{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T08:05:57Z","timestamp":1784793957790,"version":"3.55.0"},"reference-count":28,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:00:00Z","timestamp":1784246400000},"content-version":"vor","delay-in-days":16,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Fundamemntal Clinical Pharma"],"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Midazolam (MDZ) is used for sedation in critically ill patients. Although previous studies have examined MDZ pharmacokinetics in ICU patients, the differential effects of acute kidney injury (AKI) and chronic kidney disease (CKD), particularly in cohorts including COVID\u201019 and non\u2010COVID\u201019 patients, remain insufficiently characterised.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To investigate whether AKI and CKD are associated with dose\u2010normalised exposure of MDZ, 1\u2010hydroxy\u2010midazolam (1\u2010OH\u2010MDZ) and 1\u2010hydroxy\u2010midazolam glucuronide (1\u2010OH\u2010MDZ\u2010G) in critically ill adults.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this retrospective observational study, ICU patients receiving continuous intravenous MDZ were included. Plasma concentrations of MDZ, 1\u2010OH\u2010MDZ and 1\u2010OH\u2010MDZ\u2010G were converted to concentration\u2010to\u2010dose (C\/D) ratios. Cross\u2010sectional analysis used the first sample per patient; longitudinal analysis included all samples in GEE models. Analyses were adjusted for age, sex, BMI, COVID\u201019 status, CYP3A4 inhibitor use, APACHE IV score, time since MDZ initiation and CRP.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Forty\u2010seven patients contributed 137 samples. In the cross\u2010sectional analysis, C\/D ratios of MDZ and 1\u2010OH\u2010MDZ did not differ between patients with and without AKI, whereas 1\u2010OH\u2010MDZ\u2010G C\/D ratios were higher in AKI (median [IQR] 14.54 [6.14\u201326.20] vs. 4.53 [2.52\u20136.00];\n                      <jats:italic>p<\/jats:italic>\n                      \u2009&lt;\u20090.01). Longitudinal analysis showed that AKI (\n                      <jats:italic>\u03b2<\/jats:italic>\n                      \u2009=\u20090.87), AKI Stage 1 (\n                      <jats:italic>\u03b2<\/jats:italic>\n                      \u2009=\u20090.81), AKI Stages 2\u20133 (\n                      <jats:italic>\u03b2<\/jats:italic>\n                      \u2009=\u20090.97) and CKD (\n                      <jats:italic>\u03b2<\/jats:italic>\n                      \u2009=\u20090.72) were all significantly associated with higher 1\u2010OH\u2010MDZ\u2010G C\/D ratios (all\n                      <jats:italic>p<\/jats:italic>\n                      \u2009\u2264\u20090.03). No significant associations were observed for MDZ or 1\u2010OH\u2010MDZ.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>AKI and CKD are associated with accumulation of 1\u2010OH\u2010MDZ\u2010G in critically ill patients. Monitoring 1\u2010OH\u2010MDZ\u2010G may help identify patients at risk of prolonged sedation and adverse outcomes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/fcp.70108","type":"journal-article","created":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T00:35:36Z","timestamp":1784334936000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Association of Acute Kidney Injury and Chronic Kidney Disease With Concentration\u2010To\u2010Dose Ratios of Midazolam and Its Main Metabolites in Critically Ill Adults"],"prefix":"10.1111","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-4507-1781","authenticated-orcid":false,"given":"Kimberly","family":"Shudofsky","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacy VieCuri Medical Center  Venlo the Netherlands"},{"name":"Department of Clinical Pharmacy and Toxicology Maastricht University Medical Centre+  Maastricht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Abma","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy VieCuri Medical Center  Venlo the Netherlands"},{"name":"Department of Clinical Pharmacy and Toxicology Maastricht University Medical Centre+  Maastricht the Netherlands"},{"name":"Department of Clinical Pharmacy Flevo Hospital  Almere the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Driessen","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy and Toxicology Maastricht University Medical Centre+  Maastricht the Netherlands"},{"name":"Department of Clinical Pharmacy, CARIM, the Cardiovascular Research Institute Maastricht Maastricht University  Maastricht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marielle","family":"Slikkerveer","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy and Toxicology Maastricht University Medical Centre+  Maastricht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Floris","family":"Vanmolkot","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine Maastricht University Medical Centre+  Maastricht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paddy","family":"Janssen","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy VieCuri Medical Center  Venlo the Netherlands"},{"name":"Department of Clinical Pharmacy and Toxicology Maastricht University Medical Centre+  Maastricht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos","family":"le Noble","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy VieCuri Medical Center  Venlo the Netherlands"},{"name":"Department of Clinical Pharmacy and Toxicology Maastricht University Medical Centre+  Maastricht the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,17]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph17040473"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.1992.84"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(95)91209\u20106"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/healthcare7010010"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1186\/cc3010"},{"issue":"3","key":"e_1_2_13_7_1","first-page":"149","article-title":"The Effects of Acute Changes in Renal Function on the Pharmacokinetics of Midazolam During Long\u2010Term Infusion in ICU Patients","volume":"42","author":"Driessen J. 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