pharmacokenetic 3 Flashcards
what is TDM?
Therapeutic drug monitoring (TDM) is the practice of using drug levels, p/kinetics and p/dynamics to optimise drug therapy to individual patients
what is TDM used for?
Drugs with a narrow therapeutic rangeor low therapeutic index
Drugs where dose and effect are not strongly correlated
Drugs with wide inter-patient variation in clearance – theophylline
Drugs with toxicity that is not necessarily evidenced by easily observable symptoms – Gentamicin
Monitoring compliance
Confirming toxicity
what is the equation for TI?
T.I = TD50/ED50
t= toxic
e= effective
when is cp used in practice
Cp should ideally be at steady state
Remember time to SS is about five times t1/2
From the point the patient starts taking the drug
Remember that analytical methods will (most likely) return TOTAL Cp levels, with no distinction between bound and unbound drug (chromatography)
explain protein binding (TDM)
In the Plasma there is many soluble proteins
drug which Free in solution
Drug is bound to water soluable – not free to act
Does not differentiate between bound and unbound In analaytic methods
they are at equilibrium
Drug interactions with a weakly bound drug
Imagine a drug ‘A’ thatis 5% protein bound
A second drug ‘B’ is introduced
It displaces bound drugfrom the protein, increasing the free level by 3%
The free (active) drug level changes from 95% to 98%
This is a negligible 1.03 times increase:and so it is unlikely to cause a patient any problem
Drug interactions with a strongly bound drug
Imagine a drug ‘A’ thatis 95% protein bound
A second drug ‘B’ is introduced
It displaces bound drugfrom the protein, increasing the free level by 3%
The free (active) drug level changes from 5% to 8%
This is a massive 1.6 times increase:and so it is highly likely to cause a patient a problem
Saturation of protein binding
Valproic acid is ~90% bound to albumin up to Cp 75g/ml
Above this Cp, the protein binding sites are saturated and an increased dose brings about a disproportionate rise in the free fraction of valproic acid
Therapeutic effectwill rise in line with Cp(free)and may well causeproblems
Individuals vs. populations values
In TDM, we use population values as a starting point and then ‘tweak’ them to suit individuals
Use population values to start patient dosing
Once at steady state, measure patient Cp
Compare with expected Cp from population values
Adjust clearance to better represent the actual drug clearance in this patient, such that calculated Cp is in better agreement with observed Cp
Proceed using the “patient-specific” clearance in future calculations
General principles of TDM
-Information gathering
Patient’s physical details, clinical / biochemical status
Drug history, dosage regimes
Pharmacokinetic data (e.g. Vd and t1/2) for relevant drugs
Any prior pharmacokinetic information for the patient [may or may not be available, depending upon history]
Take blood and measure Cp
Work out what Cp ought to be using population values
Adjust clearance until you get good agreement
-If individual does not match population, check
concurrent drug therapy
compliance
medication error
mal-absorption
incorrect assay results
complete distribution, equilibrium Cp ?
laboratory error? e.g. incorrect sample storage
-Patient kinetics may simply deviate significantly from population kinetics
Can we get a handle on likely clearance in advance of starting therapy
Rather than wait until steady state to find out that a patient has lower (or higher) than expected clearance…
…We can assess their likely clearance from a SINGLE blood sample taken before they start treatment
This is known as estimating their creatinine clearance
what is creatinine
Creatinine is a breakdown product of creatine phosphate in muscles
Useful properties of creatinine
Creatinine is usually produced at a constant rate
It is not protein bound
It is filtered by the kidneys with little or no reabsorption
Accordingly, creatinine clearance is a good indication of patient renal function
Creatinine clearance approximates the actual glomerular filtration rate
Measuring creatinine clearance (equation)
dont need to memorise
clcr= c urine * v urine / c plasma
C urine is the creatinine concentration in the urine in mg / mL
V urine is the volume of urine collected in mL / min
C plasma is the creatinine concentration in the plasma in mg / mL
So creatinine clearance is measured in mL / minute, as expected, because clearance has units of volume per time
equation for Estimating creatinine clearance
crcl est = (140-age) * weight * constant /cs
Constant is 1.23 for men, 1.04 for women
