{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T12:16:10Z","timestamp":1769602570522,"version":"3.49.0"},"reference-count":56,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2023,4,18]],"date-time":"2023-04-18T00:00:00Z","timestamp":1681776000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brit J Clinical Pharma"],"published-print":{"date-parts":[[2023,8]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>Alprazolam is an anxiolytic compound that can lead to psychological and physiological dependence especially with prolonged use. This study utilized physiologically based pharmacokinetic (PK) and pharmacodynamic (PD) modelling to further examine the underlying mechanisms of anxiety treatment and addiction.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Data and parameter values for this study were obtained from PubMed and DrugBank literature searches. The physiologically based PK models for alprazolam were developed using PK\u2010Sim software and PD models were implemented with the MonolixSuite 2021R platform.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>After single administrations, peak unbound interstitial brain concentrations range from 4 to 33\u2009nM for 0.25\u20132\u00a0mg\u2010doses of the immediate\u2010release form and 3\u201354\u2009nM for 0.5\u201310\u2010mg doses of the extended\u2010release form. With repetitive administrations, peak concentration is 59 nM for a 2\u2010mg alprazolam immediate\u2010release dose and 122 nM for a 10\u2010mg extended\u2010release dose. Potentiation of EC<jats:sub>10<\/jats:sub> GABA\u2010gated currents from recombinant GABA<jats:sub>A<\/jats:sub>Rs composed of \u03b11\u03b22\u03b32, \u03b12\u03b23\u03b32 and \u03b15\u03b23\u03b32 subunit combinations is 92, 150 and 75%, respectively, for an alprazolam concentration of 59\u2009nM. The 10\u201390% rise times for the brain concentration\u2013time profile following a single 1\u2010mg immediate\u2010release administration is 22.8\u00a0min and 3.8\u00a0h for a 3\u2010mg extended\u2010release administration.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Unbound interstitial brain concentration\u2013time profiles of alprazolam corresponded to changes in \u03b2 rhythm activity, peak saccade velocity, mood improvement, cognitive speed slowing and digit symbol substitution test scores. PD models for these endpoints suggest that alprazolam immediate\u2010release maximal effects on cognitive slowing, cognitive impairment, sedation and mood improvement occur sequentially following the brain concentration\u2013time profile.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcp.15719","type":"journal-article","created":{"date-parts":[[2023,3,22]],"date-time":"2023-03-22T09:39:16Z","timestamp":1679477956000},"page":"2569-2581","source":"Crossref","is-referenced-by-count":4,"title":["Physiologically based pharmacokinetic and pharmacodynamic modelling of alprazolam: Implications for anxiety and addiction"],"prefix":"10.1111","volume":"89","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0208-2869","authenticated-orcid":false,"given":"Paul M.","family":"Burkat","sequence":"first","affiliation":[{"name":"Department of Psychiatry University of Pennsylvania Perelman School of Medicine  Philadelphia Pennsylvania 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