Drug Monitoring

Explain clinical drug monitoring with regard to peak and trough concentrations, minimum therapeutic concentration and toxicity

Drug monitoring:

  • Describes the individualisation of dosing by maintaining plasma drug levels within a target range
  • Is important in adjusting dose to account for inter-patient variability in response
    Variability can be:
    • Pharmacokinetic
      Adjusting drug dose by monitoring plasma levels reduces pharmacokinetic variability.
    • Pharmacodynamic
      Drug dose is adjusted by evaluating the clinical effect.

Drug levels are measured to ensure the concentration is above the minimum therapeutic concentration but below toxic levels:

  • Minimum therapeutic concentration
    The ED50, i.e. the dose required to have an effect in 50% of the population.
    • Determines desired trough levels
  • Minimum toxic concentration
    The LD50, or the dose which is lethal in 50% of the population.
    • Determines the acceptable peak levels

From these levels two related terms are derived:

  • Therapeutic range (also known as the therapeutic window)
    Difference between these levels.
  • Therapeutic index
    Ratio between these levels, i.e.
    • A higher therapeutic index gives a greater margin for safety

Indications

Drugs are monitored in order to:

  • Avoid toxicity
  • Adjust dosing for efficacy
  • Monitor compliance or determine failure of therapy

Drugs that typically require monitoring have a:

  • Narrow target range
  • Significant pharmacokinetic variability
  • Relationship between the concentration in plasma and clinical effets
  • Determined concentration range
  • Validated monitoring assay

Drugs where the effect can be measured clinically (e.g. antihypertensives) tend to be adjusted based on observed effects. This is not possible when:

  • The clinical response is the absence of a condition, e.g. antiepileptics
  • The drug has a narrow therapeutic range

Drugs commonly monitored in the ICU setting include:

Drug Therapeutic Range
Digoxin 0.8-2 microgram/L
Vancomycin 10-20 mg/L*
Tacrolimus 5-20 microgram/L
Serolimus 5-15 microgram/L
Phenytoin 10-20 mg/L
*Trough

Timing of samples

  • Sampling for toxicity should occur at times of peak concentration
    • This requires accounting for absorption and distribution
      • e.g. Digoxin levels should be performed >6 hours following a dose to allow time for distribution to occur
    • If symptomatic, samples taken at this time may demonstrate toxic concentrations
  • Sampling for monitoring should ideally occur at steady state
    • i.e. after 4-5 elimination half-lives
    • For drugs with very long half-lives (such as amiodarone), sampling tends to occur earlier to ensure toxic levels have not been reached, as steady state may take months to achieve
  • For drugs with short half-lives, trough levels (i.e. pre-dose levels) should be taken
    This is the least variable point in the dosing interval.
  • For drugs with long half lives, timing of sampling is less important

Interpretation

Interpretation of drug levels is dependent on:

  • Timing of sample
  • Duration of treatment at the current dose and dosing schedule
  • Individual characteristics that may affect the pharmacokinetics
    • Age
    • Physiology
    • Comorbidities (hepatic, renal, cardiac)
    • Drug interactions
    • Genetics
    • Environmental
  • Protein binding
    • Assays measure bound and unbound drug
      Only unbound drug is pharmacologically active.
    • If binding is changed by disease or displacement by other drug, the proportion of unbound drug may change and targeted levels may need to be adjusted accordingly
  • Active metabolites
    Active metabolites are not measured but will contribute to the response.

References

  1. Birkett DJ. Therapeutic drug monitoring. Aust Prescr 1997;20:9-11.
  2. Ghiculescu RA. Therapeutic drug monitoring, which drugs, why, when, and how to do it. Aust Prescr 2008;31:42-4.
Last updated 2017-10-04

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