Vecuronium Pharmacokinetic-Pharmacodynamic Modelling With and Without a Receptor Concentration in the Effect Compartment in Anaesthetised Patients

Ducharme, Julie; Donati, François

doi:10.1007/bf03257402

Cited by 5 publications

(5 citation statements)

References 19 publications

(25 reference statements)

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“…The sampling frequency also has an impact on PK/PD parameter estimation, and the magnitude of the effect varies depending on the type of analysis. For example, k e0 values obtained using early intensive sampling can be up to 50% smaller than those obtained with a traditional sampling scheme using a non‐compartmental PK model after a bolus dose of vecuronium ( 49). Alternatively, when compartmental analysis of traditional data sets is compared with non‐compartmental analysis of early intensive sampling data sets, EC 50 values are similar, which suggests that both approaches are valid for the drug in question ( 48, 50).…”

Section: Test Drug Administration Sampling and Analysismentioning

confidence: 94%

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Pharmacokinetic studies of neuromuscular blocking agents: Good Clinical Research Practice (GCRP)

Viby‐Mogensen

Østergaard

Donati

et al. 2000

Acta Anaesthesiol Scand

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In September 1997, an international consensus conference on standardization of studies of neuromuscular blocking agents was held in Copenhagen, Denmark. Based on the conference, a set of guidelines for good clinical research practice (GCRP) in pharmacokinetic studies of neuromuscular blocking agents is presented. Guidelines include: design of the study; relevant patient groups to investigate; test drug administration, sampling and analysis; pharmacokinetic analysis; pharmacokinetic/pharmacodynamic modeling; population pharmacokinetics; statistics; and presentation of pharmacokinetic data. The guidelines are intended to aid those working in this research area; it is hoped that they will assist researchers, editors of scientific papers, and pharmaceutical companies in improving the quality of pharmacokinetic studies.

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Section: Test Drug Administration Sampling and Analysismentioning

confidence: 94%

“…One parameter describes the concentration associated with an effect of 0.5 (EC 50 ), the other the sigmoidicity of the concentration versus effect curve (γ). The general form of the relationship is ( 49, 68):…”

Section: Pharmacokinetic/pharmacodynamic (Pk/pd) Modelingmentioning

confidence: 99%

Pharmacokinetic studies of neuromuscular blocking agents: Good Clinical Research Practice (GCRP)

Viby‐Mogensen

Østergaard

Donati

et al. 2000

Acta Anaesthesiol Scand

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“…1,16 Our results imply that in rats, the differences in clearance between the three enantiomers are less marked than in humans. 5 On the basis of these considerations and from the results obtained in this study, the use of a short infusion seems to be suitable to characterize the PK-PD relationships of mivacurium. Differences in plasma cholinesterase activity and/or concentrations between both species are likely to be the reason for the differences encountered; differences in plasma esterase activity between humans and various animal species have been reported previously.…”

Section: Discussionmentioning

confidence: 82%

“…The data in Figures 1 and 2 show that the decay in the neuromuscular effect follows closely the decay in total mivacurium in plasma; therefore, in rats, the time course of total mivacurium in plasma reflects the time course of the active enantiomers. 5 We selected the short infusion administration based on the results found by Ducharme et al 5 who showed that analysis from pooled onset and recovery data when there is a preponderance of recovery data (i.e., after a bolus injection) could lead to PD estimates that are different from those obtained from the analyses that used onset or recovery data alone. 1,16 Our results imply that in rats, the differences in clearance between the three enantiomers are less marked than in humans.…”

Section: Discussionmentioning

confidence: 99%

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Pharmacokinetic–Pharmacodynamic Modeling of Mivacurium in Rats

Trocóniz

Garrido

Garía

et al. 1997

Journal of Pharmaceutical Sciences

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The pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of the neuromuscular blocking agent mivacurium were evaluated separately in two groups of rats receiving 0.6 mg kg-1 of mivacurium in a 2.5-min intravenous continuous (iv) infusion. The PK parameters for mivacurium were determined in the first group. A two-compartment model describes the kinetics of mivacurium in plasma. The estimates of the apparent volume of distribution at steady-state and plasma clearance [mean(SE)] were 650 (123) mL kg-1 and 9.9 (0.75) mL min-1 kg-1, respectively. In the second group, the evoked tibialis anterior muscle tension was monitored. The PK parameters derived from the first group were used to compute mivacurium plasma concentrations (C) at the times the PD measurements were recorded in the second group. The concentration-neuromuscular effect [% depression of initial twitch tension (E)] relationship was analyzed by two approaches. (1) The relationship of estimated effect site concentrations versus E; a sigmoidal Emax model described the effect compartment concentrations versus E relationship. The estimate [mean(SE)] of Cess50 (steady-state plasma concentration eliciting half of maximum E) was 0.65 (0.01) microgram mL-1. The value [mean-(SE)] of Keo (rate constant of equilibration between plasma and effect site) was estimated at 0.32 (0.03) min-1. (2) The relationship of descending limb C versus E; a sigmoidal Emax model described such relationship. The estimate [mean(SE)] of C50 (post-infusion C eliciting half of maximum E) was 0.57(0.03) microgram mL-1. The PD properties of mivacurium were also evaluated in another two groups of animals receiving either 5- or 10-min continuous iv infusion; PK and PD parameters obtained from the 2.5-min infusion experiments were used to predict the time course of E in the groups receiving 0.6 mg kg-1 of mivacurium in 5- and 10-min infusions; simulations using the estimated parameters adequately describe the time course of E in those groups. The effect of mivacurium on the mean arterial blood pressure (MAP) was also investigated; a 10% nonsignificant decrease (p> 0.05) in MAP was found in all groups.

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Clinical course and cystine stone formation during tiopronin treatment

et al. 1995

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The formation of stones in patients with cystinuria can be counteracted by reducing the urinary concentration of cystine and by increasing its solubility. Thirty-one patients with homozygous cystinuria and treated with tiopronin (2-mercaptopropionylglycine) were followed for between 0.4 and 12 years (median 8.8). With the aim of avoiding cystine concentrations above 1200 mumol/l, the daily dose varied between 500 and 3000 mg (median 1500). The therapeutic effect was evaluated from the clinical symptoms and repeated radiographic examinations. The rate of stone formation during the treatment period was reduced by 60% in comparison with the pretreatment period (P < 0.001). The frequency of active stone removal was reduced by 72% (P < 0.05). The formation of new stones was associated with a higher cystine concentration than was the case during periods when stone formation and stone growth were excluded (P < 0.05). The probability of new stone formation increased with increasing concentrations of cystine up to 1100 mumol/l, but stone formation was not accentuated above 1200 mumol/l. There was no significant relationship between the 24 h excretion of cystine and stone formation. It is concluded that the formation of cystine stones can be efficiently counteracted during treatment with tiopronin, guided by analysis of the concentration of urinary cystine.

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Vecuronium Pharmacokinetic-Pharmacodynamic Modelling With and Without a Receptor Concentration in the Effect Compartment in Anaesthetised Patients

Cited by 5 publications

References 19 publications

Pharmacokinetic studies of neuromuscular blocking agents: Good Clinical Research Practice (GCRP)

Pharmacokinetic studies of neuromuscular blocking agents: Good Clinical Research Practice (GCRP)

Pharmacokinetic–Pharmacodynamic Modeling of Mivacurium in Rats

Clinical course and cystine stone formation during tiopronin treatment

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