Description
The presentation that includes TDM or Therapeutic Drug Monitoring by analysing topics like purpose, Pharmacokinetic Considerations, Methodological Difficulties.
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, cholesterol – 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 index • The effects are due to the parent drug and not its metabolites
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 anticonvulsants • 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 phenytoin • 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 disorder – MTC - upper concentration above which the rate and severity of adverse effects become unacceptable
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 outcomes • 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 lethal
• Renal clearance of Li can be affected by diuretics and NSAIDs
Anticonvulsants
• 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
Digoxin
• Has variable bioavailability • Has variable clearance (by kidney) - remember the elderly • 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
Cyclosporin
• Used as immunosuppressant in transplant rejection • Low therapeutic index and toxicity (kidney) is severe • Interactions are common - eg calcium channel antagonists • Plasma range 50-300 mg/L
Theophylline
• 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
Gentamicin
• Practice is changing - trend to once/daily dosing • Toxicity relates to trough concentrations, particularly with prolonged therapy • Desirable range:
– peak 6 - 10 mg/L – trough 1-2 mg/L
doc_280214651.ppt
The presentation that includes TDM or Therapeutic Drug Monitoring by analysing topics like purpose, Pharmacokinetic Considerations, Methodological Difficulties.
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, cholesterol – 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 index • The effects are due to the parent drug and not its metabolites
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 anticonvulsants • 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 phenytoin • 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 disorder – MTC - upper concentration above which the rate and severity of adverse effects become unacceptable
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 outcomes • 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 lethal
• Renal clearance of Li can be affected by diuretics and NSAIDs
Anticonvulsants
• 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
Digoxin
• Has variable bioavailability • Has variable clearance (by kidney) - remember the elderly • 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
Cyclosporin
• Used as immunosuppressant in transplant rejection • Low therapeutic index and toxicity (kidney) is severe • Interactions are common - eg calcium channel antagonists • Plasma range 50-300 mg/L
Theophylline
• 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
Gentamicin
• Practice is changing - trend to once/daily dosing • Toxicity relates to trough concentrations, particularly with prolonged therapy • Desirable range:
– peak 6 - 10 mg/L – trough 1-2 mg/L
doc_280214651.ppt