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Therapeutic drug Monitoring
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.
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.
Wide therapeutic window
A
Toxicity
Response
Efficacy
Drug concentration (log scale)
B
Narrow therapeutic window
Toxicity
Response
Efficacy
Drug concentration (log Scale)
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
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
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
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.
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.
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!
Drugs commonly monitored:
Drug
Amiodarone
Digoxin
Quinidine
Theophylline
Phenytoin
Carbamazepine
Sodium valproate
Phenobarbitone
Gentamicin
Amikacin
Vancomycin
Lithium
Therapeutic range (mg/L)
1.0-2.5
0.5-2.1microgram/L
2.0-5.0
10-20
10-20
5.0-12
50-100
15-40
peak>5, trough<2
peak>15, trough<5
peak20-40, trough<10
0.6-1.2mmol/L
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
High Performance Liquid Chromatography