Predictive
performance of the Domino model during low-dose ketamine infusions in
volunteers
J.
Halliday and M. Ogden, P. Corlett, G. Honey, M. Lee, T. de Smet, P. Fletcher,
D. Menon, A.Absalom
University
Departments of Anaesthesia and Psychiatry, Addenbrookes Hospital, Cambridge,
UK
Introduction:
Ketamine
is being used to investigate the glutaminergic hypofunction theory of
schizophrenia. We have performed 4 studies of the effects of target-controlled
infusions of ketamine (Domino pharmacokinetic model1). The aim of our study
was to assess the predictive performance of the Domino model, and to assess
the likely performance of 3 other models.
Methods:
Following
local ethics committee approval, 57 healthy volunteers performed cognitive
function tests and/or underwent functional MRI (fMRI) imaging whilst receiving
either saline or racemic ketamine administered using a TCI device (Anaetech
Ltd, Leeds UK) programmed with the Domino model. In study 1 (n = 14) and study
2 (n = 12), volunteers received ketamine on two occasions, once at a target
concentration of 50 ng/ml and once at a target of 100 ng/ml. During study 3 (n
= 15) volunteers received TCI ketamine at a target concentration of 100 ng/ml
on one occasion, whereas during the 4th study (n = 16) volunteers received
ketamine on one occasion but at two different target concentrations (100 ng/ml
for 105 mins followed by 200 ng/ml for a further 105 minutes). For each study,
at each target concentration, 2 or 3 venous blood samples were withdrawn
during infusion, with a further sample after the infusion ended. Samples were
centrifuged, and plasma was removed, frozen and later assayed by gas
chromatography for ketamine. The total number of samples was 251.
Prediction performance was assessed using the criteria recommended by
Varvel et al. Samples withdrawn after the infusions stopped were not included
in the divergence calculation. The slope of the regression curve of
performance errors over time was also calculated, again excluding samples
withdrawn after infusion. To estimate the predictive performance of other
models (Clements 125, Clements 250, and Hijazi), we used Stanpump to calculate
the plasma concentrations the 3 other models would have predicted at the times
the samples were withdrawn, and subjected these predicted
concentrations to the same Varvel analysis.
Results:
In
all studies the predictive accuracy of the Domino model changed over time.
Soon after a target concentration increase, the Domino model significantly
overpredicted the ketamine concentration, typically by ~100%, samples after ~
60 min were generally clustered around the predicted concentration. For later
samples the model underpredicted the concentration. The performance criteria
are summarised in Figure 1.
Figure1:
Comparison of Domino, Clements 125, Clements 250 and Hijazi model parameters.
Parameter
|
|
Parameter |
||||
|
Model |
MDPE |
MDAPE |
Wobble |
Divergence |
Slope
of PE's |
|
Domino |
-4.8 |
34.7 |
23.7 |
0.0495 |
0.4276 |
|
Clements125 |
-20.5 |
27.0 |
27.2 |
-0.0618 |
-0.0098 |
|
Clements250 |
3.9 |
24.0 |
29.1 |
-0.1615 |
-0.0959 |
|
Hijazi |
24.2 |
47.5 |
45.8 |
0.1683 |
0.4448 |
Discussion:
The
systematic change in predictive performance of the Domino model over time is
sub-optimal for fMRI and cognitive studies (where steady state plasma
concentrations are ideal). This problem is not well shown with the Varvel
criteria, but is better shown by the slope of the regression curve of the PEs
over time. For this reason, we believe that the Clements250 model may have
been a better model for control of TCI ketamine. The measured concentrations
have been subjected to NONMEM analysis to develop a new model that we will
test prospectively in a subsequent study.
References:
1.
Domino EF et al. Anesth Analg 1982; 61:87-92
2.
Varvel JR et al. J Pharmacokinet Biopharm 1992; 20:63-94
3.
Clements JA et al. Br J Anaesth 1981; 53: 27-30
4.
Hijazi Y et al. Br J Anaesth 2003; 90: 155-60