Model-based drug administration

Kuizenga, Merel H.; Vereecke, Hugo; Struys, Michel

doi:10.1097/aco.0000000000000356

Cited by 18 publications

(9 citation statements)

References 59 publications

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“…Multiphasic PK and the inability to continuously measure the achieved drug concentration can present a challenge when trying to achieve a specific drug effect. In the majority of countries worldwide (the US being the main exception), TCI pumps (infusion pumps programmed to infuse a drug guided by a mathematical PK and PD model so as to achieve a predefined plasma or effect site drug concentration expeditiously) are available in order to simplify the administration of propofol [ 153 , 189 ]. The most well-known PK/PD models for propofol have already been discussed earlier in this article.…”

Section: Methods Of Drug Deliverymentioning

confidence: 99%

Clinical Pharmacokinetics and Pharmacodynamics of Propofol

2018

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Propofol is an intravenous hypnotic drug that is used for induction and maintenance of sedation and general anaesthesia. It exerts its effects through potentiation of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) at the GABAA receptor, and has gained widespread use due to its favourable drug effect profile. The main adverse effects are disturbances in cardiopulmonary physiology. Due to its narrow therapeutic margin, propofol should only be administered by practitioners trained and experienced in providing general anaesthesia. Many pharmacokinetic (PK) and pharmacodynamic (PD) models for propofol exist. Some are used to inform drug dosing guidelines, and some are also implemented in so-called target-controlled infusion devices, to calculate the infusion rates required for user-defined target plasma or effect-site concentrations. Most of the models were designed for use in a specific and well-defined patient category. However, models applicable in a more general population have recently been developed and published. The most recent example is the general purpose propofol model developed by Eleveld and colleagues. Retrospective predictive performance evaluations show that this model performs as well as, or even better than, PK models developed for specific populations, such as adults, children or the obese; however, prospective evaluation of the model is still required. Propofol undergoes extensive PK and PD interactions with both other hypnotic drugs and opioids. PD interactions are the most clinically significant, and, with other hypnotics, tend to be additive, whereas interactions with opioids tend to be highly synergistic. Response surface modelling provides a tool to gain understanding and explore these complex interactions. Visual displays illustrating the effect of these interactions in real time can aid clinicians in optimal drug dosing while minimizing adverse effects. In this review, we provide an overview of the PK and PD of propofol in order to refresh readers’ knowledge of its clinical applications, while discussing the main avenues of research where significant recent advances have been made.

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Section: Methods Of Drug Deliverymentioning

confidence: 99%

Clinical Pharmacokinetics and Pharmacodynamics of Propofol

2018

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“…), as these patients may have considerably different PKPD characteristics. Additionally, methodological differences between studies may result in the different identification of relevant covariates, such as the timing and method of blood sampling (arterial versus venous), differences in analytical approach and the use of separate studies to develop respectively the pharmacokinetic and the pharmacodynamic model, instead of observing both endpoints in a single time-synchronised setting [1,20]. Some models are therefore restricted to the prediction of plasma-concentration without enabling effect-site controlled TCI.…”

Section: Limitations Of Contemporary Tci Modelsmentioning

confidence: 99%

“…Incorporating relevant demographic and/or physiologic covariates into the equations for volumes of distribution or rate constants or clearance does account for predictable sources of biological variability. This implies that a model with accurate covariate selection often will reduce the in-between subject variability in the model predictions of the plasma concentration compared to a model without, or with suboptimal, selection of demographic covariates [1][2][3].…”

Section: Introductionmentioning

confidence: 99%

General Purpose Pharmacokinetic-Pharmacodynamic Models for Target-Controlled Infusion of Anaesthetic Drugs: A Narrative Review

Vandemoortele

Hannivoort

Vanhoorebeeck

et al. 2022

JCM

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Target controlled infusion (TCI) is a clinically-available and widely-used computer-controlled method of drug administration, adjusting the drug titration towards user selected plasma- or effect-site concentrations, calculated according to pharmacokinetic-pharmacodynamic (PKPD) models. Although this technology is clinically available for several anaesthetic drugs, the contemporary commercialised PKPD models suffer from multiple limitations. First, PKPD models for anaesthetic drugs are developed using deliberately selected patient populations, often excluding the more challenging populations, such as children, obese or elderly patients, of whom the body composition or elimination mechanisms may be structurally different compared to the lean adult patient population. Separate PKPD models have been developed for some of these subcategories, but the availability of multiple PKPD models for a single drug increases the risk for invalid model selection by the user. Second, some models are restricted to the prediction of plasma-concentration without enabling effect-site controlled TCI or they identify the effect-site equilibration rate constant using methods other than PKPD modelling. Advances in computing and the emergence of globally collected databases has allowed the development of new “general purpose” PKPD models. These take on the challenging task of identifying the relationships between patient covariates (age, weight, sex, etc) and the volumes and clearances of multi-compartmental pharmacokinetic models applicable across broad populations from neonates to the elderly, from the underweight to the obese. These models address the issues of allometric scaling of body weight and size, body composition, sex differences, changes with advanced age, and for young children, changes with maturation and growth. General purpose models for propofol, remifentanil and dexmedetomidine have appeared and these greatly reduce the risk of invalid model selection. In this narrative review, we discuss the development, characteristics and validation of several described general purpose PKPD models for anaesthetic drugs.

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“…The Bispectral Index (BIS) monitor has been used to measure the DoH in a majority closed-loop controlled propofol anaesthesia systems [16]. We instead assume the use of the NeuroSense WAV CNS monitor.…”

Section: Equipment Modelsmentioning

confidence: 99%

Robust PID control of propofol anaesthesia: Uncertainty limits performance, not PID structure

González-Cava

Carlson

Troeng

et al. 2021

Computer Methods and Programs in Biomedicine

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Background and Objective: New proposals to improve the regulation of hypnosis in anaesthesia based on the development of advanced control structures emerge continuously. However, a fair study to analyse the real benefits of these structures compared to simpler clinically validated PID-based solutions has not been presented so far. The main objective of this work is to analyse the performance limitations associated with using a filtered PID controller, as compared to a high-order controller, represented through a Youla parameter.Methods: The comparison consists of a two-steps methodology. First, two robust optimal filtered PID controllers, considering the effect of the inter-patient variability, are synthesised. A set of 47 validated paediatric pharmacological models, identified from clinical data, is used to this end. This model set provides representative inter-patient variability Second, individualised filtered PID and Youla controllers are synthesised for each model in the set. For fairness of comparison, the same performance objective is optimised for all designs, and the same robustness constraints are considered. Controller synthesis is performed utilising convex optimisation and gradient-based methods relying on algebraic differentiation. The worst-case performance over the patient model set is used for the comparison.

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Model-based drug administration

Abstract: Evidence in the literature is increasing that TCI and closed-loop technology could assist the anaesthetists to optimize drug administration during anaesthesia.

Cited by 18 publications

References 59 publications

Clinical Pharmacokinetics and Pharmacodynamics of Propofol

Clinical Pharmacokinetics and Pharmacodynamics of Propofol

General Purpose Pharmacokinetic-Pharmacodynamic Models for Target-Controlled Infusion of Anaesthetic Drugs: A Narrative Review

Robust PID control of propofol anaesthesia: Uncertainty limits performance, not PID structure

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