{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T05:06:50Z","timestamp":1784696810880,"version":"3.55.0"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T00:00:00Z","timestamp":1784678400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>In routine clinical practice, many patients with chronic heart failure (CHF) treated with sacubitril\/valsartan do not achieve the guideline-recommended target dose of 200\u00a0mg twice daily (BID), largely because of tolerability concerns. This study aimed to develop a model-informed framework to evaluate whether sacubitril\/valsartan 100\u00a0mg BID may provide adequate expected pharmacodynamic benefit with improved tolerability in Chinese CHF patients who are unable to tolerate further dose escalation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A physiologically based pharmacokinetic (PBPK) model of sacubitril\/valsartan was developed in PK-Sim and evaluated against observed clinical data. Physiological changes were incorporated to extrapolate the model to healthy Chinese subjects, patients with renal impairment, and patients with CHF. Real-world clinical data from Chinese CHF patients with hypertension were used to inform virtual population. PBPK-predicted steady-state exposure metrics were then linked to externally sourced exposure\u2013biomarker relationships for NT-proBNP and to a blood pressure response model to compare expected biomarker response and hypotension-related tolerability across dosing strategies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The PBPK model adequately described the pharmacokinetic profiles of sacubitril, sacubitrilat, and valsartan across different populations and dosing regimens. Overall, 88.75% of predicted-to-observed exposure ratios were within 1.5-fold and 98.75% were within the conventional two-fold boundary, with average fold error and absolute average fold error values below 2. CHF and renal impairment were associated with increased systemic exposure, particularly for sacubitrilat, consistent with its renal elimination pathway. In under-titrated CHF patients, exposure\u2013biomarker translation indicated limited additional NT-proBNP reduction when the regimen was escalated from 100\u00a0mg BID to 200\u00a0mg BID, suggesting a relatively flat exposure\u2013biomarker relationship over this dose range. In contrast, escalation to 200\u00a0mg BID was associated with greater predicted systolic blood pressure reduction and greater hypotension-related tolerability concern.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This PBPK-based model-informed framework supports the guideline-recommended target dose of sacubitril\/valsartan 200\u00a0mg BID when tolerated, while providing exploratory model-informed evidence that 100\u00a0mg BID may represent a feasible alternative for patients with limited tolerance to further dose escalation. Prospective validation using longitudinal biomarker, tolerability, and clinical outcome data is warranted.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1875094","type":"journal-article","created":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T04:45:46Z","timestamp":1784695546000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Dose optimization of sacubitril\/valsartan in Chinese chronic heart failure patients: integration of physiologically based pharmacokinetic modeling and real-world data"],"prefix":"10.3389","volume":"17","author":[{"given":"Ke","family":"Ren","sequence":"first","affiliation":[{"name":"Minhang Hospital and School of Pharmacy, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Fan","sequence":"additional","affiliation":[{"name":"Minhang Hospital and School of Pharmacy, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mengqi","family":"Jia","sequence":"additional","affiliation":[{"name":"Minhang Hospital and School of Pharmacy, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Zhongshan Hospital, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Zhu","sequence":"additional","affiliation":[{"name":"Minhang Hospital and School of Pharmacy, Fudan University","place":["Shanghai, China"]},{"name":"State Key Laboratory of Advanced Drug Formulations for Overcoming Delivery Barriers, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Han","sequence":"additional","affiliation":[{"name":"Minhang Hospital and School of Pharmacy, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoqiang","family":"Xiang","sequence":"additional","affiliation":[{"name":"Minhang Hospital and School of Pharmacy, Fudan University","place":["Shanghai, China"]},{"name":"State Key Laboratory of Advanced Drug Formulations for Overcoming Delivery Barriers, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanxia","family":"Zhang","sequence":"additional","affiliation":[{"name":"Minhang Hospital and School of Pharmacy, Fudan University","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingfeng","family":"He","sequence":"additional","affiliation":[{"name":"Minhang Hospital and School of Pharmacy, Fudan University","place":["Shanghai, China"]},{"name":"State Key Laboratory of Advanced Drug Formulations for Overcoming Delivery Barriers, Fudan University","place":["Shanghai, China"]},{"name":"Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples","place":["Changsha, Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1007\/s13318-016-0354-1","article-title":"Pharmacokinetics after single ascending dose, food effect, and safety of sacubitril\/valsartan (LCZ696), an angiotensin receptor and neprilysin inhibitor, in healthy Japanese subjects","volume":"42","author":"Akahori","year":"2017","journal-title":"Eur. 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