TDM

• Therapeutic drug monitoring (TDM)

  The use of drug concentration measurements in body fluids as an aid to the management of drug therapy for the cure, alleviation or prevention of disease
• Goal of Therapeutic Drug Monitoring


  • Maximize the effectiveness of the drug and therapeutic benefit
  • Minimize drug toxicity and adverse effects
• Why Is Therapeutic Drug Monitoring Necessary?

  • To detect and prevent suboptimal treatment and avoid drug toxicity in patients
  • For individualization of drug dosage and therapy due to inter-individual variability in plasma drug concentrations
  • To monitor and detect drug and disease-based interactions
  • To explain apparent 'resistance' to the action of a drug
  • When the effect cannot readily be assessed quantitatively by clinical observation

  
• Drugs that Require Therapeutic Drug Monitoring


  • Drugs with narrow therapeutic range
  • Significant inter-individual pharmacokinetic variability
  • Nonlinear pharmacokinetics (drugs following saturation metabolism)
  • Drugs whose therapeutic effect cannot be readily assessed by clinical observation
  • Drugs whose plasma levels (or metabolite plasma levels) correlate directly with the pharmacological or toxic effects

  
• Drugs that do not require TDM

  • Usually those with a wide therapeutic range
  • Irreversible action (i.e., hit and run drugs such as MAO inhibitors, Omeprazole, Reserpine, Guanethidine)
  • Clinically quantifiable pharmacological effects which can be monitored by clinical end points
  • Drugs whose plasma levels do not correlate with therapeutic or toxic effects

  
• Specific assays


  Separate and detect metabolite and parent drugs, providing better pharmacokinetic parameter estimation of a drug and information on its metabolites

  
• Nonspecific assays


  Typically tend to identify a class of compounds and may provide an overestimation of the actual drug concentrations
• Samples Used for Therapeutic Drug Monitoring

  • Plasma/serum
  • Whole blood
  • Saliva
  • Breath
• Timing of Sample Collection

  • At steady state (SS)
  • At the appropriate time in relation to the last dose
  • Generally measured in the elimination phase
  • C peak for some antibiotics (aminoglycosides)
  • Not during the distribution phase
• The time taken to reach steady state is determined by the elimination half-life of the drug
• Clinical Interpretation of Therapeutic Drug Monitoring Reports

  If there are alterations in serum drug concentration, either lower or higher than expected, or if a patient fails to respond to therapy despite adequate serum drug concentration, then drug dosage adjustment is required

  
• Common Causes of Alterations in Serum Drug Concentration

  • If the sample was taken at the correct time with respect to the last dose
  • If a steady state has been reached
  • If the patient is adhered to the treatment
  • If there is a drug-drug interaction
  • If there is a liver/kidney dysfunction

  
• Therapeutic decisions should never be based solely on the drug concentration in the serum. The cardinal principle is to treat the patient rather than the drug concentration.

  
• Amikacin


  Broad spectrum antibiotic active against aerobic Gram-negative organisms including Pseudomonas aeruginosa and Mycobacteria. High-dose extended-interval("once-daily") aminoglycoside dosing is generally recommended to decrease toxicity and improve efficacy.
• Vancomycin


  Glycopeptide antibiotic with bactericidal activity against aerobic and anaerobic Gram-positive bacilli, including multi-resistant Staphylococci (MRSA). Used in prophylaxis and treatment of endocarditis and other serious infections caused by Gram-positive cocci.
• Phenytoin


  Widely used alone and in combination with other anticonvulsants for all forms of epilepsy except absence seizures, prophylaxis in neurosurgery or severe head injury, and to treat trigeminal neuralgia

  
• Factors Affecting Phenytoin Concentration

  • Metabolized by CYP2C9 (90%) and 2C19 (10%), limited capacity
  • Saturation kinetics (nonlinear or zero-order kinetics)
  • Individuals vary as to when their kinetics become nonlinear
  • Valproate displaces protein-bound phenytoin
  • Unbound (i.e., free phenytoin) concentrations affected by some drugs or changes in availability of albumin for binding
  • Pregnancy increases clearance
  • Induces metabolism of some other antiepileptics and many other drugs

  
• Free fraction of phenytoin

  The normal free fraction is 10%. It can be as high as 30% in patients with end stage renal disease and hypoalbuminemia.

  
• Phenytoin concentration adjustment formulas for hypoalbuminemia and renal failure

  
• Patients have lower total concentrations despite having adequate free concentrations (increased free fraction). Dosage adjustment of phenytoin not needed, just a different concentrations approach to evaluating.

  
• Phenytoin Therapeutic Range


  • Total: 10–20 mg/L
  • Free: 1–2 mg/L

  
• Digoxin


  Used in the management of certain supraventricular arrhythmias, particularly chronic atrial flutter and fibrillation, and in the management of chronic cardiac failure where the dominant problem is systolic dysfunction
• Digoxin Therapeutic Range


  0.8–2.0 mcg/L
• Lithium


  Used in treatment and prophylaxis of mania, bipolar disorder and recurrent depression