Therapeutic Drug Monitoring

Definition
Therapeutic drug monitoring refers to the measurement of drug concentration in biological fluids with the purpose of optimizing a patients drug therapy

The aim of TDM is to provide maximum beneficial effects of drugs, and minimum risks of toxicities with added advantages of pharmacoeconomics

Pharmacokinetic studies are based on the concept that Pharmacologic response of a drug is closely related to concentration of drug at the receptor site (or site of action )

Toxic level
Maximum Therapeutic Concentration

Plasma conc.

Therapeutic Range
Minimum Therapeutic Concentration

Sub therapeutic range

Time

(hrs)

Pharmaceutical data generated on drug are

usually based on studies conducted on a large patient population

Data obtained reflect an average or mean value for these concentration

Individual patient response often plays an important role in the determination of therapeutic and toxic concentration of drug in the plasma

In most scientific studies large difference have been reported in individual patients to treatment with given drug

There fore the therapeutic conc of a drug in one individual may prove to be sub therapeutic conc in another individual and toxic conc in some body else

Objectives Of TDM
Therapeutic drug monitoring can be applied for 1. Obtaining maximum beneficial outcome of drug therapy 2. Attaining the required therapeutic concentration of the drug within least time 3. Maintaining the concentration of the drug within the therapeutic range such that no toxic effects are produced 4. Regulation of drug therapy by monitoring the concentration of drug plasma and its pharmacological response

Objectives Of TDM
Providing medical advantage by reducing the chances of drug toxicity. 6. Providing economic convenience to patients by shortening their stay in the hospital 7. Monitoring the factors like disease state, patients characteristics, drug interactions in order to reduce variability between individuals. 8. Recognizing a substance or drug whose presence may lead to medical crisis.
5.

Objectives Of TDM
7.

Adjusting dose of drugs in patients having pre existing hepatic or renal impairment and thus preventing the accumulation of drugs in the body For Drugs with unpredictable dose response relationship TDM provides an effective means of individualization of dosing In a poisoned patient, the type and extent of poising can be identified immediately. And also helps in monitoring the amount of antidote & its efficiency

8.

9.

Necessity for therapeutic drug monitoring

Direct relationship exists between the drug or drug

metabolite levels in plasma and pharmacological or toxic

effects.

The therapeutic effect can not be readily assessed by the

clinical observation

Large individual variability in steady state plasma concentration exits at any given dose

Appropriate analytical techniques are available to determine

the drug and metabolite level

TDM is unnecessary when

Drugs that do not need TDM:

Drugs that used for treating diseases of which their clinical end points can easily be monitored, e.g., BP, HR, cardiac rhythm, blood sugar, blood cholesterol and triglycerides, urine volume, body temperature, inflammation, pain, headache, etc.

Clinical outcome is unrelated either to dose or to plasma

concentration

Dosage need not be individualized

Drugs with wide therapeutic range such as beta blockers and

calcium channel blockers

Drugs that used to treat less complicated or not life threatening diseases

Criteria for valid TDM:

Whether the patient is following prescription promptly.

Whether he is complying with dietary restriction if any.

Whether desired effects are being observed with the prescribed dosage or any readjustment is needed

Whether any side, adverse effects are reported

Whether incompatibility and wrong prescription have been checked

Essential for effective TDM:

Accurate dispensing of drugs

Recording the accurate time of drug administration

Possible errors during administration Blood samples collecting time from correct sites.
Whether too little or too much drugging has been done

Ensuring the correct lab assay procedure

Cost benefits of TDM

Improvement in survival, symptoms and recovery of the patient with reduction in length of treatment and consequent cost The indirect beneficial effects are more difficult to assess, but they

include physician education about dose-concentration relationship

which allow improved dosing strategy Improvement in patient compliance A great cost reduction is obtain when the laboratory performing the TDM has appropriate consultation service A number of studies on cost effectiveness have demonstrated that TDM improves patient outcome by reducing the rate of drug induced toxicity,

improving the success of treatment and decreasing morbidity

Organization of TDM Service:

1. Name and address of the patient 2. Age, weight,sex of the patient 3. History of idiosyncrasy if any

4. Disease diagnosed as
5. Details of treatment he/she is undergoing 6. Patient history for allergies or about previous medication 7. Time and date of administration 8. Duration of stay at hospital 9. Functional status of organs like liver, kidney presently or previous reports regarding the same 10. Reasons for TDM i. Poor response for drugs

ii. Toxicity observed iii. Any other

TDM Laboratory Service:

Name: Address: Time of Last dose: Time of Blood Sampling: Drug administered :
Drug Dosage Route Method of Assay Expected Value Actual Value

Sex: M/F (Pregnancy/non pregnancy ) Age:

t1/2

Safety range

Steady State

Remarks

Digoxin

Mg/kg

Od Bid Tid

HPLC/ UV/ IMMUNOASSY

hrs

Mg/l

Functions of TDM
Selection of drug 2. Design dosage regimen 3. Evaluate patient response 4. Determine need for measuring serum drug concentration 5. Assay for drug 6. Pharmacokinetic evaluation of drug levels 7. Readjust dosage regimen 8. Monitor serum drug concentration 9. Recommend special requirements
1.

Process of therapeutic drug monitoring

1.

Drug selection
Physician usually choose the drug however many physician consult with clinical pharmacist in product selection, dosage regimen design not only on he basis of therapeutic consideration but also on the basis on cost and therapeutic equivalency
Factors to be considered during selection includes medication history path physiologic states, concurrent drug therapy known allergies drug sensitivity and drug interactions factors producing variability include

Patient Factors: age, weight Pathophysiology, gender, genetic

variability, nutritional status

Drug Factors :bioavailability & biopharmaceutics pharmacokinetics, drug interactions, receptor sensitivity rapid and slow metabolism

2.Dosage regimen design

Factors to be considered includes
Pharmacokinetics of the drug Physiology of the patient Pathophysiology conditions Personal life style factors

3.Pharmacokinetics of the drug

Clearance Bioavailability Elimination half life

4.Drug dosage form

The route of drug administration Desired onset and duration of the clinical

response

5.Patient compliance
Institutionalized patients Ambulatory patients

factors that may effect include

Cost of the medication Complicated instructions Multiple daily doses Difficulty in swallowing ADR

6.Evaluation of patient response

Diagnosis Drug selection Design dosage schedule Administer drug Evaluate patient response Readjust dosage if necessary Special recommendation if necessary evaluation Pharma.kinetic determine drug conc Assay for drug Determine need for measuring PDC

Continue treatment

Stop therapy

7. Measurement of serum drug concentration

Single serum drug concentration may not yield

useful information

To clarify the adequacy of dosage regimen Consider he cost of assay the risk and discomfort for the patient

8. Assay for drug

Performed by a clinical chemistry, laboratory or a clinical pharmacokinetics laboratory

Analytical techniques includes HPLC, Gas chromatography, spectrophotometry, fluorometry, immunoassay and radioisotopic methods

Methods mainly depends on physiochemical characteristics target concentration for estimation, amount and nature of the biological specimen available instruments, cost and skills of the laboratory

personnel

Analytical method used should be validated with respect to specificity, linearity, sensitivity, precision, accuracy stability and ruggedness

9.Pharmacokinetic evaluation

Serum drug concentration lower than normal

Patient compliance Errors in dosage form Wrong drug product Poor bioavailability Rapid elimination Enlarged apparent volume of distribution Steady state not reached Timing of blood sample Improving renal/ hepatic function Drug interaction Changing hepatic blood flow

Serum drug concentration higher than anticipated

o o o o

Patient compliance

Error in dosage regimen

Wrong drug product Rapid bioavailability

o
o o o o

Slow elimination
Increased plasma protein binding Smaller than anticipated apparent volume of distribution Deteriorating renal/ hepatic function Drug interaction due to inhibition of elimination

Serum concentration correct but patient does not respond to therapy Altered receptor sensitivity Drug interaction at receptor site Changing hepatic blood flow

10.Dosage adjustment
From SDC data and patient observations the clinician or pharmacokineticist may recommend an adjustment in dosage If sufficient data is not available pharmacokineticist can derive a new dosage regimen based on available data or pharmacokinetic parameters in the literature that are based on AVG population data

11.Monitoring serum drug concentration

In many cases patients Pathophysiology may be unstable, either
improving or further deteriorating ex. Therapy for CHF For some drugs an acute pharmacologic response can be monitored in lieu of actual SDC ex. Prothrombin clotting time in anticoagulant therapy

blood pressure monitoring for hypotensive agents

12.Special recommendation
If the patients are not responding to the therapy evaluate patient compliance and instructions

Special instructions that are simple and easy to follow

13.Design of dosage regimens

Several methods may be used to design a dosage regimen Initial dosage of drug is estimated using AVG population pharmacokinetic parameters obtained from the literature Many versions of clinical pharmacokinetic software are available eg.Datakinetics(ASHSP) and Abbot base pharmacokinetic system) Individualized Dosage Regimens: This is the most accurate approach to dosage regimen design based on the

pharmacokinetics of the drug in patient and it is not feasible for

calculation of initial dose

Dosage regimens based on population average:

This is based on average pharmacokinetic parameters obtained from clinical studies published in the literature fixed model: assumes that the population AVG pharmacokinetic parameters may be used directly to calculate a dosage regimen for patient without any alteration usually pharmacokinetic parameters such as Ka. F. VD and KE are assumed to remain constant

Adaptive model: This method uses patient variables such as weight, age,
sex, body surface area and known patient Pathophysiology such as renal disease, as well as the known population AVG pharmacokinetic parameters of the drug In this case the calculation of dosage regimen takes into consideration any changing Pathophysiology of the patient and attempts to adapt or modify the dosage regimen according to the needs of the

patient

TDM Protocol
Clinical condition requiring TDM Sample collected at appropriate time store and estimate drug concentration
Good response continue the drug not responding Review the case check for compliance Yes TDM test Sub-therapeutic increase the dose Repeat the TDM good response continue the same drug no response change to second drug or add another drug No Educate patient & family therapeutic change over to second drug or add another drug toxicity TDM test adjust the dose

TDM Protocol
Clinical situation requiring TDM

Collect blood sample at appropriate time

Transport and store sample Estimate drug concentration

INTERPRET TDM RESULT IN CONTEXT OF CLINICAL SITUATION

INTERPRET TDM RESULT IN CONTEXT OF CLINICAL SITUATION

Lack of clinical response

Satisfactory clinical response

Suspected drug toxicity

Lack of clinical response

Result below therapeutic range

Result with in therapeutic range

Result above therapeutic range

Check adherence

Check adherence

Change therapy or reconsider diagnosis

If adherent consider dose increase

If adherent consider small dose increase if result is at lower end of range Alternatively consider change of therapy

Satisfactory clinical response

Result below therapeutic range

Result with in therapeutic range

Result above therapeutic range

Maintain same dose if conc is v. low review

Maintain same dose

Assess patient for sign/symptoms of toxicity

reduce dose as appropriate

Suspected drug toxicity

Result below therapeutic range

Result with in therapeutic range

Result above therapeutic range

Consider other explanation for patient signs and symptoms lab, errors

Consider other explanation for patient signs and symptoms if results are at upper end lower the dose

Suspend dosing and restart at a lower dose

Cost benefits of TDM

The direct beneficial effects include improvements in survival, symptoms and recovery of the patient with reduction in length of treatment and consequent costs Indirect includes the physician education by learning about dose-concentration relationship for the drug used which allow improved dosing strategy Improvement in patient compliance is generally observed when patients are aware of being monitored A number of studies on cost-effectiveness have demonstrated that TDM improves patient outcome by reducing the rate of drug induced toxicity, improves the success of treatment and decreasing

APPROPRIATE USE OF TDM

1.Maximizing & speeding up efficacy 2. Minimizing toxicity 3. Patient's drug history uncertain 4. Poor response to initial Rx or deterioration after good response 5. When hepatic or renal function is changing 6. During drug interactions 7. Individualizing therapy and dosage regimen adjustment 8. To make decision about future therapy

9. Pharmacokinetic profiling

FACTORS AFFECTING SDC & INTERPRETATION OF SDC

1. Disease states: renal, liver, cardiac, thyroid

2. Habits: diet, smoking, drinking

3. Pregnancy, age, weight 4. Non-compliance 5. Electrolyte balance : Digoxin vs K+ & Ca++ 6. Drug interactions 7. Plasma protein binding 8. Bioavailability 9. Sampling time

Analytical aspects of TDM

For an efficient TDM a thoroughly developed analytical procedure is necessary for estimation of SDC The method should meet the specifications of handling of biological sample The method selected should have sensitivity, specificity linearity and dynamic range, precision, accuracy, stability and finally ruggedness

It must be less time consuming and economical

The method should require small quantity of sample ideally in

the range of 0.01ml to 0.1ml (10-100ug)

The ideal requirements for analytical aspects of TDM are:

The analytical procedure should be simple

It should give result within shortest possible time It should give accurate and precise results The method should be sensitive It should require little sample for analysis The method should be economic

1.Specificity:
There should

be evidence that method is specific for

drug

There is no interference between the drug metabolites

of the drug & endogenous or exogenous substance

In addition the internal standard should be resolved

completely and also demonstrate no interference with

other compounds

2.Sensitivity:
This is the minimum detectable level or

concentration of drug in serum that may be

approximated.

3.Precision:
This the measurement of variability or

reproducibility of the data usually obtained by

replication of various drug concentration and by replication of standard concentration curves prepared

4.Accuracy;
concentration.

This refers to the difference between

the AVG assay value and the true or known drug

5.Linearity & dynamic range :Dynamic

range refers to the relationship between drug concentration & the instrument response.

6.Stability:
Standard drug concentration should be maintained

under the same storage conditions as the unknown serum

samples and assayed periodically Serum samples obtained from subjects are usually assayed along with a minimum of three std processed sample containing known std drug conc & minimum of 3

control serum samples whose conc are known to the

analyst.

7.Ruggedness:
This is the degree of reproducibility of the test

results. The determination measures the

reproducibility of the results under normal operational condition from laboratory to laboratory & analyst to analyst