Glasgow Meeting - May 2003

Progress towards the development of a commercial TCI system for remifentanil

(jbg@glenpharma.com)

With the availability of the Diprifusor™ TCI system for propofol and increasing use of unapproved research systems such as ‘Stanpump’, ‘Stelpump’ and ‘Rugloop’ for other intravenous agents, the benefits of targeting a desired drug concentration are becoming more widely appreciated. It is evident from published studies, with experimental TCI systems, that there is considerable interest in the use of TCI for the opioid analgesic, remifentanil. The pharmacokinetic properties of remifentanil ensure a rapid response to any increase or decrease in infusion rate, but administration by TCI further facilitates the ease and precision of dose titration with this agent. A clinical benefit was seen in a recent comparative study [1] where administration of remifentanil by TCI led to fewer episodes of intra-operative hypotension. This lecture reviews the steps required for the development of commercial TCI systems for remifentanil.

The amount of drug delivered by any TCI system at a particular target setting is dependent on the parameters of the PK model incorporated in the system. Simulations with eight sets of PK parameters for remifentanil indicated that the maximum difference between published models varied from 75% at 1 min to 28% at 60 min with a constant target setting. Thus it is desirable, for a commercial TCI system, to select a particular PK model to achieve standardization in drug delivery. The preferred model should also achieve an acceptable level of predictive performance, ie a small difference between measured and targeted blood concentrations. The complex model described by Minto et al [2] incorporates covariates for age and lean body mass and would provide a good basis for standardisation for the following reasons:

i) the amount of drug provided at a given target setting will be automatically adjusted for the patient’s age and lean body mass

ii) most of the published information on the efficacy and safety of remifentanil TCI, and the target concentrations required, has been derived from studies which have used this model (19 of the 25 published studies with remifentanil TCI)

iii) the model was derived from a large and diverse population (65 male and female volunteers, age range 20 to 85 years.

iv) Other studies have shown that the pharmacokinetics of remifentanil are unchanged in patients with hepatic disease [3], renal failure [4] or obesity [5].

v) The model incorporates a value for ke0 such that predicted effect-site concentration can be displayed.

Information on target concentrations has been obtained from computer simulations and from literature publications. Computer simulation studies (PK-SIM) show that with frequently used remifentanil infusion rates of 0.25 to 0.5 mcg/kg/min in a 70 kg, 170 cm, 40 year old patient, the calculated remifentanil blood concentration approaches steady state after 25 min with values of 6.3 and 12.6 ng/mL respectively. These values are consistent with target concentrations used in published studies. In 25 published studies, remifentanil was given by TCI to 1,895 patients and 42 volunteers and in 14 abstracts a further 425 patients were studied. Most of the published information refers to the use of remifentanil in association with TCI propofol or an inhalational agent for induction and maintenance of anaesthesia in ventilated adult patients. The remifentanil target concentrations used reflect the additive pharmacodynamic interaction between remifentanil and hypnotic agents [8, 9, 10]. In association with these agents, adequate analgesia for surgery has generally been achieved with target blood remifentanil concentrations in the range of 3 to 8 ng/mL with titration of the target setting against the response of the patient. For particularly stimulating procedures, target concentrations up to 15 ng/mL have been used. There is no information on the use of remifentanil TCI in children or in ICU patients.

There is no evidence from the published studies of any adverse effect of TCI on the known safety profile of remifentanil. The study by De Castro et al [1] indicates that safety may be improved.

A prefilled syringe presentation of remifentanil will not be feasible. It will therefore be possible to use any approved pump with validated TCI software incorporating the appropriate Minto model. However, in view of the likelihood of different combinations of pumps, TCI software and communication protocols it would be desirable to provide the infusion pump manufacturers with a delivery performance specification to ensure conformity in delivery performance.

The clinical efficacy and safety of remifentanil TCI has been demonstrated and published studies provide the basis for the selection of a preferred PK model and appropriate target settings. However, before this technique can be actively promoted there will be a need for drug regulatory authorities to be provided with and approve data to support an amendment to remifentanil prescribing information and for CE marking of pumps.

1. De Castro V, Godet G, Mencia G, Raux M, Coriat P. Target-controlled infusion for remifentanil in vascular patients improves hemodynamics and decreases remifentanil requirement. Anesthesia and Analgesia 2003; 96: 33-38.

2. Minto CF, Schnider TW, Egan TD, Youngs E, Lemmens HJM, Gambus PL, Billard V, Hoke JF, Moore KHP, Hermann DJ, Muir KT, Mandema, J Shafer SL. Influence of age and gender on the pharmacokinetics and pharmacodynamics of remifentanil. I Model development. Anesthesiology 1997a; 86: 10-23.

3. Dershwitz M et al. Pharmacokinetics and pharmacodynamics of remifentanil in volunteer subjects with severe liver disease. Anesthesiology 1996; 84: 812-820.

4. Hoke JF et al. Pharmacokinetics and pharmacodynamics of remifentanil in persons with renal failure compared with healthy volunteers. Anesthesiology 1997; 87: 533-541.

5. Egan TD, Huizinga B, Gupta SK, Jaarsma RL, Sperry RJ, Yee JB, Muir KT. Remifentanil pharmacokinetics in obese versus lean patients. Anesthesiology 1998; 89: 562-573.

6. Drover DR, Lemmens HJM. Population pharmacodynamics and pharmacokinetics of remifentanil as a supplement to nitrous oxide anesthesia for elective abdominal surgery. Anesthesiology 1998; 89: 869-877.

7. Mertens MJ, Engbers FH, Burm AG, Vuyk J. Predictive performance of computer-controlled infusion of remifentanil during propofol/remifentanil anaesthesia. British J Anaesthesia 2003; 90: 132-41.

8. Fechner J, Hering W, Ihmsen H, Palmaers T, Schüttler J, Albrecht S. Modelling the pharmacodynamic interaction between remifentanil and propofol by EEG-controlled dosing. European Journal of Anaesthesiology 2003, In Press.

9. Mertens MJ. Propofol-opioid interaction is synergistic but additive in the clinical concentration range. Chapter 6, PhD Thesis 2002, University of Leiden, 123-153.

10. Lang E, Kapila A, Shlugman D, Hoke JF, Sebel P, Glass PSA. Reduction of isoflurane minimal alveolar concentration by remifentanil. Anesthesiology 1996; 85: 721-8