THERAPEUTIC DRUG MONITORING(TDM)

TDM refers to the individualization of dosage by maintaining plasma or blood drug concentration within a target range (therapeutic range).

Goal of TDM is to achieve a desired beneficial effect with minimal adverse effects.

WHAT IS TDM ?

Therapeutic Index

• High therapeutic index– NSAIDs

• Aspirin• Tylenol• Ibuprofen

– Sedative/hypnotics• Benzodiazepines

– Most antibiotics– Beta-blockers

• Low therapeutic index– Lithium– Neuroleptics

• Phenytoin• Phenobarbital

– Some antibiotics• Gent/Vanco/Amikacin

– Digoxin– Immunosuppressives

Therapeutic Index

Plasma drug concentration

ToxicTherapeutic range

Tox

icity

Sub-therapeutic

Why monitor plasma drug concentrations?

• Avert toxicity• Optimize dose/therapeutic response• Detect changes in pharmacokinetics• Monitor compliance

WHY TDM ?1. Each person will have ADME at different rates based on their

a) age,weight, gender, b) genetic makeup,c) diseased conditions.

2. Useful in maintaining drug concentration within the therapeutic range which are taken for lifetime, and reduces toxic effects.

WHY TDM ?

3. Identify patient noncompliance, decrease in the efficiency of and dysfunctions in the body metabolism and elimination of drug.

4. Identify drug interactions.

5. Prescribe the exact dose thereby min the toxic effects.

Purpose of TDM• To confirm ‘effective’ concentrations• To investigate unexpected lack of efficacy• To check compliance• To avoid or anticipate toxic concentrations• Before increasing to unusually large doses• Limited role in toxicology - drug screen

DOES ALL DRUGS REQURE TDM?

TDM is useful if:Drug have narrow therapeutic range,Therapeutic effect cannot be readily assessedBy the clinical observation,Large individual variability in plasma conc.A direct relationship exists between the drug or drug metabolite levels in plasma and the pharmacological or toxic effects.Drug follow non-linear kinetics.

TDM is unnecessary when:Drugs with wide therapeutic range.Pharmacological effects can be clinically quantified,Drug follow linear kinetics,Clinical outcome is unrelated to either dose or plasma conc.

DOES ALL DRUGS REQURE TDM?

Major indications for TDM can be summarized as:-

1.Low therapeutic index,2.Poorly defined clinical end point,3.Therapeutic failure,4.Drugs with saturable metabolism,5.Wide variation in the metabolism of drug,6.Major organ failure,7.Prevention of adverse effects of life time drugs.

Therapeutic range for commonly monitored drugsAmicacin 20-30ug/ml

Cabamazepine 4-12 ug/ml

Digoxin 0.5-2.1 ug/ml

Gentamicin 5-10 ug/ml

Phenytoin 10-20 ug/ml

Procainamide 4-10 ug/ml

Quinidine 1-4 ug/ml

Theophylline 10-20 ug/ml

TDM OF ESTABLISHED DRUGS:-1. Cardio active drugs : amiodarone, digoxin, digitoxin disopyramide,

lignocaine, procainamide, propranolol and quinidine

2. Antibiotics : gentamycin, amikacin and tobramycin3. Antidepressants : lithium and tricyclic antidepressants4. Antiepileptic drugs : Phenytoin, phenobarbitone benzodiazepines, carbamazepine, Valproic acid and ethosuximide5. Bronchodilators : theophylline6. Cancer chemotherapy : methotrexate7. Immunosuppressives : cyclosporine

Criteria for TDM

Factors influencing drug variability

• Variation in drug absorption• Presence of other drugs• Drug interactions• Genetic difference• Diseases states• Physiologic differences

Process of TDM• Development of plasma profile in each patient

1)administering a predetermined dose of drug 2)Collection of blood samples 3)Determination of blood samples in each sample 4)plasma profile and pharmacokinetic model

development• Clinical effect of drug• Development of dosage regimen• Diagnosis, dosage form selection, dosage

regimen ,initiation of therapy and evaluation of clinical response

Pharmacokinetic Considerations• Is the aim to provide constant concentrations? - eg

anticonvulsants• Is the aim to achieve transient high concentrations

without toxicity? - eg gentamicin • Are drug concentrations likely to vary greatly

between individuals on the same dose? - eg phenytoin

• Remember it takes around 5 half-lives to reach steady state

Practical considerations• Can the lab actually measure the drug?• What sample is needed?• What is the right timing?• Is there an accepted ‘therapeutic range’

– MEC - threshold concentration above which efficacy is expected in most patients with the disorder

– MTC - upper concentration above which the rate and severity of adverse effects become unacceptable

HOW DOES TDM WORK?The drug dosage to reach the therapeutic

level must be determined on ADME of drug, age, weight, gender.The doctor adjusts the dose upwards and tests blood conc frequently until the appropriate steady state level is reached. If patient levels are too high, the doctor will adjust them lower, and vice versa.

Samples?

plasma or serum is used for drug assayswhole blood:- cyclosporin, tacrolimus, sirolimus there are large shifts of drug between red cells and plasma with storage and temperature change so whole blood is assayedsaliva, which gives a measure of the unbound drug concentration, may be a useful alternative when blood samples are difficult to collect.phenytoin ,Lithium, amitryptyline

TIMING OF SAMPLE COLLECTION

Peak conc

TroughConc

Time (hours)

Con

c(u

g/l

)

TIMING OF SAMPLE COLLECTION

The timing of blood collection is an important part of therapeutic drug monitoring.

Through experience and studies, doctors know when to expect peaks and troughs to occur and will request blood sample collections as either trough levels(usually drawn just before the next dose), peak levels(timing varies depend on the drug), or sometimes will request random level.

TIMING OF SAMPLE COLLECTION

Trough conc are commonly used for anti-convulsant drugs,peak conc may be useful for some antibiotics.AUC:- For some immunosuppresants and anticancer drugs.drugs with long half-lives such as phenobarbitone and amiodarone, samples can be collected at any point in the dosage interval.Correct sample timing should also take into account absorption and distribution, eg digoxin, so samples are collected after 6 hours of administration.

ANALYTICAL METHODOLOGY:-The analytical methodology employed should ideally:1.Distinguish between drug and its metabolites,2.Detect small amounts,3.Specificity 4.Unaffected by other drugs administered,and5.Should be accurate, precise, linearity.

ANALYTICAL METHODOLOGY

Commonly used analytical methods are:

1.Spectrophotometry and fluorimetry,2.Thin layer chromatography,3.HPLC and GLC, 4.Radio immuno assay(RIA)5.Enzyme immuno assay(EIA)6.Fluorescence ploarization immunoassy(FPIA)

For therapeutic drug monitoring the information required to allow interpretation of the result should include:-1. the time of the sample collection,2. the time of the last dose,3. the dosage regimen and 4. the indication for drug monitoring.

Sample timing for some important drugs:

a)Phenytoin: Since phenytoin has a long half life a single daily dose may be employed and so the timing of concentration monitoring is not critical.b) Carbamazepine: Its half life may be as long as 48 h following a single dose. A through concentration taken just after a dose together with a peak level three hours later is ideal.c) Digoxin: The measurement must be made atleast six hours after a dose to avoid inappropriate high levels.d) Theophylline: This drug has a narrow therapeutic index and timing of sampling is not critical if the patient is receiving one of the slow release formulations.e) Lithium: A 12 hr sample gives the most preciseguide to dosage adjustment.

The drug concentration in the collected samples are measured, and the other data such as high serum creatinine and high blood urea nitrogen levels are also measured to check the kidney function.

Sample concentrations lower than anticipated

Patient non complianceError in dosage regimen,Rapid elimination,Timing of samplechanging hepatic blood flowPoor bioavailability.Reduced plasma binding.

Sample concentrations higher than anticipated

Error in dosage regimen Rapid bioavailability, Slow elimination,Increased plasma protein bindingDecreased renal/hepatic function

Serum concentration correct but patient does not respond to therapy

Altered receptor sensitivity(tolerance)Drug interaction at receptor site

Pharmacokinetic software are available for dose calculation of drug with narrow therapeutic window

DATAKINETICSABBOTTBASE PHARMACOKINETIC

SYSTEM

The dosage regimen is calculated by using the NOMOGRAM by considering the age, body weight, and physiological state of the patient.

Therapeutic Drug Monitoring

Therapeutic Drug Monitoring• Relates concentrations of drug in blood to response• Blood concentrations surrogate for the concentration at

the site of action• Has been established on the principle that the

concentration correlates better than the dose with the drug effect

• Is important when – the dose cannot be titrated against response eg INR,

cholesterol– the drug is being used to prevent infrequent occurrences - eg

epilepsy

First Principle of TDM

• “Knowledge of serum concentrations is most helpful when the drug in question requires individualized dosing for optimal efficacy and more routine measures of therapeutic success are unavailable.”

Conditions that must be met• Blood concentrations can be accurately reliably and

economically measured• There is sufficient inter-individual variation in drug

handling to warrant individualisation of dose• There is a clear relationship between concentration

and beneficial and/or adverse effects, particularly if there is a narrow therapeutic index

• The effects are due to the parent drug and not its metabolites

Methodological Difficulties in establishing ‘Therapeutic Range’

• Good data relating concentration to effect are seldom available

• Ideally it would require trials where participants were randomised to different plasma concentrations with follow-up and accurate and unbiased measurement of the outcomes

• See diagram of therapeutic range

TDM - examples• Lithium - used for bipolar disorder• Toxic - neurological, cardiac, renal• Narrow therapeutic range:

– 0.8 - 1.2 mmol/L acutely– 0.5 - 0.75 mmol/L for maintenance– Chronic concentrations of 3.0 are potentially lethal

• Renal clearance of Li can be affected by diuretics and NSAIDs

Anticonvulsants• Variable dose dependant kinetics• Most metabolised through cytochrome P450 system• Concentration-related CNS toxicity can be partly

avoided by TDM• However severe skin rashes, liver and marrow toxicity

cannot be predicted or avoided• With phenytoin small dose increases can produce

disproportionate rises in blood levels and toxicity• Sometimes free (unbound) concentrations need to be

measured - eg hypoalbuminaemia, pregnancy

Digoxin• Has variable bioavailability• Has variable clearance (by kidney) - remember the elderly• Drug interactions are fairly common• Relationship between concentration and effect is not

constant - concentrations soon after dosing are difficult to interpret. Range is approx 1 to 2 nmol/L

• Patients may become more ‘sensitive’ to a given concentration - eg hypokalalaemia, hypothyroidism

• In atrial fibrillation titrate against the ventricular rate• Concentrations should be measure at least 6-8 hours after

the last dose

Cyclosporin

• Used as immunosuppressant in transplant rejection

• Low therapeutic index and toxicity (kidney) is severe

• Interactions are common - eg calcium channel antagonists

• Plasma range 50-300 mg/L

Theophylline

• Declining use in asthma• Very narrow therapeutic index: 55 - 110

umol/L (should be lower)• At the high end toxicity is common• Toxicity is severe - GI, neuro, cardiac• Interactions are common - erythromycin,

cyclosporin, cimetidine, smoking

Gentamicin

• Practice is changing - trend to once/daily dosing

• Toxicity relates to trough concentrations, particularly with prolonged therapy

• Desirable range:– peak 6 - 10 mg/L– trough 1-2 mg/L