Therapeutic Drug Monitoring
Anantha Naik Nagappa and Uday Venkat Mateti
Manipal College of Pharmaceutical Sciences, Manipal University, Manipal-576104
What is Therapeutic Drug Monitoring (TDM)?
Therapeutic drug monitoring is the maintaining the drug concentrations within the therapeutic window. While giving treatment the measurement of drug concentration is a very important parameter which has direct impact on safety and efficacy. The drug levels in the blood are going to change depending on their Pharmacokinetic/Pharmacodynamic (PK/PD) nature, physicochemical properties of the drug, physiological factors, and formulation factors. It is the rule of the thumb that the drug concentrations always maintained within therapeutic window. TDM is an active process of administering drug based on blood concentrations so that it remains above minimum therapeutic concentrations and below minimum toxic concentrations.
How the TDM services are delivering
The TDM is always estimated empirically for drugs with large margin of safety whereas drugs with low therapeutic index need to be administered cautiously. For this timely measurement of blood concentration of the drug is the established norm. The TDM is usually required by patients that are on serious condition. The blood samples at intervals matching their established half-life data are withdrawn and subjected to analysis to determine the concentrations. Based on the concentrations the dose adjustment is done. There is a need of TDM laboratory to be established in the hospital may be along with biochemistry laboratory or pharmacy practice department. The services can be rendered on demand by a healthcare professional.
Who should be heading a TDM unit in hospital?
The TDM is a service unit in the hospital which is based on study of drug concentrations in blood. The professional who is having basic knowledge and skills not only in health sciences but also in drug analysis. The appropriate professional to head TDM is a pharmacist with expertise in drug analysis.
What are the basic requirements of TDM laboratory?
The TDM laboratory should have human resources to handle the samples and subject them to various analytical and biochemical (based on ELSA for warfarin INR values). The instruments required are flame photometer for Lithium estimation. HPLC with UV and IR, there can be also LC-MS/MS with these equipment's one can give services of the most hospital requirements of TDM.
What is the criterion for justification of TDM?
The drugs carry a risk depending on therapeutic index. A drug with low therapeutic index and capable of causing harm to the patients even if little excess dose is administered. In order to protect the patients from the drug induced injuries. It becomes mandatory to measure the drug concentrations and keep them much below minimum toxic concentration to ensure patient safety. The efficacy of the treatment depends upon the blood concentrations always above the minimum effective concentrations. If the concentrations falls below their can be failure of therapeutic outcome.
Why certain drugs like Digoxin, Lithium and Phenytoin are ideal candidates for TDM?
The drugs mentioned above have a narrow therapeutic index which means. The difference between the minimum therapeutic concentration and minimum toxic concentration is very less. For example the normal therapeutic range of the drugs like Digoxin (0.8-2 ng/mL), Lithium (0.4 to 1.0 mmol/L), and Phenytoin (10 to 20 mcg/ml)
What is the process of TDM?
The periodic blood samples were obtained and were treated with anticoagulants. Further with appropriate coding were sent to TDM center. After receiving the samples the pharmacist In-charge will prepare the sample for analysis using the appropriate established protocol. After analysis the drug concentrations were calculated and are communicated to the physicians. The samples after TDM process are maintained for legal or re-verification of the results at least till the patient is discharged.
Explain the handling of samples for TDM services?
The TDM samples of biological fluid origin and liable for microbial growth. They are also blood products which can clot. Hence treatment with heparin and ascetic precautions are basic requirements for handling samples. Specific requirements depend upon drug stability and degradation profile of the molecule. The cold temperature and cold chain supply management shall ensure adequate sample quality in the point of withdraw to the laboratory for analysis.
What are the analytical issues in TDM?
The TDM is a blood concentration analysis which is subjective experimental variation and also protocol based errors. The instrumentation is used in the TDM needs to be validated for accuracy and reproducibility. There should be a pilot run with known concentration of the drug along with the sample analysis. This would help in identifying the protocol based errors and test-retest approaches also need to be adapted.
What is the role of TDM in emergency cases of poisoning?
In the emergency cases of poisoning the patient condition is actively progressing death based on the concentration of the active poison and its metabolites. The need for antidote is very much important to arrest the poisons substance causing harm to the patients. Although antidote administration is based on extent of poisoning it becomes very important to monitor the levels of poison or antidote which assist the physician in estimating the time of administration and amount of antidote to be administered.
How the justification for the expenditure of TDM?
There are several pharmacoeconomic evaluations of TDM which establishes the contribution of TDM for saving the patient life along with improved quality of life. Cost evaluation of therapeutic drug monitoring of gentamicin at a teaching hospital in Malaysia. The patient who is primary sponsor of the treatment direct or indirect is likely to demand quality healthcare services with leads to risk.
Who has to pay for TDM services?
The beneficiary of TDM is patients themselves and TDM services are established for the sake of providing risk free and safe medication while treating them. The expensiveness can be built to the patient himself if he is paying for his own treatment. In case the patient is covered by healthcare insurance the TDM expensive can be considered as diagnostics. The TDM services also are subsided by government if the scheme for the treatment clearly has listed reimbursement policy for TDM. TDM is an essential neither optimal nor a luxury. Hence the TDM services are essential in some of the disease condition and also drug monitoring.
How the TDM affect the outcome of the therapy?
The clinical outcomes are directly dependent on evidence for treatment. In TDM there is a continuous monitoring of drug levels on the times scale. The blood samples from the patients are withdrawn and the results of the analysis indicating the drug concentrations of the blood would be great help for the clinical practice. Evidence medicine practice becomes a reality with the knowledge of blood levels of the drug in a patient.
How the TDM is going to ensure the patient safety?
The patient safety is endangering for several causes and reasons in treatment. One of the major cause may be due to excessive dose are due to inadequate amount of drug in the patient. The TDM gives an insight on PK/PD handling of the drug by the patient biological system.
What are the skill areas required for managing the TDM services?
The clinical pharmacists should be able to understand and assess the individual handling of the drug by the patient biological system. For example some drugs are not at all metabolized in the blood. Identification and updating the physician about the specific nature of the drug molecule may be special area of TDM services. Pharmacist being experts in drugs should be able to deliver the drug levels. So that the information is timely available for the physicians. Identification of the patient's symptoms for those drugs becomes anther skill area which comes handy in understanding the level of seriousness of the patient. The communication like reading, writing and arithmetic are essential.
What is the role of TDM in treating infectious diseases?
The pathology of infectious diseases demands control of spreading of infection and also giving relief to the patients. The infectious condition is counted not only by innate ability of the individual patient but also the strength of bacteria to counter this immunity. In case of missed doses or sub-therapeutic levels of antibiotics. There are chances of development of antimicrobial resistance and poor outcomes. Hence the TDM ensures freedom from above consequences.
What is the role of TDM in treatment of Cancer?
The cancer treatment involves the drugs and procedures which have an extensive toxicity endangering the patient safety. The narrow therapeutic index and side effects of anticancer treatment makes it all the important to be careful while administering the drugs and procedures. Moreover the anticancer drugs especially bio therapeutic agents are highly expensive. Hence the TDM concept may aid to optimizing the expenditure of the treatment.
How TDM can be useful in treatment with expensive biological drugs?
The new drugs introduced in recent years are big molecules like biological belonging to monoclonal antibodies and cytokines and molecules prepared by recombinant DNA technology. Many of these molecules have short duration of action hence need to be administered 4-6 times a day. The segregate TDM biomarker can be used to monitor the TDM of biological which are of very minute concentrations in the range of nano picogram. In order to optimize the outcomes and cost of treatment the TDM can be utilized
What are the indications for requesting plasma drug concentrations?
The plasma drug concentrations are important in case the drug has a narrow therapeutic window, is not following normal PK/PD profile (for example if drug is following zero order kinetics or nonlinear kinetics). It also becomes necessary in ICU patients to maintain the vital parameters in control and to manage the patient who has become critically ill. The plasma drug concentration data is useful in personalizing the dose at that time and minimizing the harmful effect of the drug due to inappropriate drug concentration for the patients.
What are the advantages of TDM?
The TDM is direct evidence which has practical application in patient care. The monitoring of the drug levels are usually observed for expected clinical outcomes. The TDM optimizes the requirement of the amount of the drug and gives rational to administer the amount of drug. In case the drug being very expensive it saves money on cost of medicines as the excess drug administration becomes evident and appropriate amount being administered. The TDM is based on PK/PD profile of the drug and patient is the correct approach.
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