To the Editor
Two recently published papers describe the context sensitive half-time (CSHT) as a predictor of recovery for the novel benzodiazepine remimazolam (CNS 7056).1,2 The term CSHT was first proposed in 1992 by Hughes et al.3 and consists of curves constructed by computer simulations designed to determine how long it takes for the plasma concentration to decrease by 50% for different durations of infusion. Although Wiltshire et al.2 reported the “context sensitive half-time” of remimazolam, they used constant rate infusions for their simulations rather than a varying rate infusion designed to produce a constant concentration target-controlled infusion (TCI). Thus, we believe that the simulated remimazolam CSHT when calculated using TCI (rather than constant rate infusion) might be longer than those shown in Figure 10.2
We note that Wiltshire et al.2 present a recirculatory model as the optimal model in terms of the lowest objective function with meaningful model parameters. However, from a practical perspective (i.e., implementation in a TCI pump), a 3-compartment mammillary model would certainly be more appealing. Although the more complex model is supported from a statistical perspective, it could be that it represents only a marginal improvement from a clinical perspective. Therefore, it would be of interest to the pharmacokinetically inclined reader to see a plot showing the residuals over time, depicting the difference between the simple and the complex models. Importantly, we would not discount the potential use of the 3-compartment mammillary model with future remimazolam data sets, because it is possible that the “much poorer fits” obtained in this investigation could be avoided by the use of arterial sampling throughout the study.
The family of recovery curves published by Shafer and Varvel4 provide the foundation to understanding the “relevant decrement time” published by Bailey.5 We believe that this is a clinically relevant concept because 2 drugs with different concentration response curves will require different decrements in their concentrations for the same decrement in drug effect. For example, based on the pharmacodynamic parameters given in Table 2,2 the required decrement in the effect site concentration to recover from a bispectral index (BIS) value of 80 to 92 for remimazolam is 72%, whereas for midazolam it is only 29% (this is due to the larger Hill coefficient estimated for midazolam than for remimazolam). Thus, relevant decrement time curves (based on effect site TCI simulations for different durations of infusion) for the same specified BIS end point would be a more clinically meaningful comparison than the simulations shown in Figure 11.2 However, we also note that the estimated lowest BIS value of 55.7 for remimazolam and 75.1 for midazolam are probably poor estimates of the “true” maximum effect because the electroencephalogram data are censored.
Finally, we would encourage researchers to continue to use the existing phrase “relevant decrement time” introduced by Bailey5 rather than the new phrase “pharmacodynamic CSHT” introduced in the accompanying editorial by Johnson.6
Thomas Schnider, Prof. Dr. Med.
Institut für Anästhesiologie, Kantonsspital
St. Gallen, Switzerland
University of Berne
Charles Minto, FANZCA, PhD
Sydney, New South Wales, Australia
1. Antonik LJ, Goldwater DR, Kilpatrick GJ, Tilbrook GS, Borkett KM. A placebo- and midazolam-controlled phase I single ascending-dose study evaluating the safety, pharmacokinetics, and pharmacodynamics of remimazolam (CNS 7056): Part I. Safety, efficacy, and basic pharmacokinetics. Anesth Analg. 2012;115:274–83
2. Wiltshire HR, Kilpatrick GJ, Tilbrook GS, Borkett KM. A placebo- and midazolam-controlled phase I single ascending-dose study evaluating the safety, pharmacokinetics, and pharmacodynamics of remimazolam (CNS 7056): Part II. Population pharmacokinetic and pharmacodynamic modeling and simulation. Anesth Analg. 2012;115:284–96
3. Hughes MA, Glass PS, Jacobs JR. Context-sensitive half-time in multicompartment pharmacokinetic models for intravenous anesthetic drugs. Anesthesiology. 1992;76:334–41
4. Shafer SL, Varvel JR. Pharmacokinetics, pharmacodynamics, and rational opioid selection. Anesthesiology. 1991;74:53–63
5. Bailey JM. Technique for quantifying the duration of intravenous anesthetic effect. Anesthesiology. 1995;83:1095–103
6. Johnson KB. New horizons in sedative hypnotic drug development: fast, clean, and soft. Anesth Analg. 2012;115:220–2