Abstract:A method is described which results in smooth curarization and prompt recovery using minimal amounts of tubocurarine. Following an initial dose, usually 15 mg, paralysis is maintained by a continuous infusion delivering an amount per hour about equal to the initial dose. From a mathematical interpretation of this statement an equation for the exponential disappearance of tubocurarine from the extracellular water can be obtained. Controlled ventilation is used with a light level of halothane anaesthesia. No sup… Show more
“…Already in the early 1960s, the first attempts to simultaneously model pharmacokinetics and pharmacodynamics, based on the available plasma concentration and effect data for d‐tubocurarine, were made. In 1964, Levy implemented a log‐linear model to describe the time course of d‐tubocurarine response, assuming one‐compartment pharmacokinetics following intravenous bolus administration, based on the results of Ryan et al . The log‐linear model assumed that the effect of muscular relaxation is a linear function of the logarithm of the amount of d‐tubocurarine present in the plasma, while elimination of the amount of d‐tubocurarine in the body occurs exponentially with time.…”
Objectives The objective of this review was to provide an overview of pharmacokinetic/pharmacodynamic (PK/PD) models, focusing on drug-specific PK/PD models and highlighting their value added in drug development and regulatory decision-making. Key findings Many PK/PD models, with varying degrees of complexity and physiological understanding have been developed to evaluate the safety and efficacy of drug products. In special populations (e.g. paediatrics), in cases where there is genetic polymorphism and in other instances where therapeutic outcomes are not well described solely by PK metrics, the implementation of PK/PD models is crucial to assure the desired clinical outcome. Since dissociation between the pharmacokinetic and pharmacodynamic profiles is often observed, it is proposed that physiologically based pharmacokinetic and PK/PD models be given more weight by regulatory authorities when assessing the therapeutic equivalence of drug products. Summary Modelling and simulation approaches already play an important role in drug development. While slowly moving away from 'one-size fits all' PK methodologies to assess therapeutic outcomes, further work is required to increase confidence in PK/PD models in translatability and prediction of various clinical scenarios to encourage more widespread implementation in regulatory decision-making.
“…Already in the early 1960s, the first attempts to simultaneously model pharmacokinetics and pharmacodynamics, based on the available plasma concentration and effect data for d‐tubocurarine, were made. In 1964, Levy implemented a log‐linear model to describe the time course of d‐tubocurarine response, assuming one‐compartment pharmacokinetics following intravenous bolus administration, based on the results of Ryan et al . The log‐linear model assumed that the effect of muscular relaxation is a linear function of the logarithm of the amount of d‐tubocurarine present in the plasma, while elimination of the amount of d‐tubocurarine in the body occurs exponentially with time.…”
Objectives The objective of this review was to provide an overview of pharmacokinetic/pharmacodynamic (PK/PD) models, focusing on drug-specific PK/PD models and highlighting their value added in drug development and regulatory decision-making. Key findings Many PK/PD models, with varying degrees of complexity and physiological understanding have been developed to evaluate the safety and efficacy of drug products. In special populations (e.g. paediatrics), in cases where there is genetic polymorphism and in other instances where therapeutic outcomes are not well described solely by PK metrics, the implementation of PK/PD models is crucial to assure the desired clinical outcome. Since dissociation between the pharmacokinetic and pharmacodynamic profiles is often observed, it is proposed that physiologically based pharmacokinetic and PK/PD models be given more weight by regulatory authorities when assessing the therapeutic equivalence of drug products. Summary Modelling and simulation approaches already play an important role in drug development. While slowly moving away from 'one-size fits all' PK methodologies to assess therapeutic outcomes, further work is required to increase confidence in PK/PD models in translatability and prediction of various clinical scenarios to encourage more widespread implementation in regulatory decision-making.
“…Sir,-When referring to my use of tubocurarine to maintain neuromuscular blockade (Ryan, 1964), Drs Somogyi, Shanks and Triggs (1978) stated that I employed this drug in a manner similar to that of Evans and Spencer Gray (1953) who allowed their patients to breathe spontaneously. By 1964 most anaesthetists were using controlled ventilation and this was also my technique.…”
“…Sustained muscular relaxation has been produced by continuous administration of tubocurarine (dtc) based on the rate of disappearance and accumulation of the drug in anaesthetized man (Ryan, 1964). The degree of relaxation was judged clinically, and from mathematical interpretation of the dtc requirements Ryan derived an equation for the exponential disappearance of dtc from the plasma and interstitial fluid.…”
Pharmacokinetic data were used to calculate an i.v. bolus dose and infusion regimen for tubocurarine (dtc). This produced continuous paralysis in 12 anaesthetized patients. In nine of the patients the duration of infusion was sufficient to achieve a "steady-state" dtc concentration in the plasma (mean 1.09 microgram ml-1). At the completion of the infusion, twitch response had been abolished in half of the group, but 30 min later all had a measurable response. All plasma concentrations decreased rapidly after infusion, from a mean of 1.35 microgram ml-1, in either a mono- or bi-exponential manner. In all instances, a two-compartment open model was used to describe the plasma concentration-time data. The pharmacokinetic parameters derived from this study did not differ significantly from those reported for a single dose except that the plasma clearance was less.
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