B. Why TDM? Flashcards
what is TDM
therapeutic dose monitoring: measurement of a chemical parameter that will directly influence drug dosing procedures
what strategy is used for a drug with a large therapeutic range
maximal dose strategy
what strategy is used for a drug with a narrow therapeutic range
target level strategy
what can be used to speed up the time to Css
a loading dose
loading dose equation
Vd x Css / F
what are dosing regimens designed to deliver
- dose of drug
- route of administration
- interval between doses
what if plasma conc of drug enters the above upper limit conc
adverse effects (toxicity)
what if plasma conc of drug enters below lower limit conc
ineffective
what is the purpose of TDM
- confirm safe and effective drug concentrations
- investigate therapeutic failure (clinical trial)
- check patient compliance
- avoid or anticipate drug concs resulting in adverse effects
- assess inter-patient variability
tailoring a dose regimen to an individual patient, by maintaining plasma concentrations within the therapeutic range
what factors affect TDM measurements
- Pharmacodynamics (how drug affects body)
- Pharmacokinetics (how body affects drug)
Drug half-life
Bioavailability
Protein binding
Clearance - Dosing regimen
- Genetic polymorphisms
- Sample type and timing
- Testing methodology
how do genetic polymorphisms affect TDM measurements
- genetic differences stable in different populations
- different expression levels of different proteins
- in CYP450 enzymes in liver which oxidise drugs in metabolism etc
- example: CYP2C19 - 23% asian origin have a genetic polymorphism and only 4% caucasian origin so they will process drugs differently
what are the sources which cause PK variability
- patient compliance
- age
- physiology: gender and pregnancy
- disease: renal, hepatic, CV, respiratory
- drug-drug interactions: CYP inhibition/induction
- genetic influences: CYP polymorphisms
- environmental influences: smoking, diet (grapefruit enzymes interact with CYP3A4)
what drugs have a narrow therapeutic index
- lithium
- phenytoin
- digoxin
what drugs are highly protein-bound (so not bioavailable) or have interactions
- warfarin (97% protein bound)
- phenytoin (95%)
*if amount of albumin is decreased with renal disease, more drug will be cleared in urine
what patients have impaired clearance of a drug with a narrow therapeutic index
- renal failure patients
- digoxin (drug accumulation) as largely renal cleared
what drugs’ toxicity is difficult to distinguish from a patient’s underlying disease
- theophylline and COPD as too high levels cause respiratory problems
what drug’s efficacy is difficult to establish from their clinical condition
- phenytoin (anti-epileptic)
how are drugs typically given
oral or IV doses
example of a repeated dose schedule
continuous IV infusion
what does plasma drug conc increase to
steady state
what is maxima called
peaks
what is minima called
troughs
infusion rate equation (R)
CL x Css
oral dose equation
CL x Css x T (dosing interval) / F
