Pharmacokinetic–Pharmacodynamic Modeling of Rocuronium in Case of a Decreased Number of Acetylcholine Receptors

Haes, Ann De; Proost, Johannes H.; Baets, Mark H. De; Stassen, M.; Houwertjes, M. C.; Wierda, J. M. K. H.

doi:10.1097/00000542-200301000-00022

Cited by 15 publications

(5 citation statements)

References 23 publications

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“…Therefore, it has been suggested that myotonic discharges may substitute for normal background nerve activity and thus suppress the expression of nicotinic acetylcholine receptors [5, 6]. A smaller number of nicotinic acetylcholine receptors can enhance susceptibility to non‐depolarising agents [16], which can explain the prolonged recovery following a given dose of drug that we have found in patient 4 suffering from severe MD1. On purely theoretical grounds it can be speculated that, in addition to changes at the neuromuscular junctions, alterations to the pharmacokinetics of neuromuscular blocking drugs could also be a potential cause for an exaggerated response to rocuronium.…”

Section: Discussionmentioning

confidence: 79%

“…Both normal responses [8–11] and increased sensitivity and prolonged recovery have been reported [9, 11–15]. Structural changes at the neuromuscular junctions and decreased numbers of nicotinic acetylcholine receptors at postsynaptic membranes [5, 6] can explain these exaggerated responses to non‐depolarising agents [16]. Because of this unpredictability, neuromuscular block should be carefully monitored.…”

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confidence: 99%

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Comparison of mechanomyography and acceleromyography for the assessment of rocuronium induced neuromuscular block in myotonic dystrophy type 1

Vanlinthout

Booij

Egmond³

et al. 2010

Anaesthesia

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SummaryWe measured acceleromyography and mechanomyography simultaneously with monitoring of rocuronium-induced neuromuscular block in four patients with myotonic dystrophy type 1. Furthermore, we compared neuromuscular block measures from these patients with those from normal controls from previous studies. In myotonic dystrophy type 1 patients, the dose-response curve obtained with acceleromyography was steeper and right-shifted compared with that obtained using mechanomyography. However, the effective doses to produce 95% neuromuscular block determined with both acceleromyography and mechanomyography were similar to each other and to values found in normal patients. In the three myotonic dystrophy type 1 patients with mild to moderate disease, times to recovery from block were similar to those observed in normal controls. In both patients and normal controls, neuromuscular block recovered faster with acceleromyography. However, in one patient with severe muscle wasting, recovery of neuromuscular block was prolonged. We conclude that mechanomyography and acceleromyography cannot be used interchangeably to monitor neuromuscular block in myotonic dystrophy type 1 patients.

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Section: Discussionmentioning

confidence: 79%

mentioning

confidence: 99%

Comparison of mechanomyography and acceleromyography for the assessment of rocuronium induced neuromuscular block in myotonic dystrophy type 1

Vanlinthout

Booij

Egmond³

et al. 2010

Anaesthesia

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“…This technique was applied also for PK-PD analysis, using the sequential PK-PD method and nonparametric PK method [9][10][11]. A method for simultaneous PK-PD analysis with an ITSB technique has not yet been described in the literature.…”

Section: Introductionmentioning

confidence: 99%

Simultaneous versus sequential pharmacokinetic‐pharmacodynamic population analysis using an Iterative Two‐Stage Bayesian technique

Proost

Schiere

Eleveld

et al. 2007

Biopharm & Drug Disp

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A method for simultaneous pharmacokinetic-pharmacodynamic (PK-PD) population analysis using an Iterative Two-Stage Bayesian (ITSB) algorithm was developed. The method was evaluated using clinical data and Monte Carlo simulations. Data from a clinical study with rocuronium in nine anesthetized patients and data generated by Monte Carlo simulation using a similar study design were analysed by sequential PK-PD analysis, PD analysis with nonparametric PK data and simultaneous PK-PD analysis. Both PK and PD data sets were 'rich' with respect to the number of measurements per individual. The accuracy and precision of the estimated population parameters were evaluated by comparing their mean error (ME) and root mean squared error (RMSE), respectively. The influence of PD model misspecification on the results was also investigated. The simultaneous PK-PD analysis resulted in slightly more precise population parameter estimates than the sequential PK-PD analysis and the nonparametric PK method. In the presence of PD model misspecification, however, simultaneous analysis resulted in poor PK parameter estimates, while sequential PK-PD analysis performed well. In conclusion, ITSB is a valuable technique for PK-PD population analysis of rich data sets. The sequential PK-PD method is better suited for the analysis of rich data than the simultaneous analysis.

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“…The previously reported pharmacodynamic models3, 4, 19 do not consider the interaction between acetylcholine (ACh) and the postsynaptic receptors at the motor endplates and are thus unsuitable for simulations of twitch strength in these two conditions. In this study, we have amplified our previously published model of neuromuscular transmission 13.…”

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confidence: 99%

Myasthenia gravis and myasthenic syndrome: Simulation of twitch strength with or without therapy

2005

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To examine the quantitative relationship between indirectly evoked twitch and decreases in the number of either postsynaptic receptors or acetylcholine molecules released by a single stimulus, we studied these variables in a computer-simulated model of neuromuscular transmission. Twitch strength decreased if the number of receptors decreased to below 30% of normal or the number of acetylcholine molecules released by a stimulus decreased to below 80%. Inhibition of acetylcholine hydrolysis to 50% restored twitch strength in the presence of a decreased number of receptors. However, twitch strength was more easily restored to normalcy by augmenting the release of acetylcholine, if the release was diminished by disease. The simulations mimic the clinically known therapeutic outcomes in certain disorders of neuromuscular transmission. These results provide useful quantitative insights into the relationship between acetylcholine receptors or the stimulus-induced release of acetylcholine and muscle function in myasthenia gravis or Lambert-Eaton myasthenic syndrome.

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Pharmacokinetic–Pharmacodynamic Modeling of Rocuronium in Case of a Decreased Number of Acetylcholine Receptors

Abstract: Both the Sheiner model and the unbound receptor model may be used to fit plasma concentration-effect data of rocuronium in pigs. The unbound receptor concentration model, however, can explain the observed differences in the time course of effect, based on receptor concentration.

Cited by 15 publications

References 23 publications

Comparison of mechanomyography and acceleromyography for the assessment of rocuronium induced neuromuscular block in myotonic dystrophy type 1

Comparison of mechanomyography and acceleromyography for the assessment of rocuronium induced neuromuscular block in myotonic dystrophy type 1

Simultaneous versus sequential pharmacokinetic‐pharmacodynamic population analysis using an Iterative Two‐Stage Bayesian technique

Myasthenia gravis and myasthenic syndrome: Simulation of twitch strength with or without therapy

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