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The objective of this analysis was to develop a population pharmacokinetic\/pharmacodynamic model to describe remimazolam\u2010induced sedation with fentanyl over time in procedural sedation. MOAA\/S from 10 clinical phase I\u2013III trials were pooled for analysis, where data were collected after administration of placebo or remimazolam with or without concomitant fentanyl. A Markov model described transition states for 35,356 MOAA\/S\u2010time observations from 1071 subjects. Effect\u2010compartment models of remimazolam and fentanyl linked plasma concentrations to the Markov model, and drug effects were described using a synergistic maximum effect (E<jats:sub>max<\/jats:sub>) model. Simulations were performed to identify the optimal remimazolam\u2010fentanyl combination doses in procedural sedation. Fentanyl showed synergistic effects with remimazolam in sedation. Increasing age was related to longer recovery from sedation. Patients with body mass index greater than 25\u00a0kg\/m<jats:sup>2<\/jats:sup> had ~30% higher rates of distribution from plasma to the effect site (keo), indicating a slightly faster onset of sedation. Simulations showed that remimazolam 5\u00a0mg was more appropriate than 4 or 6\u00a0mg when administered with fentanyl 50\u00a0\u03bcg. The model and simulations support that a combination of remimazolam 5\u00a0mg with fentanyl 50\u00a0\u03bcg is an appropriate dosing regimen and the dose of remimazolam does not need to be changed in elderly patients, but some elderly patients may have a longer duration of sedation.<\/jats:p>","DOI":"10.1111\/cts.13023","type":"journal-article","created":{"date-parts":[[2021,3,26]],"date-time":"2021-03-26T07:14:42Z","timestamp":1616742882000},"page":"1554-1565","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["A population pharmacodynamic Markov mixed\u2010effects model for determining remimazolam\u2010induced sedation when co\u2010administered with fentanyl in procedural sedation"],"prefix":"10.1111","volume":"14","author":[{"given":"Jie","family":"Zhou","sequence":"first","affiliation":[{"name":"Nuventra Pharma Sciences Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Curd","sequence":"additional","affiliation":[{"name":"Nuventra Pharma Sciences Durham North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren R. 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