NextDose: A web-based Bayesian dose forecasting tool

 

Target Concentration Intervention

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 Two Steps of Target Concentration Intervention

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 FirstDose 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.

The NextDose Step

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.

Dose Calculation

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.

Dose Administration

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.

Copyright All rights reserved | Developed by Sam Holford & Nick Holford 2012-2019