Last updated 29 July 2021
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. 2020).
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.
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| Developed by Sam Holford & Nick Holford 2012-2021
Holford, N., G. Ma and D. Metz (2020). "TDM is dead. Long live
TCI!" British Journal of Clinical Pharmacology Early View(doi:10.1111/bcp.14434).
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.