L17. Target concentration intervention

Question 1

Where does Target concentration come from
What 4 values contribute to ideal dose prediction-
Which is most important?

Answer 1

1. Rearrangement of the Emax model shows the target conc can be predicted based on a desired effect.
2. Ideal dose prediction is from the individual estimates of the Emax, C50, Vd and 3. CL (most important).

Question 2

How is the target concentration found in research

Answer 2

Do a randomised concentration clinical trial

Question 3

What are the three ways to dose, who are they usually used for

Answer 3

1. Population dosing- same dose for everyone.
   Used in adults (convenience)
2. Group dosing: same dose for a group that has the same predictable features (covariates).
   Used for children - same weight, CLcr, genotype.
3. Individual dosing: dose determined by individual response to a given dose.
   Used when response is easily measured eg. BP, biomarker, INR, blood concentration- (pk)

Question 4

Which drugs are best used for Target Concentration Intervention and give an example

Answer 4

1. When the usefulness is hard to measure- clinical outcome is not easily observable/predictable or measured on a continuous scale. eg. Anti-convulsants, anti-arrhythmics, anti-coagulants
2. Big unpredictable variability (after accounting for predictable values) and a small within subject variability.
   - This is because too much variability means higher risk of inadequate benefit or increased adverse effect.

Question 5

What are the 6 steps of the Target concentration strategy: Procedure to find the individualised dose

Answer 5

Before giving medicine:

1. Choose Target conc
2. Determine V and CL using Weight and maturation
3. Calculate LD and MDR

Start the dosing:

4. Measure response - revise target conc based
5. Measure concs- revise V and CL
6. Calculated new MDR to get closer to target conc

Question 6

When should concentration of drug be measured to help revise CL for most medicines (eg. digoxin) and for medicine like gentamicin (and why)

Answer 6

Most medicines (eg. digoxin) : 1 sample should be taken at the middle of the dosing interval (after steady state has been made) as clearance determines average ss conc.

2. Medicine like gentamicin should have 2 samples taken, one at the peak and trough of a dosing interval. (eg. 1hr, 8 hr) because of the big variation in concentration over dosing interval.

Question 7

Give 3 reasons why Target concentration Intervention (TCI) is better than Therapeutic Drug monitoring (TDM) - comparing them

Answer 7

1. TCI is accurate because it aims for an optimal/target concentration: a single value which has the best balance between adverse and beneficial effects for the patient.
   Whereas TDM is based on making sure drug conc stays within Therapeutic window between Toxic/ ineffective, allowing sub-optimal outcomes at the borders.
2. TCI uses the principles of pharmacokinetics and pharmacodynamics to estimate individual parameters - eg. CL which can be used to calculate a suitable dose.
   Whereas TDM only provides a measured conc.
3. TCI provides guidance to the clinician for the next dose based on target and individual parameters eg. CL
   Whereas suitable dose cannot be calculated from therapeutic window in TDM so dose adjustments are empirical rather than based on quantitative pharmacological rationale.

Question 8

Why do we have 3 ways of dosing?

Answer 8

The pharmacodynamics and pharmacokinetics of a drug vary due to

1. Systemic components which are predictable - eg. weight, disease state, genotype
2. Random non predictable components, not based on appearance : between and within subject variability

3 levels of dosing are three levels of specifying the dose to help reduce impact of causes of variability on drug response- (eg. subtherapeutic/adverse effects)