{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T14:46:57Z","timestamp":1786978017143,"version":"build-2736575974"},"reference-count":59,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2022,6,1]],"date-time":"2022-06-01T00:00:00Z","timestamp":1654041600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2022,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Benzodiazepines induce a series of clinical effects by modulating subtypes of \u03b3\u2010aminobutyric acid type A receptors in the central nervous system. The brain concentration\u2010time profiles of diazepam that correspond to these effects are unknown, but can be estimated with physiologically based pharmacokinetic (PBPK) modeling. In this study, a PBPK model for the 1,4\u2010benzodiazepines diazepam and nordiazepam was developed from plasma concentration\u2013time courses with PK\u2010Sim software to predict brain concentrations. The PBPK model simulations accurately parallel plasma concentrations from both an internal model training data set and an external data set for both intravenous and peroral diazepam administrations. It was determined that the unbound interstitial brain concentration\u2013time profiles correlated with diazepam pharmacodynamic end points. With a 30\u2010mg intravenous diazepam dose, the peak unbound interstitial brain concentration from this model is 160 nM at 2 minutes and 28.9 nM at 120 minutes. Peak potentiation of recombinant \u03b3\u2010aminobutyric acid type A receptors composed of \u03b11\u03b22\u03b32s, \u03b12\u03b22\u03b32s, and \u03b15\u03b22\u03b32s subunit combinations that are involved in diazepam clinical endpoints is 108%, 139%, and 186%, respectively, with this intravenous dose. With 10\u2010mg peroral administrations of diazepam delivered every 24 hours, steady\u2010state peak and trough unbound interstitial brain diazepam concentrations are 22.3 \u00b1 7.5 and 9.3 \u00b1 3.5 nM. Nordiazepam unbound interstitial brain concentration is 36.1 nM at equilibrium with this diazepam dosing schedule. Pharmacodynamic models coupled to the diazepam unbound interstitial brain concentrations from the PBPK analysis account for electroencephalographic drug effect, change in 13\u2010 to 30\u2010Hz electroencephalographic activity, amnesia incidence, and sedation score time courses from human subjects.<\/jats:p>","DOI":"10.1002\/jcph.2071","type":"journal-article","created":{"date-parts":[[2022,5,9]],"date-time":"2022-05-09T13:28:41Z","timestamp":1652102921000},"page":"1297-1309","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Physiologically Based Pharmacokinetic and Pharmacodynamic Modeling of Diazepam: Unbound Interstitial Brain Concentrations Correspond to Clinical End Points"],"prefix":"10.1002","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0208-2869","authenticated-orcid":false,"given":"P.M.","family":"Burkat","sequence":"first","affiliation":[{"name":"Department of Psychiatry Crozer Health  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