Department of Clinical Pharmacology, · The essence of therapeutic drug monitoring with drug concentration relationship between the pharmacological activity and drug concentration

Therapeutic drug monitoring

Department of Clinical Pharmacology,

Wrocław 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 drug’s 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 doctor’s 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

patient’s 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 – α–1–glycoprotein 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 μg/l

digitoxin 10 – 25 μg/l

Indications for therapeutic

monitoring of cardiac glycosides

divergence between expected, based on rational premises, and obtained effect of therapy

patient’s 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)

concomitant administration of other drugs increasing quinidine concentration (cimetidine, itraconazole, katoconazole, ciprofloxacin, metronidazole, erythromycin, clarythromycin, fluvoxamine)


procainamide 4 – 10 mg/l


monitoring of antiarrhythmic drugs –

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


monitoring of antiarrhythmic drugs

– 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 μg/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


monitoring of antiepileptic drugs –

continuation

failure of monotherapy because of too

low concentration of drug as an effect of:

non – compliance of patient to doctor’s

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 μg/l

desipramine 125 – 300 μg/l

imipramine 150 – 250 μg/l

nortriptyline 50 – 150 μg/l

fluoxetine 100 – 800 μg/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

concomitant administration of other drugs 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 kidney’s 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


monitoring of theophylline –

continuation

pathological conditions (diseases of the liver

and kidneys)

patient’s age (infants, elderly people)

tobacco smoking

diet

consumption of high amounts of fat

high – protein and low – carbohydrate diet


monitoring of theophylline –

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 μg/l (serum)

4 – 40 μg/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 patient’s

dosage

possibility of quick doctor’s intervention in

case of changing clinical condition of the

patient


concentration drug monitoring –

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


concentration drug monitoring –

continuation

possibility of checking patient’s

compliance with the doctor’s

recommendations

shortening of therapy time

decrease of the cost of therapy

Documents

Department of Clinical Pharmacology, · The essence of therapeutic drug monitoring with drug concentration relationship between the pharmacological activity and drug concentration