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
what kinetics occur with non-linear kinetics
- saturating kinetics
- enzymes saturated which metabolises drug (rate limiting step)
*alcohol consumption, no Css
equation for rate of metabolism
Vm x Cp / Km + Cp
what is Vm
maximum rate of elimination
what is Km
Michaelis Menten constant: concentration at which we reach half the rate of metabolism
when is linear PKs likely
therapeutic range < Km
*adsorption kinetics are rate limiting step
when is non-linear (saturated) kinetics likely
therapeutic range > Km
*enzymatic turnover is rate limiting step
what drug properties that require TDM
- drugs with non-linear pharmacokinetics
- narrow therapeutic ranges
- above the upper limit the drug can have adverse effects (toxicity)
- complex pharmacokinetics
sources of variation in PK parameters between patients
- normal genetic variation in expression of proteins involved in uptake, metabolism and
secretion of drugs - variation in pharmacodynamics (natural way patients respond to drugs)
- drug-drug interactions (+ food constituents) - competition for CYP450
- age
how is drug monitoring performed
- by measuring plasma drug concentrations (used here)
- by its clinical effect eg lowering of blood-pressure or the reduction in inflammation
- by its biochemical effects eg glucose modulation by insulin or increase in
prothrombin time by warfarin (indirectly)
what is the most widely used sample
- blood plasma or serum
at steady-state
convenient and standardised
*anticoagulant = plasma
*clotting factors = serum
other types of samples
- whole blood
- CSF
- saliva
- urine
analytical methodology for TDM
- quantitative method with high throughput (results <24 hours)
- distinguishes between compounds of similar structure – unchanged drug and metabolites (small changes make big changes)
- detects low concentrations with high accuracy and precision (lots of components in blood)
- simple enough to use as a routine assay
- not affected by other drugs administered simultaneously (test sensitive to detect between drugs)
- compromise between specificity and cost
analytical methodologies used for TDM which involve drug polarity
- HPLC (high performance liquid chromatography)
- GC (gas chromatography)
*components of plasma separated
*non-polar stationary phase: solid (non-polar components move slower)
*polar mobile phase: liquid or analyte vaporised into inert gas (polar components move quicker)
analytical methodologies used for TDM which involves antigen-antibody interactions
- Enzyme-linked immunosorbant assay (ELISA): secondary AB enzyme-linked to produce a colourmetric/fluorescent marker we can quantify
- Radioimmunoassay (RIA): most sensitive and expensive. Produce radioisotopes which we quantify with particular AB (radio labels)
- Fluorescence polarization Immunoassay (FPIA): detect AB interaction by change in polarity of fluorescent molecule associated with AB when it binds an antigen for drug quantification
