The science of therapeutic drug monitoring 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 toxic and below the lower limit range, the drug is ineffective because all patients will not have same response, hence clinical pharmacology departments.
TDM studies initiated to determine the clinical value of TDM testing and certain instances clear clinical value was demonstrated.
TDM is defined as the use of drug concentration in the body fluids as an aid to management of patients receiving drug therapy for the cure, alleviation or prevention of disease OR TDM is a process in clinical pharmacology which 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 which ensures that a patient is treated with least expensive, must effective therapeutic agent, in a manner that will maximise efficacy and minimize side effects. TDM is done only for few selected drugs with narrow therapeutic range where the challenges is to avoid both sub therapeutic and over toxic dose.
It is a tool that can guide clinicians to provide effective and safe drug therapy in 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.
To 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 following reasons.
The overuses of medications by patients and over prescribing by physician have repeatedly been cited as cause of drug induced disease.
Ex; Hospital patients- 8-10 drugs receive.
Nursing home patients-5-9 drugs receive.
Ambulatory patients- 5-6 drugs receive.
Multiple drug therapy increases the drug induced disease, hence it is mandatory that patients receive only that are absolutely necessary.
- ADVERSE REACTIONS:
Adverse drug reactions of drugs are a major public health problem and it accounts for 3-5% admitting to hospitals.
More careful prescribing and monitoring 60-80% adverse reactions can be prevented.
- MEDICATION ERRORS:
Hospitalised patients usually face problems with by nurse wrong drug administration or pharmacist in dispensing multiple doses.
Unit dose drug distribution significantly decreases the medication errors.
Prescribed therapy also represents major public health problems.
Non compliant patients can be identified and appropriate education is given.
BASIC PRINCIPLES OF TDM
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 relevant patient profile 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 TO BE CONSIDERED DURING 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 & 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 renally cleared
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. Absorption: Absorption refers to the ability and process of a dosage reaching the blood stream. There are different routes of drug administration. The most common are: Oral, Intramuscular, Subcutaneous, Rectal etc 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. Half-life information is used to determine the correct drug dose required to attain the desired therapeutic range. Metabolism: Drug metabolism occurs primarily in the liver, and also in the GI tract. Drug metabolism is the process in which the body breaks down and converts the drug into active chemical substances. 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: It plays 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, neurocystic cercosis 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 the 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
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 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 centre in Southern India offers an external quality control program (for biochemical tests). 11. Quality control in drug assays: 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 TDM is a multidisciplinary function and requires collaboration and good communication between scientists, clinicians, nurses and pharmacologists. 1. Decision to request drug level: To assess therapy following change in dosage. Lack of response/compliance. Change in clinical state of patient. Suspected toxicity.
Potential drug interactions due to concomitant medications. 2. Biological sample: After decision is taken, 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 steady state (SS) (minimum 5 half-life). Approximately SS may reach earlier if a loading dose has been administered. However, drugs with long half-life should monitor before before SS is achieved to ensure that individuals with impaired metabolism or renal excretion are not in the risk of developing toxicity at the initial dosage prescribed. If toxicity suspected the concentration should be measured as soon as possible. Blood sample should be collected in 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-atleast after 6 h. Lithium- at least after 12 hours 3. Requisition proform: Patient demography (Age, sex, ethnicity). Timing of sample. Dosage regimen. Co medication, if any indication for minitor. PK and therapeutic range of drug. Commonly measured in TDM is suspected toxicity in high concentration.
4.Measurement in laboratory: Drug assay should be performed within a clinical time given. Selected assay procedure should be validated. Assay procedure should be evaluated with an external quality assurance. Senior laboratory staff should check results in light of clinical request. 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 drug 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, Fluorescence polarization immunoassay (FPIA). 5. Communication of results by laboratory: The results communicated as quickly as possible once it checked by the senior laboratory personnel (With in 24 h). Drug concentrations measured are reported in mass or molar ratio units. Usually mass units are commonly used to interpret back dose calculation. Results should be 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’. By 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 in little of available information. Physicians usually accept and implement recommendations of TDM team. Hence, 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 trucked away in a corner of an 1800 bed teaching public hospitals. In 1992 reported experiences in the management of epilepsy. Even though TDM has grown itself into an unavailable part of health care system and the position has gained due respect and support from the patients and medical professionals
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 the Indian hospitals. Another point to ponder is that even if regulations are framed in due course, will there is enough pharmacists with necessary experience to work in the hospital set up as the current trend is the mass migration of pharmacist 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 professions 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 daunting challenge. Many pharmacy schools have started to understand the impotence 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 one year rotating internship aimed at creating competent clinical pharmacist 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 academics 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 foundations 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 to achieve high quality and superiorly trained clinical pharmacist. There should be constructive collaboration between the individual pharmacist, academic leaders, and hospital administration tp 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 as by gaining the support and acceptance of the entire medical profession and community as 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 the increased efficacy and decrease incidences and side effects Ex theophyllin, methotrexate. 2. Used in developing dosing protocol this will avoid non-optimum initial therapy. 3. It provides additional input in pharmacotherapy. Monitoring encourages professional interaction between members of the health care teams and physician and pharmacist. 5. Monitoring determines the safety of the dosage regimen. 6. It provides an opportunity for clinical pharmacist to excel in therapeutic challenges