Attenuation of Response to Repeated Drug Administration: A Proposal for Differentiating Tachyphylaxis and Tolerance

Svensson, Craig K.

doi:10.1124/jpet.121.000978

Cited by 4 publications

(1 citation statement)

References 66 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Svensson proposed a mechanistic distinction between (acute) tolerance and tachyphylaxis, where tachyphylaxis is reserved for attenuation of drug response by cellular depletion. 18 Cellular depletion is not directly a logical explanation for the observed difference between step-up and step-down as the mechanism of action of remimazolam is based on enhancing the effects of γ-aminobutyric acid, and we are not aware of any depletion downstream of the receptor. Development of acute tolerance was therefore explored.…”

Section: Discussionmentioning

confidence: 90%

Target-controlled Infusion of Remimazolam in Healthy Volunteers Shows Some Acute Tolerance

Vellinga,

Koomen,

Eleveld

et al. 2023

Anesthesiology

View full text Add to dashboard Cite

Background Remimazolam exhibits sedative properties by binding to γ-aminobutyric acid type A receptors. Remimazolam is administered as bolus dose or continuous infusion, but has not been studied using target-controlled infusion (TCI). We quantified the relationship between the remimazolam concentration, modified observers assessment of alertness and sedation (MOAAS) score and bispectral index (BIS) using TCI. Methods We performed a three-period, cross-over, dose-ranging clinical trial in 24 healthy volunteers using age- and sex-stratification. Data collected in the first period, where remimazolam was administered alone using a step-up and step-down TCI protocol, were used for this analysis. Remimazolam concentrations, MOAAS scores and BIS values were collected at each step at steady state. Data were analyzed using non-linear mixed-effects modelling methodology. Results The relationship between remimazolam, BIS and MOAAS differed between step-up and step-down infusions at similar remimazolam target concentrations. Tolerance, driven by remimazolam or CNS7054, significantly improved overall model fit (p<0.01) for both BIS and MOAAS models. Following 30 minutes of repeated bolus dosing, mimicking the regimen in the label for procedural sedation, the BIS and probability of MOAAS 2/3 were predicted to be 54 (95% PI: 44,67) and 2% (0,32%) versus 58 (48,70) and 8% (0,36%) in a model without and with tolerance, respectively. Following 60 minutes of continuous infusion, mimicking the regimen in the label for general anaesthesia, the BIS and probability of MOAAS 0 were predicted to be 40 (33,50) and 87% (18,100%) versus 50 (41,60) and 59% (6,99%) in a model without and with tolerance, respectively. Conclusions In this study, we showed that remimazolam-induced sedation is prone to tolerance development, which is potentially mediated by the CNS7054 concentration. The clinical consequences are however limited in situations where remimazolam is titrated to effect.

show abstract

Section: Discussionmentioning

confidence: 90%