{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T03:04:15Z","timestamp":1789700655460,"version":"4.0.1"},"reference-count":37,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp; Syst Pharma"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    A whole\u2010body mechanistic PBPK model for meropenem (MPN) was developed in PK\u2010Sim and validated using published plasma and tissue concentration\u2013time data in healthy volunteers and critically ill patients. Renal elimination was implemented as glomerular filtration plus active tubular secretion (basolateral uptake via OAT3 with apical efflux), and non\u2010renal clearance via DHP\u2010mediated hydrolysis. The model was scaled to sepsis or septic shock by incorporating disease\u2010specific physiological changes and optimizing OAT3 activity and tissue permeability to reproduce observed variability. Simulations in a virtual septic population assessed unbound interstitial concentrations in clinically relevant tissues under ILAS\u2010recommended typical and maximum dosing MPN regimens. Antibacterial effect against\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>Escherichia coli<\/jats:italic>\n                    <\/jats:styled-content>\n                    and\n                    <jats:styled-content style=\"fixed-case\">\n                      <jats:italic>Klebsiella pneumoniae<\/jats:italic>\n                    <\/jats:styled-content>\n                    was evaluated using a published PK\/PD model driven by simulated unbound tissue concentrations. The PBPK model reproduced observed plasma profiles in healthy volunteers and captured plasma and subcutaneous interstitial exposure in sepsis. Simulations showed clear dissociation between plasma and interstitial exposure and marked tissue\u2010specific heterogeneity. Predicted clearance increased in sepsis (augmented renal clearance) and decreased in septic shock (impaired renal function and secretion). Although maximum dosing increased plasma and tissue exposure, PD simulations indicated effects were already near the plateau with standard dosing, yielding minimal additional antibacterial benefit from routine dose escalation. Transporter\u2010informed PBPK\/PD modeling explains dynamic, severity\u2010dependent changes in meropenem clearance and tissue exposure in sepsis, highlights limitations of plasma\u2010only assessment, and supports individualized, mechanism\u2010informed optimization rather than universal dose scaling.\n                  <\/jats:p>","DOI":"10.1002\/psp4.70335","type":"journal-article","created":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T04:47:11Z","timestamp":1788324431000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Transporter\u2010Drive Interstitial Tissue Exposure and Pharmacodynamic Response of Meropenem in Sepsis: A Mechanistic\n                    <scp>PBPK<\/scp>\n                    Modeling Study"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2556-9434","authenticated-orcid":false,"given":"Laura Ben","family":"Olivo","sequence":"first","affiliation":[{"name":"Pharmaceutical Sciences Graduate Program Federal University of Rio Grande Do Sul  Porto Alegre Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica Luisa Silva","family":"de Lemos","sequence":"additional","affiliation":[{"name":"Biological Sciences Graduate Program: Pharmacology and Therapeutics Federal University of Rio Grande Do Sul  Porto Alegre Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinicius Jardim","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Biological Sciences Graduate Program: Pharmacology and Therapeutics Federal University of Rio Grande Do Sul  Porto Alegre Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9706-0389","authenticated-orcid":false,"given":"Bibiana Verlindo","family":"de Ara\u00fajo","sequence":"additional","affiliation":[{"name":"Pharmaceutical Sciences Graduate Program Federal University of Rio Grande Do Sul  Porto Alegre Brazil"},{"name":"Biological Sciences Graduate Program: Pharmacology and Therapeutics Federal University of Rio Grande Do Sul  Porto Alegre Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,1]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1080\/14787210.2020.1788387"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciac506"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkad223"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13054\u2010020\u20102763\u20104"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1128\/aac.00727\u201023"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dku413"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1155\/2022\/1867674"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.2174\/1389200223666220428081109"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2019.106135"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.123.000960"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/24.suppl_a.311"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.36.7.1532"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.49.5.1881\u20101889.2005"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.36.7.1437"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.36.12.2794"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01964413"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkp139"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.clpt.6100312"},{"key":"e_1_2_9_20_1","unstructured":"Automeris \u201cWebPlotDigitizer \u201d(2023) https:\/\/apps.automeris.io\/wpd\/."},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.13102"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262\u2010016\u20100475\u20103"},{"key":"e_1_2_9_23_1","unstructured":"H. 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