{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T03:13:55Z","timestamp":1789442035592,"version":"build-2803163510"},"reference-count":42,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2021,11,13]],"date-time":"2021-11-13T00:00:00Z","timestamp":1636761600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100014717","name":"National Outstanding Youth Science Fund Project of National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81903722"],"award-info":[{"award-number":["81903722"]}],"id":[{"id":"10.13039\/100014717","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2022,5]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>The pharmacokinetics (PK) of hetrombopag were found to be nonlinear across evaluated dose ranges. The aim of this study was to develop a mechanism\u2010based population pharmacokinetic\/pharmacodynamic (PopPK\/PD) model and to provide a reasonable expected therapeutic dose for a future confirmatory clinical study of hetrombopag.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Nonlinear mixed\u2010effects modelling was performed using pooled 2168 hetrombopag concentrations and 1526 platelet counts from 72 healthy subjects and 32 chronic idiopathic thrombocytopenic purpura (ITP) patients from two phase I studies and one phase II study. The final model was evaluated via goodness\u2010of\u2010fit plots, visual predictive check and nonparametric bootstrap. Simulations from the validated PopPK\/PD model were used to devise an expected therapeutic dose for later confirmatory clinical study.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The pharmacokinetic data of hetrombopag were well described by a modified target\u2010mediated drug disposition (TMDD) model with dual sequential first\u2010order absorption. Mean parameter estimates (interindividual variability) were CL\/F 7.66\u2009L\/h (63.5%), <jats:italic>V<\/jats:italic><jats:sub>c<\/jats:sub>\/<jats:italic>F<\/jats:italic> 30.0\u00a0L (77.2%) and <jats:italic>K<\/jats:italic><jats:sub>deg<\/jats:sub> 0.693\/h (87.1%). The pharmacodynamic profile was well described by a five\u2010compartment lifespan model with four\u2010transit and one\u2010platelet compartments. Simulation results suggested that chronic ITP patients following 10\u00a0mg once\u2010daily hetrombopag would able to achieve an ideal platelet count level (50\u2010200\u2009\u00d7\u200910<jats:sup>9<\/jats:sup>\/L).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>TMDD was the primary reason leading to nonlinear PK profile of hetrombopag. Our PK\/PD modelling and simulation results support 10\u00a0mg once\u2010daily as the recommended therapeutic dose for chronic ITP patients in subsequent confirmatory clinical study of hetrombopag.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.15130","type":"journal-article","created":{"date-parts":[[2021,10,27]],"date-time":"2021-10-27T14:50:38Z","timestamp":1635346238000},"page":"2084-2095","source":"Crossref","is-referenced-by-count":5,"title":["Impact of target\u2010mediated drug disposition on hetrombopag pharmacokinetics and pharmacodynamics in Chinese healthy subjects and patients with chronic idiopathic thrombocytopenic purpura"],"prefix":"10.1111","volume":"88","author":[{"given":"Zhenlei","family":"Wang","sequence":"first","affiliation":[{"name":"Clinical Trial Center\/NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug West China Hospital of Sichuan University  Chengdu 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Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuwen","family":"Pei","sequence":"additional","affiliation":[{"name":"Clinical Trial Center\/NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug West China Hospital of Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongsheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Clinical Trial Center\/NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug West China Hospital of Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3404-4824","authenticated-orcid":false,"given":"Li","family":"Zheng","sequence":"additional","affiliation":[{"name":"Clinical Trial Center\/NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug West China Hospital of Sichuan University  Chengdu 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