research Center, Academy of Chinese Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Weifeng","family":"Jin","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4133-5483","authenticated-orcid":false,"given":"Li","family":"Yu","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1007\/s10928-005-9002-0","article-title":"Pharmacokinetic-pharmacodynamic modelling: History and perspectives","volume":"33","author":"Csajka","year":"2006","journal-title":"J. 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