Therapeutic Drug Monitoring (TDM) involves the analysis, assessment, and evaluation of circulating concentrations of drugs in serum, plasma, or whole blood.
The purpose of therapeutic drug monitoring is to ensure the medication dose is at the therapeutic range and not in the toxic range. Each individual varies in the metabolic process thus based on the metabolic process the medication dosages differ in each patient.
Drugs with a high therapeutic index
- Most antibiotics
Drugs with a low therapeutic index
- Some antibiotics
- Gentamycin/Vancomycin/ Amikacin
Basic Principles of Therapeutic Drug Monitoring
To confirm an optimum therapeutic drug monitoring following are some important criteria that need to be considered:
- At the appropriate time interval of drug administration, there is a need to estimate the patient’s plasma drug concentration.
- Adequate information should be known on the pharmacological and pharmacokinetic profiles of the administered drugs.
- There should be adequate and relevant information on the patient’s profile such as demographic data, laboratory, clinical status and other clinical evidence.
- There is needed to interpret the plasma drug concentration for the individualization of drug regimen according to the need of patients.
Objectives and Significance/Indications of Therapeutic Drug Monitoring
- Therapeutic drug monitoring is important for drugs that have a narrow therapeutic range. (Drugs which are below the range are not effective and the drugs which have above range are toxic). Thus, small changes in the concentration of such drugs, lead to no effects or toxic effects. Thus, for the prevention of ineffectiveness and toxic effects, it is important to monitor the drug that has a narrow therapeutic range.
- Therapeutic drug monitoring is important for the optimization of dosage according to the therapeutic response seen in particular patients.
- There is the importance of therapeutic drug monitoring for the drugs such as; theophylline which shows an abrupt dose-response curve.
- TDM is indicated to use for a drug such as; digitalis for which there is a struggle in estimating or interpreting the therapeutic response or toxic effects. Digitalis produces nausea and vomiting in digitalis toxicity as well as in congestive heart failure when used at therapeutic dose level.
- Therapeutic drug monitoring is also important to detect the changes in pharmacokinetic parameters of drugs in certain patients due to disease or any influence condition.
- TDM is very helpful for drugs that show saturable metabolism like Phenytoin.
- TDM is used for those drugs that have poorly defined the end point or are difficult to predict the clinical effect. For example: immunosuppressant drugs.
- Therapeutic drug monitoring is an important tool to monitor patient compliance but the major limitation is that it is costly and generally used in clinical trials only.
- Therapeutic drug monitoring is useful for those drugs whose therapeutic effects cannot be readily assessed by clinical observation. There is variation in plasma concentration of similar drugs in different variables in such cases TDM is an important tool to analyze drug concentration.
- Therapeutic drug monitoring indicating to the established relationship between the concentration of drugs in plasma and its therapeutic or toxic effects.
- Therapeutic drug monitoring is important for those drugs which follow non-linear kinetics.
- Therapeutic drug monitoring is important to investigate the unexpected lack of efficacy.
- TDM is indicated in renal disease: There is an alteration in plasma concentration of drug as alter in the dose of the drug. This relationship is affected by renal disease. In which high plasma concentration is associated with a renal impairment which leads to toxicity even in small increases in the dose of the drug. It is mostly seen with the drug which has a narrow therapeutic index such as; in the case of digoxin, lithium and aminoglycoside antibiotics.
- Drug interactions: There is a need to monitor the therapeutic concentration/response of drugs when there is concurrent administration of more than two drugs. It is essential because concurrent administration of drugs may alter the relationship between dose and plasma concentration. For example, the administration of thiazide increases the plasma concentration of lithium.
- Therapeutic drug monitoring is useful for the diagnosis of suspected toxicity and decides for the case of drug abuse.
- TDM is also used in guiding the purpose for withdrawal of drug therapy.
Need of Therapeutic Drug Monitoring
- There is an indication of TDM if the consequences of overdosing and underdosing are serious.
- TDM is indicated if there is a small difference between a therapeutic and toxic dose range.
- TDM is indicated if there is a certain change in the physiologic state of the patient that may unpredictably influence the circulating drug concentrations.
- TDM is indicated because of drug interaction in such cases where the patient is on more than two drugs.
- There is a need for TDM to establish a therapeutic regimen in several physiological conditions like; pregnancy, neonate, children, elderly; and pathological conditions such as renal disease, hepatic disease, etc.
- There is a need for TDM when there is an unexpected lack of efficacy or toxicity.
- TDM helps in monitoring patient compliance.
Limitations of Therapeutic Drug Monitoring:
- TDM is unnecessarily performed for a wide therapeutic range of drugs.
- TDM is also unnecessarily or does not need to perform for those drugs whose pharmacological effects can be clinically quantified.
- It is not applicable for those drugs that follow linear kinetics.
- The clinical outcome cannot be correlated to either dose or plasma concentration for certain drugs.
Drugs that are not suitable for TDM:
- TDM is not suitable for those drugs which have a wide therapeutic index.
- In concerned with toxicity which is not a realistic concern such as for Penicillin.
- TDM is not suitable for those drugs whose effects can be estimated by functional laboratory tests like anticoagulants.
- It is not suitable when the plasma concentration of the drug cannot predict with relation to its effects. For example- Anticoagulants.
- It is not suitable when the relationship of the response of drugs is undefined. ExampleAntidepressants.
Factors Affecting the Therapeutic Drug Monitoring
Following are the variables that affect the outcomes of TDM. While these factors get varies from drug to drug.
Following are the major sources of the variability in the pharmacokinetic parameters that results in the alteration in the therapeutic response thus may contribute to the discrepancy in the interpretation of results of TDM.
- There is lack of patient compliance leads to insufficient plasma drug concentration to achieve an optimum therapeutic effect.
- There is the influence of different ages such as; neonates, children and elderly on various pharmacokinetic parameters which result in alteration in the therapeutic response as well as plasma drug concentration.
- According to gender and the condition of pregnancy, alteration in the physiological parameters occurs which leads to variability in the pharmacokinetics of the drug.
- There is also the influence of various pathological/disease conditions such as; hepatic, renal, and respiratory on the pharmacokinetic properties of the drug. Thus, it may cause difficulty in the estimation of TDM.
- Drug Interactions: This is a special issue, in which one drug affects the pharmacokinetics as well as a pharmacodynamic profile of other drugs which results in alteration in the response of the drug which causes a discrepancy in the TDM estimation. Many practitioners prescribed alternative systems of medicine such as; ginseng, liquorice, tannic acids, plantain, hawthorn and kyushin, which has documented drug interaction with many modern systems of medicine i.e. allopathy medicine which resulted in the alteration in the plasma concentration and therapeutic response. Thus, this issue should be considered while interpretation of TDM results.
- Other factors such as; environmental influences also affect the therapeutic response of drugs through altering the pharmacokinetic profile.
There is a need to use proper analytical methods for estimating the TDM. It is very important to consider the sensitivity and specificity of the test method. For example- TDM is not suitable for monitoring of anticoagulant effect which can be effectively estimated by using functional laboratory tests.
Time of Sampling:
Drug therapy can be optimized by using therapeutic drug monitoring by applying optimum sampling strategies. In this strategy, the sampling time is determined to produce the most accurate estimation of pharmacokinetic parameters and exposure indices. There is variation in the plasma drug concentration at each time interval and with dosing duration. Thus, the selection of time of sampling is a very critical process that affects the outcome of TDM.
In such cases, trough values are mostly used for sampling time, in which there is less variable drug concentration observed and this value is often used to establish a therapeutic range of drugs.
Type of Sampling:
There is a need to give additional consideration to the type of sample tested because the use of some anticoagulants may affect the TDM of a particular drug. For example, the use of heparin affects the TDM of lithium.
There is an alteration in the protein binding capacity of the drug in various pathological conditions and during drug interactions which resulted in a change in the concentration of bound and unbound drugs, which leads to loss of efficacy or drug toxicity. Thus, there is a need to consider the effect of protein binding while interpreting the results of TDM.
In many TDM cases, the plasma concentration of a primary drug is taken into consideration for assessing the therapeutic response of the drug but it is also necessary to consider the active metabolites which are though not measured by considering they may not contribute to the therapeutic response. For example- The therapeutic response of primidone is measured by estimating the plasma concentration of phenobarbitone which is an active metabolite. In such cases, there is a need to measure both the parent drug and as well as metabolites to establish a complete picture of the relationship between the total plasma concentration of the active compounds and the therapeutic effect in a patient.
In the interpretation of TDM results, the clinician should also consider the other variables/features such as; smoking, drug formulation and circadian effect, use of an alternative system of medicine that may affect the relationship between the plasma concentration and the clinical effect.
Indian Scenario of Therapeutic Drug Monitoring
In India, therapeutic drug monitoring was introduced in the 1980s and it has seen growing continuously. In India, there is the involvement of two main departments in TDM services; first is by large teaching hospital where the services are provided by the clinical pharmacology department and the other is private sectors who are dealing with the estimation of the drug by the clinical biochemist department.
From 1980 to 1990, the TDM service began in a small way with the use of simple high-performance liquid chromatography techniques by one or two research assistants in teaching hospitals for drug analysis. After decades of 1990, there is an increase in the TDM services and growth of laboratories with an increase in the staff and instrumentation facility in the TDM.
Every year there is improvement in the TDM services indicated by an increase in a greater number of drugs and the number of requests for TDM. Computerization and the availability of simple techniques/methods with the use of highly sophisticated instrumentation have made this service available even in rural areas. Despite this, there are also increased in the service center, while the TDM remains within the boundaries of the department of clinical biochemistry which are only associated with ‘drug estimation but does not participate in the monitoring and interpretation service. Only in a few places/centers, there is the existence of an ideal team of TDM which comprises a clinical pharmacist, clinical pharmacologist, and analytical scientist. In addition, there are limited data are obtained and physicians are not fully trained for the interpretation of TDM results.
Today TDM service is also available for the outpatient clinic which is sometimes run twice a week with huge handling of new cases as well as old cases. There is also a sufficient staff of pharmacists, technicians, and medical officers are involved in the collection of history, sample collection, and drug analysis. While there are separate senior clinical pharmacologist teams involved in the monitoring services as well as they are associated with providing advice on dosage adjustment, managing patient compliance, and identification of adverse reactions. In most of the TDM centers, there is the use of automated equipment and ready-to-use kits for the estimation of drugs and metabolites by using fluorescence polarization (FPIA) and enzyme-mediated immunoassay (EMIT) techniques. Advantages here are short turnaround times and ease of use.
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