1. Therapeutic drug Monitoring

2. What is therapeutic drug monitoring (TDM)?
Individualization of drug doses by maintaining plasma/blood drug concentrations within a target range---- therapeutic range
therapeutic window.
Takes care of inter-individual variability.

3. Therapeutic Window
Therapeutic failure results when either the concentration is too low, ineffective therapy, or is too high, producing unacceptable toxicity. Between these limits of concentration lies a region associated with therapeutic success – regarded as a Therapeutic window.

4. Wide therapeutic windowB
Toxicity
Efficacy
Response
Drug concentration (log scale)

5. Narrow therapeutic window
Efficacy
Toxicity
Response
Drug concentration (log Scale)

6. Major sources of Variability:
Compliance
Age- neonates, children, elderly
Physiology- gender, pregnancy
Disease- Hepatic, renal, cardiovascular, respiratory
Drug interactions
Environmental influences on drug metabolism
Genetic polymorphisms

7. For which drugs is monitoring helpful?
Marked pharmacokinetic variability
Concentration related therapeutic and adverse effects
Narrow therapeutic index
Defined therapeutic (target) concentration range
Desired therapeutic effect difficult to monitor

8. TDM useful in 2 major situations:
Drugs used prophylactically to maintain absence of a condition--- seizures, cardiac arrhythmias. depressive/manic episodes, transplant rejection
To avoid serious toxicity--- Aminoglycoside antibiotics

9. Sampling and drug analysis:
Plasma/ serum; cyclosporin- whole blood.
Timing: least variable point in dosing interval– predose/trough concentration.
Wait for steady state to be achieved---at least 5 half-lives. Exceptions are there! Drugs with long half-life.
HPLC, GLC, Immunoassays- sensitivity, specificity.

10. Information required for interpretation:
Timing of sample in relation to last dose
Duration of treatment in with current dose
Age, gender
Other drug therapy
Relevant disease states
Reason for TDM- lack of effect, routine monitoring, suspected toxicity.

11. Plasma protein binding:
Free drug vs total drug concentration.
Importance of plasma protein binding.
Remember that only total drug concentration is measured but only the free drug is active!

12. Drugs commonly monitored:
Drug Therapeutic range (mg/L)
Amiodarone
Digoxin microgram/L
Quinidine
Theophylline
Phenytoin
Carbamazepine
Sodium valproate
Phenobarbitone
Gentamicin peak>5, trough<2
Amikacin peak>15, trough<5
Vancomycin peak20-40, trough<10
Lithium mmol/L

13. Target concentration intervention
ESTIMATE INITIAL DOSE
Target Dose
Loading Dose
Maintenance Dose 
BEGIN THERAPY
ASSESS THERAPY
Patient Response
Drug Level
REFINE DOSE ESTIMATE
ADJUST DOSE

14. High Performance Liquid Chromatography