clinical pharmacokinetics-ii [dosing of drugs, tdm]
TRANSCRIPT
DR. BADAR UDDINUMAR
To discuss dosing schedules of drugs
based on pharmacokinetic principles
To discuss therapeutic drug
monitoring
Effective dose: It is the amount of
drug which will produce specific
intensity of effect i.e.; either to treat
the disease or prevent the disease
successfully
Median effective dose (ED50): It is the amount of a drug which produces the desired therapeutic effect in 50% of experimental animals
OR It is the dose of a drug required to produce
a specific intensity of effect in 50% of individuals
It is measure of effectiveness of a drug
Lethal dose: It is the amount of a drug
which will kill certain percentage of
experimental animals to whom the drug is
administered
Fatal dose: When lethal dose reaches
100% or LD100 is known as fatal dose
Median lethal dose (LD50): It is the
amount of a drug which is fatal to 50%
of the experimental animals [i.e.; which kills 50% of the experimental
animals]
It is the measure of acute toxicity of
drugs
Initial loading dose: In some
conditions certain drugs are given in
large doses in the beginning to
obtain an effective blood level
rapidly, this is known as initial
loading dose
Maintenance dose: After achieving
a desired blood level by initial loading
dose, smaller quantity of drug is then
required to maintain the blood level,
this is known as maintenance dose
e.g. initial loading dose of sparfloxacin
is 400 mg. on the first day then
maintenance dose is 200 mg / day as
single daily dose Initial loading dose of digoxin is 1-1.5
mg the maintained at 0.25 mg once or
twice daily dose
Loading Dose
Dose = Cp(Target) x VdDose = Cp(Target) x Vd
What is the loading dose required for drug A if;
Target concentration is 10 mg/L Vd is 0.75 L/kg Patients weight is 75 kg
Answer is on the next slide
Dose = Target Concentration x VD
Vd = 0.75 L/kg x 75 kg = 56.25 L
Target Conc. = 10 mg/L Dose = 10 mg/L x 56.25 L = 565 mg This would probably be rounded to 560 or
even 500 mg
Maintenance Dose = CL x CpSSav
CpSSav is the target average steady state drug concentration
The units of CL are in L/hr or L/hr/kg
Maintenance dose will be in mg/hr so for total daily dose will need multiplying by 24
What maintenance dose is required for drug A if;
Target average SS concentration is 10 mg/L
CL of drug A is 0.015 L/kg/hr
Patient weighs 75 kg
Answer on next slide
Maintenance Dose = CL x CpSSav
CL = 0.015 L/hr/kg x 75 = 1.125 L/hr
Dose = 1.125 L/hr x 10 mg/L = 11.25 mg/hr
So will need 11.25 x 24 mg per day = 270 mg
Effective Dose50 [ED50]
Toxic Dose50 [TD50]
Therapeutic Index
Therapeutic window
Not all people respond to a similar dose
of a drug in the exact same manner
This variability is based upon individual
differences and is associated with toxicity
DrugTherapeutic Concentration Range
Aminoglycoside (gentamicin, tobramycin)
0.5 < - > 8 mg/L
Digoxin 0.5 < - > 8 2.0 ug/L
Phenytoin 10 < - > 8 20 mg/L
Theophylline 10 < - > 8 20 mg/L
This variability is thought to be caused by:
•Pharmacokinetic factors contribute to differing concentrations of the drug at the target area
•Pharmacodynamic factors contribute to differing physiological responses to the same drug concentration -
•Unusual, idiosyncratic, genetically determined or allergic, immunologically sensitized responses
The therapeutic index (also known as therapeutic ratio), is a comparison (ratio) of the amount of a drug that causes the therapeutic effect to the amount that causes death
Quantitatively, it is the ratio of median lethal dose to median effective dose
It is an approximate assessment of the safety of the drugs
A high therapeutic
index is preferable
to a low one
This corresponds to a
situation in which one
would have to take a
much higher dose of a
drug to reach the
lethal threshold than
the dose taken to elicit
the therapeutic effect
Larger the TI greater is the relative safety of the drug
For therapeutic use TI of a drug must be more than one
A drug might have different TI depending on its clinical use e.g.; Aspirin used in headache TI is high
Aspirin used in Rheumatoid arthritis TI is very low
Drugs with high
TI:
Penicillin [dose up to
48 lac units]
Diazepam [up to
200 mg at once, LD
is 750 mg]
Drugs with low
TI:
Digitalis [digoxin]
Anticancer drugs
Phenobarbitone
Warfarin
In animal studies, the therapeutic index is usually defined as the ratio of the TD50 to the ED50
The precision, possible in animal experiments may make it useful to estimate the potential benefit of a drug in humans
The therapeutic index of a drug in humans is almost never known with real precision
Drug trials and accumulated clinical experience often reveal a range of usually effective doses and a different (but sometimes overlapping) range of possibly toxic doses
The clinically acceptable risk of toxicity depends critically on the severity of the disease being treated
For example, the dose range that provides relief from an ordinary headache in the great majority of patients should be very much lower than the dose range that produces serious toxicity
However, for treatment of a lethal disease such as Hodgkin's lymphoma, the acceptable difference between therapeutic and toxic doses may be smaller
It is the ratio of the lethal dose to
1% of population to the effective
dose to 99% of the population
(LD1/ED99)
This is a better safety index than the LD50
for drugs that have both desirable and
undesirable effects, because it factors in
the ends of the spectrum where doses
may be necessary to produce a response
in one person but can, at the same dose,
be lethal in another
Useful range of concentration over
which a drug is therapeutically
beneficial
Therapeutic window may vary from
patient to patient
Drugs with narrow therapeutic windows
require smaller and more frequent doses
or a different method of administration
Drugs with slow elimination rates may
rapidly accumulate to toxic levels….can
choose to give one large initial dose,
following only with small doses
Some Principles
An established relationship between
concentration and response or toxicity
A sensitive and specific assay
An assay that is relatively easy to perform
A narrow therapeutic range
A need to enhance response/prevent
toxicity
Lack of therapeutic response
Toxic effects evident
Potential for non-compliance
Variability in relationship of dose and
concentration
Therapeutic/toxic actions not easily
quantified by clinical endpoints
Assuming patient is at steady-state Assuming patient is actually taking the drug
as prescribed Assuming patient is receiving drug as
prescribed Not knowing when the [drug] was measured in
relation to dose administration Assuming the patient is static and that changes
in condition don’t affect clearance
Not considering drug interactions
Invasive: blood, spinal fluid, biopsy Noninvasive: urine, feces, breath,
saliva
Most analytical methods designed for plasma analysis
C-14, H-3
At the end of the lecture the students will be able to-
Explain with examples the principles of dosing schedules of drugs based on pharmacokinetic principles
Explain with examples the clinical significance of therapeutic drug monitoring