J. Mark K. H. Wierda

Early reversal of profound rocuronium-induced neuromuscular blockade by sugammadex in a randomized multicenter study: efficacy, safety, and pharmacokinetics

Background:Sugammadex reverses the neuromuscular blocking effects of rocuronium by chemical encapsulation. The efficacy, safety, and pharmacokinetics of sugammadex for reversal of profound rocuronium-induced neuromuscular blockade were evaluated. Methods:Ninety-eight male adult patients were randomly assigned to receive sugammadex (1, 2, 4, 6, or 8 mg/kg) or placebo at 3, 5, or 15 min after 0.6 mg/kg rocuronium. Patients were anesthetized with propofol and fentanyl. The primary endpoint of the study was the time to achieve a recovery of train-of-four ratio to 0.9. Neuromuscular blockade was measured using acceleromyography. Concentrations of rocuronium and sugammadex were determined in venous blood and urine samples. A population pharmacokinetic model using NONMEM (GloboMax LLC, Hanover, MD) was applied. Results:The mean time to recovery of the train-of-four ratio to 0.9 after dosing at 3, 5, and 15 min decreased from 52.1, 51.7, and 35.6 min, respectively, after administration of placebo to 1.8, 1.5, and 1.4 min, respectively, after 8 mg/kg sugammadex. Sugammadex was safe and well tolerated. However, 20.4% of patients showed signs of inadequate anesthesia after its administration. The median cumulative excretion of rocuronium in the urine over 24 h was 26% in the placebo group and increased to 58–74% after 4–8 mg/kg sugammadex. The mean plasma clearances of sugammadex and rocuronium were 0.084 and 0.26 l/min, respectively. Conclusions:In male subjects, sugammadex safely reversed profound neuromuscular blockade induced by 0.6 mg/kg rocuronium in a dose-dependent manner. Sugammadex enhanced the renal excretion of rocuronium, and its clearance is approximately one third that of rocuronium.

A temporary decrease in twitch response during reversal of rocuronium-induced muscle relaxation with a small dose of sugammadex.

BACKGROUND:We present a case in which a temporary decrease in train-of-four (TOF) response was observed after reversal of muscle relaxation with a small dose (0.5 mg/kg) of sugammadex administered 42 min after 0.9 mg/kg of rocuronium. At the end of the operation, the TOF ratio was >0.9, and the patient woke normally, without signs of muscle weakness. We describe this temporary decrease in muscle response during muscle relaxation reversal as muscle relaxation rebound and hypothesize that it occurs when the dose of sugammadex is sufficient for complex formation with rocuronium in the central compartment, but insufficient for redistribution of rocuronium from peripheral to central compartments. METHODS:To investigate our hypothesis, we developed and fit a simple pharmacokinetic– pharmacodynamic model of rocuronium, sugammadex, and their interaction to the patient TOF response data. RESULTS:Simulations using the fitted model indicate that muscle relaxation rebound can occur for doses of sugammadex in a limited critical range. CONCLUSIONS:Sufficiently large doses of sugammadex eliminate the possibility for muscle relaxation rebound, which does not require dissociation of the sugammadex/ rocuronium complex.

An extended pharmacokinetic/pharmacodynamic model describing quantitatively the influence of plasma protein binding, tissue binding, and receptor binding on the potency and time course of action of drugs

An extended pharmacokinetic/pharmacodynamic (PK/PD) model is presented, in which the effect of binding of the drug to plasma proteins and to tissue binding sites in a peripheral compartment, and nonspecific and receptor binding in the effect compartment are taken into account. It represents an extension of the classical Sheiner model, and the model proposed by Donati and Meistelman. The present model is characterized by the following parameters:kue (exit rate constant of unbound drug from the effect compartment),Pue (ratio of the unbound clearances to and from the effect compartment),fue (fraction of drug in effect compartment that is not bound to nonspecific binding sites),Kd (equilibrium dissociation constant of drug-receptor binding), andRwt (concentration of receptor binding sites in effect compartment). The rate of association and dissociation of the drug-receptor complex can be incorporated in the model. The influence of the pharmacokinetic parameters (V1,V2,fu,fu2,CLu10,CLu20,CLu12,CLu21) and the PK/PD model parameters (kue,Pue,fue,Kd,Rwt) on various dynamic parameters is analyzed. These include potency (single dose needed to produce 90% effect,ED90), constant infusion dosing rate needed to maintain a constant effect of 90%, time to maximum effect (onset time), and duration to 90% recovery. The neuromuscular blocking agent vecuronium is used as an example. It is shown that both potency and time course of action are strongly dependent on the ratioVt/fu,CLu10,kue,Pue (at equipotent doses the time course is not affected byPue),fue,Kd, andRwt (only ifRwt is high), whereas they are less affected by the ratioV2/fu2,CLu20,CLu12, andCLu21. In general, the model parameters affect theED90 and the time course of action in the same direction, e.g., an increase ofV1 results in an increase ofED90 and an increase of onset time and duration. However, the unbound clearanceCLu10, the intercompartmental unbound clearanceCLu12 and the receptor affinityKd have an opposite effect onED90 and the time course parameters, e.g., an increase ofCLu10 results in an increase ofED90 and a decrease of onset time and duration. This effect may be responsible for the inverse relationship between onset time and potency of neuromuscular blocking drugs observed in animal experiments and clinical studies. We demonstrate that PK/PD analysis using the traditional effect compartment model (Sheiner model) results in an apparent value ofkc), which is a function ofkue,fue,Kd,Rwt, as well as the unbound drug concentration in the effect compartmentCue. On the other hand, the model proposed by Donati and Meistelman gives correct values ofkc0 (equal to the productfue·kue), but the receptor affinityKd and the receptor densityRwt obtained by this method are apparent values, which depend onfu,fue, andPue.

Predictability of processed electroencephalography effects on the basis of pharmacokinetic-pharmacodynamic modeling during repeated propofol infusions in patients with extradural analgesia

BackgroundPharmacokinetic–pharmacodynamic (PKPD) modeling can be used to characterize the concentration–effect relation of drugs. If the concentration–effect relation of a hypnotic drug is stable over time, an effect parameter derived from the processed electroencephalographic signal may be used to control the infusion for hypnosis. Therefore, the stability of the propofol concentration–electroencephalographic effect relation over time was investigated under non–steady state conditions. MethodsThree propofol infusions (25 mg · kg−1 · h−1 for 10 min, 22 mg · kg−1 · h−1 for 10 min, and 12.5 mg · kg−1 · h−1 for 20 min) were administered to 10 patients during extradural analgesia. Each successive infusion was started immediately after the patient had regained responsiveness after termination of the preceding infusion. Electroencephalography was recorded from bilateral prefrontal to mastoid leads. Electroencephalographic amplitude in the 11- to 15-Hz band and the Bispectral Index were used as electroencephalographic effect variables. PKPD parameters were calculated with use of parametric and nonparametric models based on electroencephalographic data and arterial propofol concentrations derived during the initial infusion, and these were used to predict electroencephalographic effect during the subsequent infusions. The predictability of the electroencephalographic effects was determined by the coefficient of determination (R2) and of the −2 log likelihood of the sequential infusions. ResultsThe direction of electroencephalographic changes in response to the infusions was reproducible. Although PKPD parameters could be estimated well during the initial infusion (median [range] parametric R2 = 0.74 [0.56–0.95] for electroencephalographic amplitude and 0.90 [0.27–0.99] for Bispectral Index), none of the modeling techniques could predict accurately the electroencephalographic effect during subsequent infusions (R2 = 0.00 [−0.31–0.46] for electroencephalographic amplitude and 0.15 [−0.46–0.57] for Bispectral Index;P < 0.01). ConclusionsThe relation between blood propofol concentrations and the electroencephalographic effect under non–steady state conditions is not stable over time and is too complex to be modeled by any of the applied PKPD models.

Inhibition of the enzymic degradation of suxamethonium and mivacurium increases the onset time of submaximal neuromuscular block

Background The factors that influence the onset time of submaximal (< 100%) neuromuscular block are not fully known. The authors hypothesized that differences in the rate of decrease in the plasma concentration result in differences in the rate of equilibration between plasma and biophase and thus in different onset times. If this hypothesis is valid, inhibition of the enzymic degradation of muscle relaxants should increase the onset time of neuromuscular block. Methods Twenty pigs received either suxamethonium or mivacurium. Dose finding (70% block) was done for each pig. The enzymic degradation of the muscle relaxant was randomly inhibited by selective inhibition of plasma cholinesterase activity by tetraisopropyl pyrophosphoramide (10 pigs) or was not inhibited (10 pigs). Plasma cholinesterase activities and the mechanomyographic muscle response after peroneal nerve stimulation (0.1 Hz) were measured. Results Inhibition of plasma cholinesterase activity (by 93% and 89%, respectively) increased the onset time of suxamethonium from a median of 40 s (range, 20-45 s) to 131 s (range, 114-166 s; P = 0.009) and of mivacurium from a median of 52 s (range, 40-59 s) to 105 s (range, 90-125 s; P = 0.009). Inhibition of degradation decreased the effective dose of suxamethonium that resulted in 70% depression of the initial twitch height from 900 [micro sign]g/kg (range, 400-1,000 [micro sign]g/kg) to 150 [micro sign]g/kg (range, 135 - 150 [micro sign]g/kg) and of mivacurium from 100 [micro sign]g/kg (range, 80-150 [micro sign]g/kg) to 35 [micro sign]g/kg (range, 20-50 [micro sign]g/kg). Conclusions Inhibition of the enzymic degradation of suxamethonium and mivacurium increases the onset time of submaximal neuromuscular block. Therefore, pharmacokinetics influence the onset time of submaximal neuromuscular block. These results imply that to obtain an ultrashort onset time, muscle relaxants should be developed that not only have a low affinity for the receptor but also rapidly disappear from plasma.

Pharmacokinetic/pharmacodynamic Modeling of Rocuronium in Myasthenic Patients Is Improved by Taking into Account the Number of Unbound Acetylcholine Receptors

Patients with myasthenia gravis are more sensitive than healthy patients to nondepolarizing neuromuscular blocking drugs. We performed a pharmacokinetic/pharmacodynamic modeling study of rocuronium in eight myasthenic patients and eight matched control patients. Patients were anesthetized with propofol and sufentanil and a mixture of nitrous oxide/oxygen. Mechanomyographical monitoring of the adductor pollicis was applied. Rocuronium was infused at a rate of 25 &mgr;g · kg−1 · min−1 in myasthenic patients and 116.7 &mgr;g · kg−1 · min−1 in control patients and was terminated at 70% neuromuscular block. Arterial blood samples were drawn during onset and offset of the block and for 4 h after the administration of rocuronium. Plasma concentrations were determined by high-performance liquid chromatography. Pharmacokinetic/pharmacodynamic modeling was performed by using the Sheiner model and the unbound receptor model (URM), which takes into account the number of unbound acetylcholine receptors. The effective concentration at 50% effect and the steepness of the concentration-effect relationship were significantly decreased in myasthenic patients. Both the URM and the Sheiner model provided an adequate fit in myasthenic patients. The acetylcholine receptor concentration was significantly decreased in myasthenic patients. The URM explains the observed differences in time course and potency, whereas the Sheiner model does not.

Do plasma concentrations obtained from early arterial blood sampling improve pharmacokinetic/pharmacodynamic modeling?

In pharmacokinetic/pharmacodynamic (PK/PD) modeling the first blood sample is usually taken 1 to 2 min after drug administration (late sampling). Therefore, investigators have to extrapolate the plasma concentration to Time 0. Extrapolation, however, erroneously assumes instantaneous and complete mixing of drug in the central volume of distribution. We investigated whether plasma concentrations obtained from early arterial blood sampling would improve PK/PD modeling. In 14 pigs, one of five neuromuscular blocking agents (NMBAs) was administered into the right ventricle within 1 sec and arterial sampling was performed every 1.2 sec (1st min). The response of the tibialis muscle was measured mechanomyographically. The influence of inclusion of data from early arterial sampling on PK/PD modeling was determined. Furthermore, the concentrations in the effect compartment at 50% block (EC50) derived from modeling were compared to the measured concentration in plasma during a steady state 50% block. A very high peak in arterial plasma concentration was seen within 20 sec after administration of the NMBA. Extensive modeling revealed that plasma concentrations obtained from early arterial blood sampling improve PK/PD modeling. Independent of the type of modeling, the EC50and KeObased on data sets that include early arterial blood sampling were, for all five NMBAs, significantly higher and lower respectively, than those based on data sets obtained from late sampling. Early arterial sampling shows that the mixing of the NMBA in the central volume of distribution is incomplete. A parametric PD (sigmoid Emax) model could not describe the time course of effect of the NMBAs adequately.

Pharmacokinetic-pharmacodynamic modeling of rocuronium in case of a decreased number of acetylcholine receptors: a study in myasthenic pigs.

Background In myasthenic patients, the sensitivity for nondepolarizing relaxants is increased and the time course of effect is prolonged due to a reduced number of functional acetylcholine receptors at the neuromuscular junction. The authors investigated both the performance of the link model proposed by Sheiner and a pharmacodynamic–pharmacokinetic model taking into account the number of unbound acetylcholine receptors in myasthenic pigs. Methods After obtaining the approval of the Animal Experiments Committee of their institution, the authors studied eight myasthenic pigs and eight control pigs. Myasthenia gravis was induced by injecting Torpedo acetylcholine receptors in weeks 1 and 4. On the day of the experiments, the pigs were anesthetized and intubated, and the appropriate muscles and nerves were prepared for the measurements. Rocuronium was administered by infusion to reach 90% twitch height block. Arterial blood was sampled during onset and offset of effect, and the plasma concentration of rocuronium was measured with high-performance liquid chromatography. Plasma concentration–time effect data were analyzed using two different pharmacokinetic–pharmacodynamic models, the link model according to Sheiner and a pharmacokinetic–pharmacodynamic model taking into account the unbound receptor concentration. Muscles were removed after the experiment for laboratory analysis of the acetylcholine receptor concentration. Results All eight pigs of the myasthenic group developed clinical signs of myasthenia gravis (muscle weakness) and showed increased sensitivity toward rocuronium. Pharmacokinetic modeling revealed no significant differences between myasthenic and control pigs. In pharmacokinetic–pharmacodynamic analysis, visual inspection as well as the Akaike Information Criterion (3,605 vs. 3,769) and the residual SD (3.2 vs. 3.6%) revealed a better fit for the unbound receptor model in myasthenic animals compared to the Sheiner model. Pharmacokinetic–pharmacodynamic analysis with the unbound receptor model demonstrated a decreased EC50 of 0.27 &mgr;m (ranging from 0.17 to 0.59 &mgr;m) compared to 2.71 &mgr;m (ranging from 2.42 to 4.43 &mgr;m) in control animals. The results of the Sheiner pharmacokinetic–pharmacodynamic analysis were in the same range. Both the laboratory analysis and pharmacokinetic–pharmacodynamic modeling showed a decrease in receptor concentration of more than 75%. Conclusion 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.

An isolated, antegrade, perfused, peroneal nerve anterior tibialis muscle model in the rat: A novel model developed to study the factors governing the time course of action of neuromuscular blocking agents

Background A model of an antegrade, perfused, isolated rat peroneal nerve anterior tibial muscle was developed to study potentially important factors governing the time course of action of (nondepolarizing) neuromuscular blocking agents such as concentration, blood flow, and temperature. The model allows observation of the effects of selective changes in these factors. Methods The authors isolated the anterior tibial muscle and cannulated the anterior tibial artery and vein, providing a way for single-pass perfusion with blood from a donor rat. A force transducer was connected to the tibialis anterior muscle and a stimulator was connected to the tibial nerve. The influence of intrinsic potency (EC90) and muscle blood flow rate on the time course of pancuronium and rocuronium was investigated. Results The model remained stable for at least 4 h with respect to twitch height, muscle structure and function, and blood chemistry. Doubling the muscle-blood flow resulted in a significantly faster onset and offset for both pancuronium and rocuronium. Trebling the intrinsic potency (EC90) was not associated with significant changes in the time course of action of the relaxants. Conclusion The authors developed and validated a model that allows us to study biophase kinetics of neuromuscular blocking agents in the anterior tibial muscle of the rat. In this model, muscle-blood flow rather than EC90 appears to predominantly determine the onset and offset time of nondepolarizing muscle relaxants.

Structure-Pharmacokinetic and Pharmacodynamic Relationships of Steroidal Neuromuscular Blocking Agents

In anesthesiology there is still a need for a short-acting non-depolarizing neuromuscular blocking agent (NMBA) for intubation, replacing the depolarizing agent suxamethonium. In order to find a rational basis for the development of new short-acting NMBA’s, it is essential to know the factors governing the time course of action of this class of drugs.