A Population Pharmacodynamic Markov Mixed-Effects Model For Determining Remimazolam-Induced Sedation When Co-Administered With Fentanyl In Procedural Sedation

The clinical effects of remimazolam (an investigational, ultra-short acting benzodia zepine being studied in procedural sedation) were measured using the Modified Observer's Assessment of Awareness/Sedation Scale (MOAA/S). The objective of this analysis was to develop a population pharmacokinetic/pharmacodynamic model to describe remimazolam-induced sedation with fentanyl over time in procedural sedation. MOAA/S from 10 clinical phase I-III 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-time observations from 1071 subjects. Effect-compartment models of remimazolam and fentanyl linked plasma concentrations to the Markov model, and drug effects were described using a synergistic maximum effect (E-max) model. Simulations were performed to identify the optimal remimazolam-fentanyl 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 kg/m(2) had similar to 30% higher rates of distribution from plasma to the effect site (keo), indicating a slightly faster onset of sedation. Simulations showed that remimazolam 5 mg was more appropriate than 4 or 6 mg when administered with fentanyl 50 mu g. The model and simulations support that a combination of remimazolam 5 mg with fentanyl 50 mu g 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.Study HighlightsWHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?A pharmacokinetic/pharmacodynamic model of remimazolam is available for the bispectral index, but the relationship to sedation (measured by Modified Observer's Assessment of Awareness/Sedation Scale) in procedural sedation is unknown.WHAT QUESTION DID THIS STUDY ADDRESS?What is the optimal dose of remimazolam when administered with fentanyl in procedural sedation and are there subgroups that require dosage adjustments?WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?Exposure-response modeling supported the recommended dose (remimazolam 5 mg with fentanyl 50 mu g) in procedural sedation and showed that the dose of remimazolam does not need to be changed in elderly patients, but some elderly patients may have a longer duration of sedation.HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?Using a Markov model resulted in excellent agreement of observed and predicted transitions between sedation states but did less well at predicting the actual level of sedation. The magnitude of "deep sedation" was overpredicted. Relative differences among dosing regimens can still be assessed to support dose selection when the bias is consistently conservative. Thus, the conservativeness of a model should be considered in the interpretation of modeling and simulation results.