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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.
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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 B Toxicity Efficacy Response Drug concentration (log scale)
Narrow therapeutic window Efficacy Toxicity Response 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 Therapeutic range (mg/L) Amiodarone 1.0-2.5 Digoxin 0.5-2.1microgram/L Quinidine 2.0-5.0 Theophylline 10-20 Phenytoin 10-20 Carbamazepine 5.0-12 Sodium valproate 50-100 Phenobarbitone 15-40 Gentamicin peak>5, trough<2 Amikacin peak>15, trough<5 Vancomycin peak20-40, trough<10 Lithium 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