Bvii: Explain clinical drug monitoring with regards to peak & trough concentrations, minimum therapeutic concentration & toxicity

Therapeutic Drug Monitoring

  • TDM = tailoring a drug dose by maintaining plasma [ ] (Cp) within a certain range
  • Helps combat drug variability
    • PK variability = b/w dose & Cp
    • PD variability = b/w drug [ ] & receptor

TDM Uses

  • Clinical findings do not indicate optimal drug Cp i.e. prophylactic anti-epileptics
  • OD can have serious toxic effect
  • Drug has narrow therapeutic range
  • Check compliance
Therapeutic Window
  • Minimum toxic [ ] = minimum [  ] where toxicity usually occurs
  • Minimum effective [ ] = Cp below which there is no clinical benefit
  • Therapeutic [ ] = range of [  ] where drug is effective
    • AIM: be in therapeutic window at all times

Factors Relevant To Interpreting Drug Measurements

PK Factors

  • Timing of sample
    • Peak & trough are min & max doses achieved during repeated dosing cycles
      • Peak = occurs after dose
      • Trough = lowest [ ] before next dose, least variable parameter
    • Short t ½ = take trough
    • Long t ½ (phenytoin) = any time
    • Digoxin → after distribution t ½ = >6hrs
  • Steady state concentration
    • Intermittently dosed drugs will achieve SS in 3 – 5 half lives
  • Relationship of Cp to effect site [ ]
    • Effect site = [ ] of drug at receptor site ≠ Cp
    • i.e. drug penetrates variable → Vancomycin for ventriculitis
  • Factors influencing Cp
    • Vd, tissue binding, metabolism, clearance
  • PPB
    • Sample = unbound drug + bound drug
    • Disease can ∆ PPB
    • i.e. hypoalbuminaemia & phenytoin (acidic drug)
      • Phenytoin therapeutic range = 10 – 20mg/L

→ unbound = 1 – 2mg/L

      • Hypoalbuminaemia → unbound = 0.2mg/L
    • The ↑free phenytoin is cancelled because of ↑clearance → so even though unbound is within normal range, it looks less because there’s less total drug in sample

→ If this is not accounted for when you dose you ↑↑ risk of toxicity

PD Factors

  • Relationship between Cp & drug effect
    • If there’s no relationship (e.g. levetiracetam), no point to measure
  • Active metabolites
    • Difficult to measure, not represented in assay sample
  • Variability in drug response
    • i.e. groups of population where low [ ] yields good therapeutic response

Pragmatic Factors

  • Is it easy to do the test?
  • Will it come back at a relevant time?
  • Is it easy to collect the sample?
  • Cost
  • Accuracy