Therapeutic Index

The therapeutic index is:

• \(Therapeutic \ Index = {LD_{50} \over ED_{50}}\), where:
  • ED₅₀
    The dose required to produce the minimum clinical effect in 50% of the population.
  • LD₅₀
    The dose which is lethal in 50% of the population.
• An indication of how safe a medication is at the prescribed dose
  • A higher TI indicates a greater margin for safety
    A drug generally has a good safety profile if it has a TI >10.
  • Drugs with a narrow TI have a small range between dose for efficacy and dose for harm
    

Narrow therapeutic index drugs are also known as “critical dose drugs” or drugs with a “narrow therapeutic range”. They are defined as drugs where the TI:

• TI is <2
• Ratio of the minimum toxic concentration and minimum therapeutic concentration is <2
• Safe use requires titration and monitoring

A related term is the therapeutic range, or therapeutic window, which is the difference between the minimum therapeutic concentration and the minimum toxic concentration.

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 effects
• 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:

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.
3. Tamargo J, Le Heuzey JY, Mabo P. Narrow therapeutic index drugs: a clinical pharmacological consideration to flecainide. Eur J Clin Pharmacol. 2015;71(5):549–67.
4. Gerlach, A.T., Saliba, L. (2016). Practical Pharmacokinetics and Pharmacodynamics. In: Martin, N.D., Kaplan, L.J. (eds) Principles of Adult Surgical Critical Care. Springer, Cham.