Pharmacokinetic and pharmacodynamic characterization of remimazolam in older Japanese adults who underwent general anesthesia at early stage of infusion

Figures

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  Fig. 1. Overview of the basic pharmacokinetic and pharmacodynamic model for remimazolam (RMZ). CL, elimination clearance of RMZ; CLM, elimination clearance of CNS7054; Q2 and Q3, intercompartmental clearance of RMZ; Q2M; intercompartmental clearance of CNS7054; kT, transit rate constant; kE0, rate constant of distribution from plasma to the effect site; V1, central volume of distribution of RMZ; V2 and V3, peripheral volume of distribution of RMZ; V1M, central volume of distribution of CNS7054; peripheral volume of distribution of CNS7054; BIS, bispectral index.

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  Fig. 2. Goodness-of-fit plots of the final pharmacokinetic and pharmacodynamic model. Observed plasma concentrations of RMZ or CNS7054 versus population predictions (a and e) or individual predictions (b and f), as well as conditional weighted residuals (CWRES) versus time after infusion (c and g) or population predictions of RMZ or CNS7054 (d and h). Observed BIS versus population predictions (i) or individual predictions (j), and CWRES versus time after infusion (k) or population predictions (l). The open circles show the observed values, and each dotted line indicates a line of identity.

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  Fig. 3. Prediction-corrected visual predictive check plot of the final pharmacokinetic and pharmacodynamic model. Open circles show the observed plasma concentrations (a and b) or bispectral index (BIS) (c) The top dotted, middle solid, and bottom dotted lines represent the 95th, 50th, and 5th percentiles, respectively, calculated from 1000 simulated datasets.

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  Fig. 4. Simulations of plasma RMZ concentrations and the effect site (a and b) and BIS-time profiles (c) in the 1000 replication datasets of a patient administered for general anesthesia with induction (12 mg/kg/h) and maintenance (1 mg/kg/h). The time to loss of consciousness was set to 1.71 min after the infusion. These simulations were conducted using the final pharmacokinetic and pharmacodynamic model. The solid, dotted and bold lines indicate the medians in patients weighing 40, 60 and 80 kg, respectively. In (c), the shaded area shows the target range of BIS (40−60)21.