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Therapeutic Drug Monitoring by xiaohuicaicai


									     Therapeutic Drug Monitoring
• Relates concentrations of drug in blood to response
• Blood concentrations surrogate for the concentration at
  the site of action
• Has been established on the principle that the
  concentration correlates better than the dose with the
  drug effect
• Is important when
   – the dose cannot be titrated against response eg INR,
   – the drug is being used to prevent infrequent occurrences -
     eg epilepsy
        Conditions that must be met
• Blood concentrations can be accurately reliably
  and economically measured
• There is sufficient inter-individual variation in
  drug handling to warrant individualisation of dose
• There is a clear relationship between
  concentration and beneficial and/or adverse
  effects, particularly if there is a narrow therapeutic
• The effects are due to the parent drug and not its
             Purpose of TDM
•   To confirm ‘effective’ concentrations
•   To investigate unexpected lack of efficacy
•   To check compliance
•   To avoid or anticipate toxic concentrations
•   Before increasing to unusually large doses
•   Limited role in toxicology - drug screen
  Pharmacokinetic Considerations
• Is the aim to provide constant concentrations? - eg
• Is the aim to achieve transient high concentrations
  without toxicity? - eg gentamicin
• Are drug concentrations likely to vary greatly
  between individuals on the same dose? - eg
• Remember it takes around 5 half-lives to reach
  steady state
            Practical considerations
•   Can the lab actually measure the drug?
•   What sample is needed?
•   What is the right timing?
•   Is there an accepted ‘therapeutic range’
    – MEC - threshold concentration above which
      efficacy is expected in most patients with the
    – MTC - upper concentration above which the rate
      and severity of adverse effects become
  Methodological Difficulties in
 establishing ‘Therapeutic Range’
• Good data relating concentration to effect
  are seldom available
• Ideally it would require trials where
  participants were randomised to different
  plasma concentrations with follow-up and
  accurate and unbiased measurement of the
• See diagram of therapeutic range
            TDM - examples
• Lithium - used for bipolar disorder
• Toxic - neurological, cardiac, renal
• Narrow therapeutic range:
  – 0.8 - 1.2 mmol/L acutely
  – 0.5 - 0.75 mmol/L for maintenance
  – Chronic concentrations of 3.0 are potentially
• Renal clearance of Li can be affected by
  diuretics and NSAIDs
• Variable dose dependant kinetics
• Most metabolised through cytochrome P450 system
• Concentration-related CNS toxicity can be partly
  avoided by TDM
• However severe skin rashes, liver and marrow
  toxicity cannot be predicted or avoided
• With phenytoin small dose increases can produce
  disproportionate rises in blood levels and toxicity
• Sometimes free (unbound) concentrations need to be
  measured - eg hypoalbuminaemia, pregnancy
• Has variable bioavailability
• Has variable clearance (by kidney) - remember the
• Drug interactions are fairly common
• Relationship between concentration and effect is not
  constant - concentrations soon after dosing are difficult
  to interpret. Range is approx 1 to 2 nmol/L
• Patients may become more ‘sensitive’ to a given
  concentration - eg hypokalalaemia, hypothyroidism
• In atrial fibrillation titrate against the ventricular rate
• Concentrations should be measure at least 6-8 hours
  after the last dose
• Used as immunosuppressant in transplant
• Low therapeutic index and toxicity (kidney)
  is severe
• Interactions are common - eg calcium
  channel antagonists
• Plasma range 50-300 mg/L
• Declining use in asthma
• Very narrow therapeutic index: 55 - 110
  umol/L (should be lower)
• At the high end toxicity is common
• Toxicity is severe - GI, neuro, cardiac
• Interactions are common - erythromycin,
  cyclosporin, cimetidine, smoking
• Practice is changing - trend to once/daily
• Toxicity relates to trough concentrations,
  particularly with prolonged therapy
• Desirable range:
  – peak 6 - 10 mg/L
  – trough 1-2 mg/L

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