Therapeutic Drug Monitoring:

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Therapeutic Drug Monitoring

• Putting science into practice

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TDM Putting science into practice

• Six Fundamental Concepts
• Indications for Monitoring
• Mandatory TDM drug properties
• Information needed to individualize dosages
• Problems encountered in TDM
• Organ System Alterations Affecting TDM
• TDM Benefits
• When to sample

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TDM res ipsa loquitor

• TDM Consult service
• Clinical pharmacokinetic dosing service
• Clinical pharmacokinetic service
• Pharmacotherapy dosing service
• Who to call when the drug doesnt do what it is
  supposed to do despite prescribing and having
  administered the appropriate amount at the
  appropriate time for the appropriate patient

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Treat the patient, never, ever, treat the level!
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Six Fundamental Concepts of TDM

• Concept 1 Movement of drugs in the body can be
  described by simple mathematical equations
• Concept 2 There is a relationship between drug
  concentration and pharmacologic effect
• pharmacodynamics vs. pharmacokinetics
• Concept 3 Drug is removed from the body in
  units of volume rather than weight
• Concept 4 The half-life of a drug is the same
  at any time during the dosing interval
• Concept 5 It takes five half-lives to reach
  steady-state
• Concept 6 Free drug concentrations are
  responsible for the pharmacologic activity of
  drugs

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Indications for Monitoring Plasma Levels of Drugs

• To alter drug utilization as a consequence of
  disease or physiological state
• To evaluate dose-related toxicity
• Inadvertent over dosage
• Surreptitious drug taking or intentional over
  dosage
• To evaluate therapeutic inefficacy
• Noncompliance with prescribed therapy
• Poor drug absorption
• Unexpectedly rapid drug elimination
• To guide dose selection in prophylactic therapy
• To guide dose adjustment based on changing
  interpatient pharmacokinetic principles
• Rapid attainment of effects are desired or
  mandated

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Mandatory TDM drug properties

• Strong correlation between concentration and
  pharmacologic effect
• Complete PK knowledge of the drug
• Narrow therapeutic index
• Wide interpatient variability
• Sensitive and specific assay available
• Toxicity or lack of efficacy is dangerous

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Does your institution need/want this?

• Assess frequency of requests for drug levels
• Aminoglycosides
• Vancomycin
• Anticoagulants
• Antiepileptics

• Assess action taken upon receipt of levels
• Assess frequency of levels appearing to be out
  of range or toxic

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Information needed to individualize dosages -1

• Patient information
• Age
• Height
• Weight
• Genetic variability?
• Medical conditions
• Goal of drug therapy
• Desired concentration
• Desired ratio of peaktrough
• Desired AUIC

• Drug administration information
• Dosage form
• Route of administration
• Dose administered
• Times of dose administration
• Compliance
• Dose number
• Dose number on this regimen vs. number of doses
  totally received

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Information needed to individualize dosages -2

• Serum concentration data
• Serum concentration value
• Time serum concentration specimen obtained
• Reliability of assay

• Other drugs
• If interfere or impact monitored medications
  concentration in sampled compartment
• Pertinent labs
• Renal function
• Liver function
• Cardiac function

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Problems encountered in TDM

• Changes in PK variables
• Population data used vs. your patients
  individual parameters
• Altered organ function temporary or permanent
• Drug interactions
• Displacement
• Altered rate of metabolism
• Dr. D. Dugans lecture!

• Methodology Errors
• Inappropriate dosing time
• Dose inaccurate
• Altered dosing intervals
• Sample errors
• Wrong time
• Wrong dose number (fourth dose in total but not
  fourth dose on this regimen)
• Wrong patient

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Organ System Alterations Affecting TDM
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TDM Services Comedy or tragedy, that is the
question

• Errors/Misuse of TDM
• Bussey Hoffman (1983)
• 70 of levels found to be invalid
• 43 collection 40 misapplication
• Levels ignored
• 40 gentamicin (Levin,1981)
• 66 phenytoin (Wilson,1974)

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TDM Benefits

• Improved patient outcomes
• Decreased morbidity/mortality
• Decreased length of hospital stay
• Decreased incidence of adverse events
• Institutional benefits
• Increased number of patients properly maintained
• Fewer wasted levels
• Improved efficacy and productivity

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TDM Benefits - 2

• British Med J
• 65 patients with GN sepsis
• Receiving gentamicin
• 84 cure in patients with adequate peaks
• 23 cure in those without

• J Infect Dis
• 105 patients with GN sepsis
• 97.6 survival with adequate peaks attained
• 79.1 survival in those with inadequate peaks

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TDM Benefits - 3

• Banh HL, Burton ME, Sperling MR. Interpatient and
  intrapatient variability in phenytoin protein
  binding. Ther Drug Monit 2002 Jun24(3)379-85.
• monitoring of total serum concentrations is
  unreliable and free phenytoin serum
  concentrations should be considered for
  monitoring in hospitalized patients
• Kishino S, Koshinami Y, Hosoi T, Suda N, Takekuma
  Y, Gandoh S, Furukawa H, Todo S, Miyazaki K.
  Effective fluconazole therapy for liver
  transplant recipients during continuous
  hemodiafiltration. Ther Drug Monit 2001
  Feb23(1)4-8
• To guarantee safe and effective fluconazole
  therapy, the trough levels should be monitored
  routinely during CHDF

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TDM Team Draft or Volunteer

• Director usually a MD (pathologist)
• Pharmacist
• Usually one with advanced training in this area
  and/or one with extensive experience
• May want multiple levels of pharmacists involved
• Phlebotomist
• Having a designated person responsible for
  drawing levels makes the likelihood of erroneous
  or inappropriate levels being run less likely
• Laboratory technician someone who can run the
  assays accurately and precisely

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Flow of TDM Service
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When to sample

• After distribution
• Individualize based on medications ADME
• Digoxin PYT daily
• Lidocaine - immediately
• At steady-state
• Trough vs. Cmin
• Peak vs. Cmax

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TDM Putting science into practice

• Six Fundamental Concepts
• Indications for Monitoring
• Mandatory TDM drug properties
• Information needed to individualize dosages
• Problems encountered in TDM
• Organ System Alterations Affecting TDM
• TDM Benefits
• When to sample