Last updated 16 June 2024
The target concentration
principle is the central dogma of rational dose individualization. It forms the
basis of the Target Concentration Intervention (TCI) approach to concentration controlled dosing. The principle is based on the assumption that drug effects are determined
by the unbound drug concentration at the receptor. Observed responses involve a
chain of events after receptor activation. These responses are secondary to the
drug binding to the receptor.
For all practical purposes
the unbound concentration in blood is a useful predictor of the receptor
concentration. There may be delays in reaching and binding to the receptor but once steady state is reached the time related
dissociation between unbound concentration in blood and the consequent effect
are nearly always negligible.
The target concentration is
the concentration which produces the desired target drug effect.
Once the target drug effect
has been decided then the relationship between effect and concentration
(pharmacodynamics) can be used to predict the target concentration required to
achieve the target effect.
It is however common to
find that the pharmacodynamics are not well known. In that case the target
concentration can be defined by the steady state concentration associated with
the target drug effect. This can be calculated from the dose and dosing interval
known to be safe and effect for typical patient and the population drug
clearance. The simplest reasonable guess at the target concentration is thus
the average steady state concentration.
In clinical practice the
concentrations used to individualize drug dose are defined by tradition using
empirically based suggestions made in the literature. These concentrations are
often described as a therapeutic range typically without a clear pharmacodynamic
basis. This range can give some guidance into the distribution of
concentrations that are safe (not too high) and effective (not too low). In
that case it is better described as the acceptable range to distinguish it from
the therapeutic window. The acceptable range is similar to
the reference range concept used for other laboratory measurements such as
serum sodium or plasma glucose. The therapeutic window mistake occurs when the
acceptable range, derived from a population sample, is used to interpret the
concentration measured in an individual. Unfortunately, if the measurement is
within the therapeutic window it is commonly interpreted to mean that no dose
change is required. Dose adjustment only happens if the concentration is
outside of the window. This is the hallmark of the therapeutic drug monitoring
approach (TDM) which is demonstrably inferior to target concentration
intervention (TCI) which uses concentration measurements to predict the dose
that will achieve the target and achieves better
clinical outcomes (Metz, Holford
et al. 2019, Holford, Ma et al. 2022).
The lack of a scientific
rationale for choosing a target concentration means measured concentrations are
based on convenience e.g. concentrations taken just before the next dose (the
trough concentration). The trough concentration is arguably the worst time to
measure a concentration in order to estimate key
pharmacokinetic parameters such as clearance. To make things even worse trough
concentration measurements are confused with the target concentration and
clinicians attempt to empirically adjust the dose so try to obtain a measured
concentration the same as the target concentration. While this will eventually
converge on the right dose it is an inefficient and time
wasting process that means the patient is sub-optimally treated.
The steady state
concentration (Css) is exactly linked to the area under the concentration time
curve over a dosing interval (DI) at steady state (Css=AUC0-DI/DI).
Surrogates for the steady state target concentration have been devised based on
simple algorithms to calculate the associated AUC from several concentration
measurements. These algorithms, most commonly the trapezoidal method, are
biased and will always underestimate the true AUC. This is because the highest
measured concentration is, except by very rare chance, always less than the
actual highest concentration. In addition, the trapezoidal approximation
assumes linear changes of concentration with time during absorption which
further underestimates the true AUC. All trapezoidal AUC methods will therefore
lead to an underestimate of the steady state concentration associated with the
effect. The AUC based methods get worse when limited sampling strategies are
used with just one or two concentrations used to predict the AUC. When these
two approximations are combined the results become ever more dubious.
The solution to the dosing
challenge is to clearly separate the target concentration from the measurement.
The measurement is used, along with a PK model and Bayesian prior information,
to estimate the PK parameters for the individual. The PK parameters are then
used with the target concentration to predict the dose that will achieve the
target. This can be done with any number of measurements including no
measurements at all. If only a few concentrations are measured it becomes more
important to pay attention to the optimal timing of the concentrations in order to improve the estimation of the PK parameters.
In order to estimate clearance the ideal time is when the concentration
measurement is determined only by clearance. In principle this occurs during a
constant rate infusion when concentration has approached steady state. Because
drug infusion long enough to approach steady state are uncommon this is not a
useful method. As an approximation, the concentration in the middle of the
dosing interval at steady state may be close to the average steady state
concentration. This is certainly a better time than either a single peak or
trough to estimate clearance.
When concentrations change
a lot during the dosing interval (e.g. gentamicin with a 24 h dosing interval)
then two concentration measurements are recommended. The first 30 minutes after
the peak (end of infusion) and the second at 8 h after the infusion start. It
is not a good idea to take a trough concentration at 24 h after the infusion
start because the concentration will often be less than the limit of detection.
Copyright All rights
reserved | Developed by Sam Holford & Nick Holford 2012-2024
Holford, N. H., G. Ma and D. Metz (2022). "TDM is dead. Long live
TCI!" Br J Clin Pharmacol 88(4): 1406-1413.
Metz, D. K., N. Holford, J.
Y. Kausman, A. Walker, N. Cranswick, C. E. Staatz, K. A. Barraclough and F.
Ierino (2019). "Optimizing Mycophenolic Acid Exposure in Kidney Transplant
Recipients: Time for Target Concentration Intervention." Transplantation 103(10):
2012-2030.