An interstitial compartment is necessary to link the pharmacokinetics and pharmacodynamics of mivacurium

Anaesthesiologists adjust drug dosing, administration system and kind of drug to the characteristics of the patient. They then observe the expected response and adjust dosing to the specific requirements according to the difference between observed response, expected response and the context of the surgery and the patient.The approach above can be achieved because on one hand quantification technology has made significant advances allowing the anaesthesiologist to measure almost any effect by using noninvasive, continuous measuring systems. On the other the knowledge on the relations between dosing, concentration, biophase dynamics and effect as well as detection of variability sources has been achieved as being the benchmark specialty for pharmacokinetic-pharmacodynamic (PKPD) modelling.The aim of the review is to revisit the most common PKPD models applied in the field of anaesthesia (i.e. effect compartmental, turnover, drug-receptor binding and drug interaction models) through representative examples. The effect compartmental model has been widely used in this field and there are multiple applications and examples. The use of turnover models has been limited mainly to describe respiratory effects. Similarly, cases in which the dissociation process of the drug-receptor complex is slow compared with other processes relevant to the time course of the anaesthetic effect are not frequent in anaesthesia, where in addition to a rapid onset, a fast offset of the response is required. With respect to the characterization of PD drug interactions different response surface models are discussed. Relevant applications that have changed the way modern anaesthesia is practiced are also provided.

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“… B) the interstitial ECm model ( S chiere et al . ) and C) the two‐compartments ECm ( B jörnsson et al . ).…”

Section: Pkpd Models Used In Anaesthesiamentioning

confidence: 97%

“…In the original manuscript values of k 1p and k e0 of 0.374 and 0.151 min −1 were reported. When the standard effect compartmental model was fitted to the data the estimate obtained for k e0 was 0.041 min −1 .…”

Section: Pkpd Models Used In Anaesthesiamentioning

confidence: 99%

Pharmacokinetic–pharmacodynamic modelling in anaesthesia

Gambús

Trocóniz

2014

Brit J Clinical Pharma

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“…A slow ke0 limits the rate of onset of action. While a simple first-order rate constant is often sufficient to describe drug transport to the effect site, mivacurium is an exception to this, requiring modelling of an interstitial compartment for accurate prediction of pharmacodynamics [19] . Other PD parameters describe various characteristics of drug effect.…”

Section: Pharmacokinetics and Pharmacodynamics Of Non-depolarizing Neuromuscular Blocking Drugsmentioning

confidence: 99%

Immobility

Olkkola¹,

Eleveld²

2019

Personalized Anaesthesia

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Surgical anaesthesia usually requires hypnosis, antinociception (ensuring blood pressure and heart rate control) and immobility with varying degrees of muscle relaxation. However, the relative contribution of these three components to the state of anaesthesia may vary between different anaesthesias and surgical procedures. While volatile anaesthetics may be used to produce anaesthesia in and by themselves, most often anaesthesia is produced by a combination of drugs. Anaesthesia produced by the concomitant use of hypnotics, analgesics and neuromuscular blocking drugs is called "balanced anaesthesia".The degree of neuromuscular block induced by neuromuscular blocking drugs and the depth of anaesthesia (induced by other drugs) both affect muscle relaxation [1] . While in the early days of our profession deep ether anaesthesia alone provided sufficient muscle relaxation for many procedures, the introduction of neuromuscular blocking drugs nowadays allows us to specifically target specific degrees of muscle relaxation in an easy and safe manner. Provided the airway is secured and adequate ventilation and hypnosis are ensured, adverse effects of neuromuscular blocking drugs are few.After briefly reviewing pertinent physiology, the different degrees of neuromuscular block depth are defined and the tools to measure them are described. The chapter then focuses on the properties of modern neuromuscular blocking drugs (only cisatracurium, mivacurium, and rocuronium will be discussed) and suxamethonium. Finally, the clinically optimal neuromuscular block is defined, and the different routes to achieve this goal are explored. Neuromuscular junctionAn action potential causes synaptic vesicles of the motor nerve endings containing the neurotransmitter acetylcholine to fuse with the plasma membrane and release their content into the neuromuscular junction. Acetylcholine then binds to postjunctional nicotinic acetylcholine receptors on the motor endplate. These receptors consist of two alpha and one beta, delta and epsilon subunits. They are directly linked to ion channels. If acetylcholine is bound to both alpha

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“…To evaluate the influence of model misspecification, a second series of data sets was generated, using a PK-PD link model with an interstitial compartment situated between plasma and effect compartment as described earlier for mivacurium [11]. The PD parameters were chosen to mimic the twitch height profile of the original model as closely as possible, as shown in Figure 2: rate constant of transport between plasma and interstitial compartment (k is ) 0.5 min À1 , k e0 0.3085 min À1 , EC 50 1120 mg l À1 and g 2.922.…”

Section: Data Generationmentioning

confidence: 99%

“…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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An interstitial compartment is necessary to link the pharmacokinetics and pharmacodynamics of mivacurium

Cited by 5 publications

References 26 publications

Pharmacokinetic–pharmacodynamic modelling in anaesthesia

Pharmacokinetic–pharmacodynamic modelling in anaesthesia

Immobility

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

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