Therapeutic Drug Monitoring

History:

• The science of Therapeutic Drug Monitoring (TDM)grew out of the recognition that certain drugs have a narrow therapeutic range.
• The concentration above the upper limit of the range, the drug can be toxic, and below the lower limit range, the drug is ineffective because all patients will not have the same response, hence clinical pharmacology departments.
• TDM studies were initiated to determine the clinical value of TDM testing and in certain instances, clear clinical value was demonstrated.

Definition of Therapeutic Drug Monitoring

Therapeutic drug monitoring is defined as the use of drug concentration in the body fluids as an aid to the management of patients receiving drug therapy for the cure, alleviation or prevention of disease OR TDM is a process in clinical pharmacology that specializes in measuring the concentration of certain drugs in the body fluids and clinically interpreting is to obtain useful and often life-saving information.

Drug monitoring is that process that ensures that a patient is treated with the least expensive, most effective therapeutic agent, in a manner that will maximize efficacy and minimize side effects.TDM is done only for a few selected drugs with a narrow therapeutic range where the challenge is to avoid both sub-therapeutic and over-toxic doses.

• It is a tool that can guide clinicians to provide effective and safe drug therapy to the individual patient.
• It is important when the dose cannot be titrated against response Ex INR, cholesterol and the drug is being used to prevent infrequent occurrences Ex Epilepsy.

Objectives And Purposes

• To attain rapid and safe concentration of drug in plasma within the desired therapeutic range in order to provide the safest approach to optimal drug therapy.
• Coordinate clinical pharmacology, pharmacology, pathology, chemistry, toxicology, analytical chemistry, and medicines.
• To remove empirical trial and approach.
• To confirm effective concentration, to investigate unexpected lack of efficacy, to check compliance, to avoid toxic concentration, limited in toxicology.

Need For Therapeutic Drug Monitoring

The number of studies in recent years has pointed to a need for more intensive monitoring of drug therapy. These reports have identified the following reasons.

a) Polypharmacy:

The overuse of medications by patients and overprescribing by physicians have repeatedly been cited as causes of drug-induced disease.

Example:

1. Hospital patients- 8-10 drugs receive.
2. Nursing home patients-5-9 drugs receive.
3. Ambulatory patients- 5-6 drugs receive.

Multiple drug therapy increases drug-induced disease, hence it is mandatory that patients receive only what is necessary.

b) Adverse Reactions:

• Adverse drug reactions of drugs are a major public health problem and they account for 3- 5% of admissions to hospitals.
• More careful prescribing and monitoring of 60-80% of adverse reactions can be prevented.

c) Medication Errors:

• Hospitalized patients usually face problems with by nurse’s wrong drug administration or pharmacist in dispensing multiple doses.
• Unit dose drug distribution significantly decreases medication errors.

Non-Compliance:

• Prescribed therapy also represents major public health problems.
• Non-compliant patients can be identified and appropriate education is given.

Basic Principles of Therapeutic Drug Monitoring

• Measurement of patient’s serum or blood drug concentration (SDC) taken at appropriate time after drug administration.
• Knowledge of pharmacological and pharmacokinetic profiles of the administered drugs.
• Knowledge of relevant patient profiles like demographic data, clinical status, laboratory, and other clinical investigations.
• Interpretation of SDC after taking into consideration all of the above information and individualizing drug regimen according to the clinical needs of the patient.

Factors The Therapeutic Drug Monitoring

1. Patient demographics
2. Patient Compliance
3. Individuals capacity to distribute/metabolize/excrete the drug
4. Genetic factors
5. Concomitant disease, Tropical disease, and nutritional deficiencies
6. Alternative system of medicine
7. Ethnic differences and extrapolation of the normal range
8. Alcohol and tobacco use
9. Quality of medication and generic formulation
10. Control of drug assay
11. Medication or sampling errors
12. Laboratory errors
13. Cost-effectiveness.

1. Patient demographics:

The patient’s age, sex, body weight, and ethnicity should be considered when interpreting TDM results. Age, sex, and lean body weight are particularly important for really cleared 3 drugs as knowledge of these allows calculation of creatinine clearance. Ethnicity may be an important consideration for TDM of some hepatically cleared drugs.

2. Patient Compliance:

If the concentration of the drug is lower than expected, the possibility of non-compliance should be considered before a dose increase is recommended. The simplest way to check for non-compliance is to ask the patient in a non-judgmental way about their compliance.

3. Individuals capacity to distribute/metabolize/excrete the drug:

Pharmacokinetics is the study of what the body does to a drug after administration. It is divided into four categories: Absorption, Distribution, Metabolism, and Excretion.

1. Absorption: Absorption refers to the ability and process of a dosage reaching the bloodstream. There are different routes of drug administration. The most common are Oral, Intramuscular, Subcutaneous, Rectal, etc.
2. Distribution: Once the drug is absorbed, a certain drug concentration is reached in the body. The volume in which the drug is distributed is a product of the drug’s dose divided by the plasma concentration.
3. Half-life information is used to determine the correct drug dose required to attain the desired therapeutic range.
4. Metabolism: Drug metabolism occurs primarily in the liver, and also in the GI tract. Drug metabolism is the process by which the body breaks down and converts the drug into active chemical substances.
5. Excretion: Drug excretion from the body occurs through the kidneys, or fluids excreted through the lungs, GI, or skin. Renal dysfunction reduces drug clearance and may contribute to drug accumulation and increased risk of adverse drug effects.

4. Genetic factors: They play an as yet poorly defined role in therapeutic drug monitoring, as is the case of the poor ability of some racial groups to acetylated drugs.

5. Concomitant disease, Tropical disease, and nutritional deficiencies:

Ill health is a serious problem impeding progress in most developing countries. This includes diseases highly prevalent in these countries such as infections, diarrhea, worm infestations, tuberculosis, pneumocystis necrosis, and nutritional deficiencies, plus a higher proportion of patients with diabetes and AIDS. Patients often seek treatment late in their illness.

6. Alternative system of medicine:

• India is unique in having at least three systems of medicine coexisting with ‘Western’ medicine (allopathic); ayurveda, homeopathy, and unani. Some allopathic practitioners often co-prescribe medicines from alternative systems, particularly for chronic disorders.
• Our own experience in the TDM clinic identified an interaction with ‘shankhapushpi’ an ayurvedic preparation purported to be an anti-epileptic (phenytoin) and memory enhancer.

7. Ethnic differences and extrapolation of the normal range:

• The fact that interpopulation variations in drug pharmacokinetics can result in higher or lower plasma drug concentrations is well known. For example, the metabolism of phenytoin via para-hydroxylation is subject to wide inter-individual variation. Man has reported that the 4 effective anticonvulsant dosage may be lower in Indians than in Europeans while other authors have indicated that ethnic differences may have a significant influence on the plasma clearance of phenytoin.

8. Alcohol & Tobacco use:

• Chronic use of alcohol has been shown to cause non-specific hepatic microtonal enzyme induction, resulting in increased clearance and decreased serum concentrations of hepatically cleared drugs such as Phenytoin.
• Cigarette smoking increases the hepatic clearance of theophylline and patients who have recently stopped smoking may have unexpectedly high theophylline concentrations.

9. Quality of medication and generic formulation:

Worldwide, there is an increasing prescription of generic products which are actively promoted by health authorities for economic reasons. The prescription of generics by primary care physicians has risen in England from 35% in 1985 to 55% in 1995. Quality of products (drug content, bioavailability) is important, especially for drugs with a narrow margin of safety which is just those drugs for which TDM is relevant.

10. Quality control in drug assays:

For TDM programs, quality control is vitally important, and in developing countries, there are hardly any procedures for laboratory accreditation or external quality control. In India, one center in Southern India offers an external quality control program (for biochemical tests).

11. Medication or sampling errors:

In cases where the TDM result is incompatible with drug administration records, the possibility of a medication or sampling error should be considered. For Example, the drug may have been given to the wrong patient, or blood may have been mistakenly drawn from a patient in a neighboring bed.

12. Laboratory errors:

• If a laboratory error is suspected, the laboratory should be contacted and asked to repeat the assay.
• Alternatively, a new blood sample can be drawn and sent to a different laboratory for assay.

13. Cost-effectiveness:

Rapid and cost-effective measurement of most drugs for which TDM is indicated can be achieved using commercial kits run on automated analyzers using a number of different methodologies including fluorescence polarisation immunoassay.

Therapeutic Drug Monitoring Process

1. The decision to request drug level
2. Biological sample
3. The request
4. Laboratory measurement
5. Result communication by laboratory
6. Clinical interpretation
7. Therapeutic Management

TDM is a multidisciplinary function and requires collaboration and good communication between scientists, clinicians, nurses, and pharmacologists.

1. The decision to request drug level:

• To assess therapy following the change in dosage.
• Lack of response/compliance.
• Change in the clinical state of the patient.
• Suspected toxicity.
• Potential drug interactions due to concomitant medications.

2. Biological sample:

• After the decision is taken, the biological sample is collected for the measurements.
• Usually, Serum or plasma samples are collected for TDM.
• Blood samples should be collected once the drug concentration has attained a steady state (SS) (minimum 5 half-life).
• Approximately SS may reach earlier if a loading dose has been administered.
• However, drugs with long half-lives should be before SS is achieved to ensure that individuals with impaired metabolism or renal excretion are not at risk of developing toxicity at the initial dosage prescribed.
• If toxicity is suspected the concentration should be measured as soon as possible.
• Blood samples should be collected in the elimination phase rather than absorption/distribution phases.
• Usually, blood samples are collected at the end of the dosage interval.
• If given as IV infusion peak concentrations are also measured (After 30 mins cessation of IV infusion).
• Usually, drug concentrations are monitored in venous blood, serum, or plasma and it’s important that the appropriate matrix is assayed.
• Errors in the timing of samples are likely responsible for the greatest number of errors in interpreting the results Ex: Digoxin at least after 6 h. Lithium- at least after 12 h.

3. Requisition proform:

• Patient demography (Age, sex, ethnicity).
• Timing of sample.
• Dosage regimen.
• Co-medication, if any indication for monitoring.
• PK and therapeutic range of drugs.
• Commonly measured in TDM is suspected toxicity in high concentrations.

4. Measurement in the laboratory:

• Drug assay should be performed within a clinical time given.
• The selected assay procedure should be validated.
• The assay procedure should be evaluated with external quality assurance.
• Senior laboratory staff should check results in light of clinical requests.
• Usually, the results of the assay should be available to the clinician before the results are given.
• The analytical methodology employed should ideally 1. Distinguish between compounds of similar structure-unchanged drugs and metabolites.2. Detect small amounts. 3. Be simple enough to use a routine assay. 4. Be unaffected by other drugs administered simultaneously.
• Various analytical techniques are spectrophotometry and fluorimetry. Thin layer chromatography (TLC), HPLC, GLC, Radio immune assay (RIA), Enzyme immune assay, and Fluorescence polarization immunoassay (FPIA).

5. Communication of results by laboratory:

• The results are communicated as quickly as possible once it checked by the senior laboratory personnel (Within 24 hours).
• Drug concentrations measured are reported in mass or molar ratio units.
• Usually, mass units are commonly used to interpret back dose calculation.
• Results should clearly state the therapeutic concentration range for drug assayed.

6. Clinical interpretation:

• Clinical interpretation can ‘add value’ and convert ‘therapeutic measurement service’ into ‘TDM service’.
• Relating a drug concentration to a published therapeutic range is not an adequate interpretation.
• Concentration must always be interpreted in the light of clinical response, individual patient demographics, and dosage regimen used.
• Therapeutic ranges are available but should only be used as a guide.

7. Therapeutic management:

• The clinician caring for a patient will modify a drug dosage regimen with little available information.
• Physicians usually accept and implement the recommendations of the TDM team.
• Hence, a member of the TDM team with appropriate clinical expertise should be available to conduct a successful TDM.

Indian Scenario For Therapeutic Drug Monitoring

• TDM service began in a small way in 1988 with a single HPLC and one research assistant in a tiny laboratory tucked away in a corner of an 1800-bed teaching public hospital. In 1992 reported experiences in the management of epilepsy.
• Even though TDM has grown itself into an unavailable part of the health care system and the position has gained due respect and support from the patients and medical professionals 7 equally, it seems that the Indian government officials are turning a blind eye to these developments taking place globally.
• In India, there are no regulatory guidelines for having a qualified clinical pharmacist in Indian hospitals.
• Another point to ponder is that even if regulations are framed in due course, will there be enough pharmacists with the necessary experience to work in the hospital setup as the current trend is the mass migration of pharmacists to the pharmaceutical industries?
• The main reason for this phenomenon is the lack of recognition of the post of clinical pharmacist at the regulatory level.
• The students after completion of their studies are either forced to take up a job in an industry or move into academics, the last option being to seek jobs abroad where the pharmacy profession is well received.
• Though the situation is gradually changing as students are recognizing the scopes of the profession beyond the traditional limits the prospect of serving such a huge, mostly uneducated, exploding population is a daunting challenge.
• Many pharmacy schools have started to understand the importance of pharmacy practice and are including it in the four-year syllabus of the UG course.
• Another positive sign is the introduction of Pharm D courses in a handful of institutions in India. Its six-year doctoral course including a year rotating internship aimed at creating competent clinical pharmacists for the hospital in India.
• The current scenario can only be brought under control by the timely intervention from the government authorities, as a nurturing regulatory environment is a necessity for the development of health professions like pharmacy and also with the collaborative efforts from the academic leaders and government authorities.
• TDM has the bright potential to grow into a very strong pharmacy wing in the health care system, particularly in a country like India with such a strong medical foundation and dynamic and varied population waiting to receive any additional patient services.
• Consistency between the educational programs and the practice environment is a very important factor in achieving high-quality and superiorly trained clinical pharmacists.
• There should be a constructive collaboration between the individual pharmacist, academic leaders, and hospital administration to provide adequate information technology, equipment drug information resources, and sites for training and resources.
• The only way that clinical pharmacy can grow unhindered in India is by gaining the support and acceptance of the entire medical profession and community as a whole, and this in turn sets in the hands of the present-day pharmacy students and pharmacy professionals.

Applications of Therapeutic Drug Monitoring

1. Monitoring of certain drugs with increased efficacy and decreased incidences and side effects Ex theophyllin and methotrexate.
2. Used in developing dosing protocol this will avoid non-optimum initial therapy.
3. It provides additional input in pharmacotherapy.
4. Monitoring encourages professional interaction between members of the health care teams and physicians and pharmacists.
5. Monitoring determines the safety of the dosage regimen.
6. It provides an opportunity for clinical pharmacists to excel in therapeutic challenges.

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