TDM

Therapeutic drug monitoring
Department of Clinical Pharmacology,

Wrocaw Medical University
Therapeutic index
concentration range characterized by a

high efficacy of action and low risk of
upper toxic symptoms
The essence of therapeutic drug
monitoring with drug
concentration
relationship between the pharmacological

activity and drug concentration in blood
or in other available biological material
Therapeutic Drug Monitoring TDM
action leading to achieve such a dosage of

the drug in a patient that the obtained
levels of concentration remain within the
therapeutic range
Factors conditioning the
efficacy of therapeutic drug
monitoring
the use of pharmacokinetic rules
combined analysis of obtained results and
clinical status of the patient
verification of pharmacological activity of
administered drugs by means of other
methods
Criteria for the selection of drugs
for monitoring
low therapeutic index
dangerous toxic effects of the drug and
unnoticeable clinical effect
close interrelationship between the drug
concentration and its activity
administration in a long-term therapy
Criteria for the selection of drugs
for monitoring continuation
the use in life-threatening diseases

significant individual differences in the
range of pharmacokinetics
non linear pharmacokinetics
high distribution coefficient
Basic clinical indications
for the use of therapeutic drug
monitoring
lack of the expected result of therapy or

occurrence of unexpected toxic symptoms
in spite of the administered dosage scheme
Basic clinical indications for
the use of therapeutic drug
monitoring - continuation
lack of the possibility of adequate clinical

or laboratorial control of the efficacy and
power of the pharmacological effect of a
drug, especially in long lasting therapy
and in the prophylactic use
monitoring continuation
pathological conditions in which

symptoms associated with unsuccessfully
treated disease are the same as toxic
symptoms of the drugs effect
individual pharmacokinetic differences

depend on the age and genotype of the
patient
Basic clinical indications
for the use of therapeutic drug
coincidence of diseases in organs
responsible for the drugs in the organism
(renal failure, severe liver diseases,
gastrointestinal diseases, pathological states
in hypo or dysproteinemia, disturbances in
water and electrolyte balance and acid-base
balance)
concomitant administration of other

drugs, especially if there is a possibility of
interaction between them
protection against toxic effects of some

drugs especially administered at high
doses to achieve better therapeutic action
of drug (calcium folinate + methotrexate)
Basic clinical indications for the
use of therapeutic drug
estimation of the therapeutic value of new

drugs
Rules for rational
pharmacotherapy based on
measurements of blood serum
drug concentration
development of such a dosage scheme of the
drug that in a study state its concentration
remains between the minimal active and the
minimal toxic concentrations
Factors changing drug kinetics
concomitant diseases specially renal and
liver diseases, alimentary tract disease,
thyroid disease, disturbances in protein
binding
receptors reactivity
concomitant administration of other drugs
and interaction of drugs
- continuation
genetic genotype, sex and age determine
the individual variability
improper dosage administration
poor bioavailability of drugs
environmental factors, especially tobacco
smoking
continuation
tbe use of drugs by patients incompatible
with doctors prescription
analytical disturbances, e.g.: the presence of
Digoxin Like Immunoreactive Substance
DLIS in serum
Genetically directed
therapeutic monitoring
concomitant use of pharmacogenetics and

traditional therapeutic monitoring of drugs
concentrations in the organism to increase
the efficacy and safety of pharmacotherapy
Genetically directed therapeutic
monitoring - continuation
patients genotype and phenotype estimation

before initiation of treatment allows a priori
dose modification of such drugs as:
mercaptopurine, tioguanine, fluorouracil,
azathioprine, trastusumab, irinotecan,
tricyclic antidepressants, antiarrhythmic
Timing of blood sampling for the
estimation of drug concentration
after achieving the steady state

before administration of another dose of the
drug, especially in the morning (minimal drug
concentration, Cmin through concentration)
Timing of blood sampling for the
estimation of drug concentration
continuation
in rare cases during administration of toxic

drugs, e.g. aminoglycoside antibiotics the
estimation of maximal concentration (Cmax
peak concentration) is recommended
Recommendations for the
estimation of free level of drug
concentration
diseases of the liver and kidney with
associated hypoalbuminemia
concomitant use of therapeutic substances
with concurrent displacement of the other
drugs from serum protein bindings
Recommendations for the
estimation of free level of drug
concentration continuation
non linear serum protein binding

(salicylates, prednisolon, phenylobutazone,
theophylline, disopyrimide)
increase of acid 1glycoprotein level in
some pathological conditions, e.g. myocardial
infarction
Calculation of changed dose or
changed dose interval for drugs
undergoing linear pharmacokinetics
indicated drug concentration

Changed Former ________________________________________
= x
dose dose estimated drug concentration
Changed Former estimated dose interval

dose = dose x _________________________
interval interval indicated dose interval
Drugs whose administration is based
on therapeutic drug monitoring:
cardiac glycosides (digoxin, digitoxin)
antiarrhythmic drugs (amiodarone,
disopyramide, flecainide, lidocaine,
procainamide, propafenone, propranolol)
antiepileptic drugs (phenytoine,
phenobarbital, carbamazepine,
primidone, ethosuximide, valproic acid)
Drugs whose administration
is based on therapeutic drug
monitoring continuation:
tricyclic antidepressant drugs (amitriptyline,

desipramine, imipramine, norptriptyline)
lithium
aminoglycosides antibiotics (gentamycin,
tobramycin, netilmycin, amikacin, dibecacin,
streptomycin, kanamycin)
Drugs whose administration
is based on therapeutic drug
monitoring continuation:
theophylline
methotrexate
cyclosporine
tacrolimus
Therapeutic concentration
range of cardiac glycosides
digoxin 0,8 2,0 g/l

digitoxin 10 25 g/l
Indications for therapeutic
monitoring of cardiac glycosides
divergence between expected, based on
rational premises, and obtained effect of
therapy
patients clinical condition restricting
correct evaluation of complications after
administration of cardiac glycosides
pregnancy
lactation
monitoring of cardiac glycosides
continuation
diseases of the liver, kidneys, hypo and
hyperthyroidaemia, hypoalbuminaemia
concomitant administration of drugs
increasing the digoxine concentration in
plasma by about 60 300% (amiodarone,
diltiazem, quinidine, verapamil, nifedipine,
indomethacin, spironolactone, gentamycin,
tetracyclines, cefradine, erythromycin)
Therapeutic concentration range of
quinidine 2 5 mg/l
monitoring of antiarrhythmic drugs
quinidine
cirrhosis, hypoproteinemia, circulatory
insufficiency, renal insufficiency
age (infants)
increasing quinidine concentration
(cimetidine, itraconazole, katoconazole,
ciprofloxacin, metronidazole, erythromycin,
clarythromycin, fluvoxamine)
procainamide 4 10 mg/l
procainamide
genetically determined acetylation
polymorphism to active pharmacological
metabolite
N acetylo procainamide
kidney insufficiency
high individual variability of processes:
adsorption, distribution, metabolism
lidocaine 1,5 5 mg/l

lidocaine
Pathological conditions, in which liver blood
supply decreases (congestive heart failure,
cardiac shock)
concomitant use of drugs increasing the
lidocaine concentration (propanolol,
mexiletine, cimetidine)
drug infusion lasting longer than 24h
propafenone 42 1679 g/l

monitoring of antiarrhythmic
drugs propafenone
genetically determined oxidation

polymorphism
Therapeutic concentration range
of antiepileptic drugs
phenytoin 10 20 mg/l
phenobarbital 10 40 mg/l
carbamazepine 4 11 mg/l
primidone 5 15 mg/l
ethosuximide 40 100 mg/l
valproic acid 50 100 mg/l
Indications for therapeutic drug
monitoring of antiepileptic drugs
narrow therapeutic index of antiepileptic

drugs
continuation
failure of monotherapy because of too
low concentration of drug as an effect of:
non compliance of patient to doctors
recommendations
adsorption disturbances
pharmacokinetic changes caused by
external and internal factors

continuation
Occurrence of undesired drug effects
during antiepileptic therapy associated
with:
concomitant liver, renal diseases and other
pathological conditions which are
associated with the loss of protein,
especially albumins
continuation
Occurrence of undesired drug effects during

antiepileptic therapy associated with:
decreasing the antiepileptic drugs
concentration (erythromycin, klarythromycin
+ carbamazepine)
continuation
Occurrence of undesired drug effects during

antiepileptic therapy associated with:
concomitant administration of some
antiepileptics increasing their concentration
(valproic acid + phenytoine)
continuation
early age (premature infants, infants)
pregnant women with epilepsy
(concentration of free fraction of phenytoine,
karbamazepine, valproic acid increases in
the third trimester )
non linear kinetics (phenytoine)
of tricyclic antidepressants:
amitriptyline 120 250 g/l

desipramine 125 300 g/l
imipramine 150 250 g/l
nortriptyline 50 150 g/l
fluoxetine 100 800 g/l
monitoring of tricyclic
antidepressants
narrow therapeutic index, lack of
satisfactory clinical effect and increase of
depression
genetically determined oxidation
polymorphism
occurrence of undesired drugs effects
administration of high doses of
antidepressants
antidepressants continuation
suspicion of lack of cooperation between

patient and doctor
diseases of the heart, liver and kidneys
advanced age
overdosage or suspicion of drug poisoning
antidepressants continuation
Possibility of interactions
(drugs and other substances increasing
the tricyclic antidepressant drugs

cimetidine, haloperidol, phenothiazines
cosegregates, chloramphenicol,
fluconazole, verapamil, diltiazem,
propafenone, quinidine, ritonavir, oral
contraceptives)
Lithium 0,3 1,3 mmol/l

monitoring of lithium
high nephro and neurotoxicity
increasing the cardiotoxicity of lithium
preparations (thiazide diuretics,
monosteroidal anti-inflammatory drugs,
general anaesthetics)
coexistence of other diseases
pregnancy
of aminoglycosides
amikacin 20 30 mg/l
gentamycin 5 12 mg/l
dibekacin 5 12 mg/l
netylmycin 5 12 mg/l
tobramycine 5 12 mg/l
streptomycin 15 40 mg/l
vankomycin 20 40 mg/l
monitoring of aminoglycosides
narrow therapeutic index

high oto- and nephrotoxicity
administration of other oto- and
nephrotoxic drugs
age-dependent differences in toxicity
monitoring of aminoglicosides
continuation
kidney insufficiency
therapy with high doses
hypovolemia
insufficiency of kidneys and hearing in the
history
repeated therapy of aminoglycosides
the use in peritoneal dialysis, hemodialysis
patients and patients with kidneys
transplantation
theophylline 8 20 mg/l
monitoring of theophylline
difficult to anticipate relationship between
standard daily dose of the drug and its
serum concentration in some patients
narrow therapeutic index
high individual variations in drug
elimination, especially in biotransformation
of the drug even in patients with efficient
liver
continuation
pathological conditions (diseases of the liver
and kidneys)
patients age (infants, elderly people)
tobacco smoking
diet
consumption of high amounts of fat
high protein and low carbohydrate diet

continuation
concomitant administration of other drugs and
substances increasing the theophylline
concentration (macrolides antibiotics,
fluoroquinolones, cimetidine, zileuton, oral
contraceptives)
concomitant administration of other drugs and
substances decreasing the theophylline
concentration (barbiturates, rifampicin,
phenytoin, preparations of Hypericum perforatum
monitoring of methotrexate
administration of methotrexate in high doses with
calcium folinate
coexistence of kidneys and liver failure, the
presence of exudation in body cavities
increasing the toxicity of methotrexate (salicylates,
sulphonamides, probenecid, non steroidal anti
inflammatory drugs, cefalothin, penicillin,
aminoglycosides antibiotics, cisplatin,
cyclosporine)
cyclosporine
inductive therapy: 150 350 ng/l
sustaining therapy: 100 250 ng/l

tacrolimus
0,2 2,0 g/l (serum)
4 40 g/l (whole blood)

monitoring of immunosuppressive
drugs cyclosporine, tacrolimus
low therapeutic index

high pharmacokinetic variability in and
intra individually
frequent administration of drugs in
severely ill patients
monitoring of immunosuppressive
drugs cyclosporine, tacrolimus
continuation
the possibility of determination of the risk
of transplant rejection or nephrotoxic
action of the drug
interaction between concomitantly used
drugs
verification of cooperation of the patient
and the doctor
Benefits associated with therapeutic
concentration drug monitoring
increasing the efficacy and safety of
administered drugs
possibility of tailoring individual patients
dosage
possibility of quick doctors intervention in
case of changing clinical condition of the
patient
continuation
decrease in the incidence of undesired drug
reactions
possibility of drug administration in high
doses
possibility of detection of imminent risk of
undesired reactions before their clinical
appearance
continuation
possibility of checking patients

compliance with the doctors
recommendations
shortening of therapy time
decrease of the cost of therapy

TDM

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

TDM

Uploaded by

Copyright:

Available Formats

Therapeutic drug monitoring

Department of Clinical Pharmacology,

concentration range characterized by a

relationship between the pharmacological

action leading to achieve such a dosage of

the use in life-threatening diseases

lack of the expected result of therapy or

lack of the possibility of adequate clinical

pathological conditions in which

individual pharmacokinetic differences

concomitant administration of other

protection against toxic effects of some

estimation of the therapeutic value of new

concomitant use of pharmacogenetics and

patients genotype and phenotype estimation

after achieving the steady state

in rare cases during administration of toxic

non linear serum protein binding

indicated drug concentration

Changed Former estimated dose interval

tricyclic antidepressant drugs (amitriptyline,

digoxin 0,8 2,0 g/l

lidocaine 1,5 5 mg/l

propafenone 42 1679 g/l

genetically determined oxidation

narrow therapeutic index of antiepileptic

pharmacokinetic changes caused by

external and internal factors

Occurrence of undesired drug effects during

Occurrence of undesired drug effects during

amitriptyline 120 250 g/l

suspicion of lack of cooperation between

the tricyclic antidepressant drugs

Lithium 0,3 1,3 mmol/l

narrow therapeutic index

high protein and low carbohydrate diet

sustaining therapy: 100 250 ng/l

4 40 g/l (whole blood)

low therapeutic index

possibility of checking patients

You might also like