THE DEVELOPMENT AND FUTURE OF TCI

JB Glen, AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire SK10 4TG,UK

Luckily, the simplicity of the clinical application of TCI is far removed from the complexity of the mathematical basis of the concept, as originally described by Krüger-Thiemer [1] and Schwilden [2]. A small band of pioneers with an understanding of mathematics, pharmacokinetics, computers and clinical anaesthesia practice has translated the equations described into the reality of a simple method to achieve and maintain a pseudo steady-state blood concentration of various iv therapies; and to facilitate the titration of this concentration to achieve the effect desired in a patient. Systems for clinical use with the acronyms, CATIA, TIAC, CACI and CCIP were developed from 1983 onwards and the first prototype ‘Diprifusor’*system was described by White and Kenny [3] in 1990. As the use of multiple acronyms for the same basic concept is confusing, Glass et al [4] proposed the descriptor ‘target-controlled infusion’ (TCI) for all of these systems.

All of the above systems, some using different mathematics and different pharmacokinetic input parameters, were used successfully in anaesthetic practice and yet a commercial system (‘Diprifusor’ TCI) first became available only in 1996. Despite lengthy academic experience, TCI was a new concept for drug and device regulatory agencies and a major challenge in the commercialisation of TCI has been the need to subdivide issues between these two divisions of regulatory agencies and at the same time to encourage the two groups to communicate with each other. There was also a need for clear delineation of the responsibilities of the drug company, in selecting the PK model and providing guidance on target concentration settings in the drug labelling, from those of the infusion pump manufacturer. In the case of the ‘Diprifusor’ system, this was achieved by the supply of a TCI module by Zeneca to pump companies. This module contains the infusion control algorithms and a PK model with a specific set of parameters for propofol selected by the company for clinical trials. Incorporation of this module in pumps from different manufacturers ensures that the output of all pumps at a particular target setting will be the same. In addition, while many different PK models for propofol have been used successfully, guidance on target concentration settings is relevant only to the output achieved with standardized systems incorporating the ‘Diprifusor’ TCI module. The pump manufacturer, having incorporated the module in a pump, has no need to repeat clinical studies but must demonstrate that the delivery performance profile meets a specification derived by the drug company with devices used in clinical trials. Thus this laboratory performance study provides a link for the regulators between the two components of a regulatory submission.

Further clinical validation of ‘Diprifusor’ TCI is now in hand to extend the application of TCI for propofol to conscious sedation and ICU sedation. Use for patient controlled sedation is being considered and modification of the PK model will be required to allow its use for anaesthesia in children. Towards this end, the recent availability of population pharmacokinetic models for propofol will be useful [5,6].

To date TCI systems have been used to deliver a range of hypnotic and analgesic agents in anaesthetic practice; and academic developments have progressed well ahead of the availability of systems for other drugs. Methods that permit the targeted concentration to be that at the effect site [7] have potential advantages but will be even more difficult to present to regulatory authorities. Nevertheless, validation of such systems would be desirable and would be likely to facilitate the development of feed-back control systems based on EEG measures of effect. The development of TCI has been accompanied by the increased availability of simulation programs for teaching purposes. Use of programs such as IVA-SIM, PK-SIM, and more recently TIVA-TRAINER have greatly improved our understanding of the pharmacokinetic rationale for the differences observed between agents and in turn have led to improvements in clinical practice.

‘Diprifusor’ TCI for propofol has undoubtedly been a success for anaesthetists, with the technique being preferred in comparative studies[8].The potential benefits of the TCI mode of administration are summarised in Table 1 and it would be expected that these benefits would encourage the development of TCI systems for other iv agents, particularly those given over a moderate period of time in the anaesthesia or critical care environment.

Table 1. Benefits of TCI mode of administration for iv drugs

1. Improved control and predictability of the pharmacodynamic effect achieved

2. Ability to achieve a therapeutic concentration rapidly and to maintain a constant blood level.

3. Alternatively in elderly or debilitated patients a desired effect can be achieved slowly by extending the time required to reach the target setting.

4. Ability to make proportional changes in blood concentration rapidly by adjustment of the target concentration setting. Improved titratability

5. Avoidance of peak blood concentrations and possible risk of associated toxicity.

6. No need for calculation of infusion rate . Automatic adjustment for differences in body weight, lean body mass, age and gender if complex model available

7. Display of calculated effect site concentration facilitates titration of the target blood concentration to achieve a desired effect

8. Estimation of the time required to reach a lower plasma concentration.

9. A more logical and modern approach

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The commercial impact of ‘Diprifusor’ TCI is currently being appraised and it likely that for the succesful application of the technique to other molecules some changes are required. These could include the use of standard presentations of drug and the ability to monitor the financial return to companies investing in clinical validation studies.

[1] Krüger-Theimer E. Europ J Pharmacol 1968; 4: 317-324

[2] Schwilden H. Eur J Clin Pharmacol 1981; 20: 379-386

[3] White M, Kenny GNC. Anaesthesia 1990; 45: 204-209

[4] Glass PSA, Glen JB,Kenny GNC, Schüttler J, Shafer SL. Anesthesiology 1997; 86: 1430-1

[5] Schnider TW, Minto CF, Gambus PL et al. Anesthesiology 1998; 88: 1170-1182

[6] Schüttler J, Ihmsen H. Anesthesiology 2000; In press

[7] Shafer SL, Gregg KM. J Pharmacokinet Biopharm 1992; 20: 147-169

[8] Russell D. Anaesthesia 1998; 53, Supplement 1,42-45

* ‘Diprifusor’ is a trade mark, the property of the AstraZeneca group of Companies