The goal of target
concentration intervention (TCI) is to achieve the target effect by first
calculating the dose to achieve the target
concentration then secondly administering the proposed dose. This second
part is why it is described as an intervention method.

The first step of TCI is to
determine the initial dosing scheme. This is called the FirstDose
step. The second step of TCI is to observe the
response to treatment and use the observed response to help individualize
subsequent doses. This is called the NextDose step.

The initial dosing scheme
may include a loading dose and a maintenance dose with a defined dosing
interval. The maintenance dose divided by the dosing interval give the
maintenance dose rate. Estimates of patient parameters used in the FirstDose step come from population parameters with
adjustment using basic observations (covariates) such as weight
or renal function. Note that these parameters reflect the value expected in
a similar group of patients sharing the same basic observation values. They are
not estimates of the individual values of the
parameters. Individual estimates need information from observed responses after
starting treatment.

Patient responses after
starting treatment may be broadly described as biomarkers. Biomarkers are
patient variables that change in response drug treatment. They should not be
confused with basic observations (covariates) such as age, sex or genotype
which do not change as a consequence of drug treatment.

Response observations
provide information about the individual. This information helps to estimate
individual parameters. The individual parameter estimates can then be used to
calculate an individualized dose using the same methods described in the Dose
Calculation section. It is important to recognize that the NextDose
step does not use the observed responses directly to individualize the dose.
The observed responses are used to estimate the patient parameters which are
then used for dose calculation.

Commonly used response
observations are drug concentration but drug effects such as blood pressure
(for antihypertensive agents) or the International Normalized Ratio (for
warfarin) are response observations that can be used to individualize the dose.

Pharmacokinetic principles
can be used to calculate the loading and maintenance dose rate. The loading
dose (LD) depends mainly on the volume
of distribution (V) while the maintenance dose rate (MDR) depends mainly on
the clearance
(CL). Both the loading dose and maintenance dose rate depend upon the target
concentration (TC).

Most simply the loading
dose is calculated from V multiplied by TC. This simple calculation is a good
starting point but it assumes the loading dose is given instantaneously (a
bolus dose). A bolus dose is never truly practical because there is always a
finite time for giving the dose. The peak concentration after a loading dose
requires a description of the input rate and duration.

If dosing uses a continuous
input e.g. intravenous infusion, then the LD dose is usually calculated to
achieve the steady state concentration expected from the continuous dosing. The
LD can be calculated to achieve a peak concentration after the first dose that
is the same as the expected steady state peak concentration. That method is
quite general but the actual calculation can be complex.

The maintenance dose rate
is simpler to calculate than the loading dose. It just requires CL to be
multiplied by TC. The maintenance dose can then be calculated from the dosing
interval desired by the user.

The FirstDose
and NextDose steps lead to calculation of a target
dose for the patient. The decision to prescribe the proposed dose is up to the
judgement of the prescriber and practical limitations based on available dose
sizes. Effective use of TCI requires that the prescribed dose be as close as
practical to the proposed dose. Prescriber judgement may be exercised by using
a modified target concentration. The proposed dose is calculated using the
methods described here and a practical dose prescribed.

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reserved | Developed by Sam Holford & Nick Holford 2012-2019