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
- 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
- Peak & trough are min & max doses achieved during repeated dosing cycles
- 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