Therapeutic drug monitoring. Department of Clinical Pharmacology, Wrocław Medical University

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

Basic clinical indications for the use of therapeutic drug monitoring continuation pathological conditions in which symptoms associated with unsuccessfully treated disease are the same as toxic symptoms of the drug s effect

Basic clinical indications for the use of therapeutic drug monitoring continuation individual pharmacokinetic differences depend on the age and genotype of the patient

Basic clinical indications for the use of therapeutic drug monitoring continuation 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)

Basic clinical indications for the use of therapeutic drug monitoring continuation concomitant administration of other drugs, especially if there is a possibility of interaction between them

Basic clinical indications for the use of therapeutic drug monitoring continuation 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 monitoring continuation 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

Factors changing drug kinetics - continuation genetic genotype, sex and age determine the individual variability improper dosage administration poor bioavailability of drugs environmental factors, especially tobacco smoking

Factors changing drug kinetics 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, C min 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 (C max 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 Changed = Former x indicated drug concentration 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

Indications for therapeutic 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

Indications for therapeutic 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)

Therapeutic concentration range of procainamide 4 10 mg/l

Indications for therapeutic 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

Therapeutic concentration range of lidocaine 1,5 5 mg/l

Indications for therapeutic 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

Therapeutic concentration range of propafenone 42 1679 μg/l

Indications for therapeutic 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

Indications for therapeutic drug 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

Indications for therapeutic drug monitoring of antiepileptic drugs 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

Indications for therapeutic drug monitoring of antiepileptic drugs continuation Occurrence of undesired drug effects during antiepileptic therapy associated with: concomitant administration of other drugs decreasing the antiepileptic drugs concentration (erythromycin, klarythromycin + carbamazepine)

Indications for therapeutic drug monitoring of antiepileptic drugs continuation Occurrence of undesired drug effects during antiepileptic therapy associated with: concomitant administration of some antiepileptics increasing their concentration (valproic acid + phenytoine)

Indications for therapeutic drug monitoring of antiepileptic drugs 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)

Therapeutic concentration range 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

Indications for therapeutic drug 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

Indications for therapeutic drug monitoring of tricyclic 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

Indications for therapeutic drug monitoring of tricyclic 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)

Therapeutic concentration range of Lithium 0,3 1,3 mmol/l

Indications for therapeutic drug 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

Therapeutic concentration range 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

Indications for therapeutic drug monitoring of aminoglycosides narrow therapeutic index high oto- and nephrotoxicity administration of other oto- and nephrotoxic drugs age-dependent differences in toxicity

Indications for therapeutic drug 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

Therapeutic concentration range of theophylline 8 20 mg/l

Indications for therapeutic drug 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

Indications for therapeutic drug 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

Indications for therapeutic drug 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

Indications for therapeutic drug 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 concomitant administration of other drugs increasing the toxicity of methotrexate (salicylates, sulphonamides, probenecid, non steroidal anti inflammatory drugs, cefalothin, penicillin, aminoglycosides antibiotics, cisplatin, cyclosporine)

Therapeutic concentration range of cyclosporine inductive therapy: 150 350 ng/l sustaining therapy: 100 250 ng/l

Therapeutic concentration range of tacrolimus 0,2 2,0 μg/l (serum) 4 40 μg/l (whole blood)

Indications for therapeutic drug monitoring of immunosuppressive drugs cyclosporine, tacrolimus low therapeutic index high pharmacokinetic variability in and intra individually frequent administration of drugs in severely ill patients

Indications for therapeutic drug 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

Benefits associated with therapeutic 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

Benefits associated with therapeutic 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