**3. General principles of Therapeutic Drug Monitoring (TDM)**

A basic tenet of clinical pharmacology is that the pharmacologic activity of an exogenously administered agent is related to the free drug concentration available at its receptor or ligandbinding site. A mayor underlying hypothesis in clinical pharmacokinetics is that the concen‐ tration of the agent in blood, serum or some other measurable compartment is related to the concentration of free (or non-bound) drug at its effector site [50]. Drugs are administered to achieve a therapeutic objective. Once this objective is defined, a drug and its dosage regimen are chosen for the patient. Drug therapy is subsequently managed together with steps required to initiate therapy, this management is usually accomplished by monitoring incidence and intensity of both therapeutic and toxic effects.

#### **3.1. Therapeutic range**

The therapeutic range (therapeutic index) is the ratio between the toxic dose and the thera‐ peutic dose of a drug. The closer this ratio is to 1, the more difficult the drug is to use in clinical practice. The therapeutic index for immunosuppressant drugs is very low, whereas that for amoxicillin is extremely high. Clinical use of drugs with a narrow therapeutic index has led to the monitoring of drug concentrations in patients – therapeutic drug monitoring – in which the plasma concentration of a drug is measured and the dose adjusted to achieve a desired therapeutic drug concentration. Generally defined as the range of drug concentrations associated with maximal efficacy and minimal toxicity, there is currently no standard defining an acceptable level of toxicity or efficacy, nor are there consistent procedures used to establish a therapeutic range [51].

In general, a therapeutic range should never be considered in absolute terms, as it represents no more than a combination of probability charts. In other words, a therapeutic range is a range of drug concentrations within which the probability of the desired clinical response is relatively high and the probability of unacceptable toxicity is relatively low [52].

Since the development of the range is probabilistic in nature, a concentration that is within the "therapeutic range" for a given drug does not exclude the possibility that signs and symptoms of toxicity experienced by an individual patient are related to the monitored drug. A concen‐ tration outside of the range also does not indicate that a patient will experience toxicity or reduced efficacy; however, the likelihood of either is certainly lower [51]. It is important to recognize that the therapeutic range is not necessarily valid outside of the population used to establish it. This is particularly critical for immunosuppressive drugs, as most patients that are treated with these drugs receive additional immunosuppressive agents. A change in dosing of one drug may have a profound impact on the pharmacodynamic relationship of another. The nature of the transplanted organ (e.g., cadaveric versus living-related donor kidneys), age, and co-morbid illness can all have important influences on the pharmacodynamic response. The importance of these factors should not be ignored [51].

### **3.2. Interpretation of plasma drug concentration**

*2.8.1. Mechanism of action*

318 Current Issues and Future Direction in Kidney Transplantation

cellular immunity [1].

*2.8.2. Side effects*

Glucocorticoids lyse (in some species) and induce the redistribution of lymphocytes, causing a rapid, transient decrease in peripheral blood lymphocyte counts. To effect longer-term responses, steroids bind to receptors inside cells; either these receptors, glucocorticoid-induced proteins, or interacting proteins regulate the transcription of numerous other genes. Addi‐ tionally, glucocorticoid-receptor complexes increase IκB expression, thereby curtailing activation of NF-κB, which increases apoptosis of activated cells. Of central importance, key proinflammatory cytokines such as IL-1 and IL-6 are down regulated. T cells are inhibited from making IL-2 and proliferating. The activation of cytotoxic T lymphocytes is inhibited. Neu‐ trophils and monocytes display poor chemotaxis and decreased lysosomal enzyme release. Therefore, glucocorticoids have broad anti-inflammatory effects on multiple components of

Steroids are effective in reducing the incidence of acute rejection but are an important cause of morbidity and probably mortality. Moreover, they have adverse effects on cardiovascular risk factors such as hypertension, hyperglycemia, or hyperlipidemia, deleterious effects on

A basic tenet of clinical pharmacology is that the pharmacologic activity of an exogenously administered agent is related to the free drug concentration available at its receptor or ligandbinding site. A mayor underlying hypothesis in clinical pharmacokinetics is that the concen‐ tration of the agent in blood, serum or some other measurable compartment is related to the concentration of free (or non-bound) drug at its effector site [50]. Drugs are administered to achieve a therapeutic objective. Once this objective is defined, a drug and its dosage regimen are chosen for the patient. Drug therapy is subsequently managed together with steps required to initiate therapy, this management is usually accomplished by monitoring incidence and

The therapeutic range (therapeutic index) is the ratio between the toxic dose and the thera‐ peutic dose of a drug. The closer this ratio is to 1, the more difficult the drug is to use in clinical practice. The therapeutic index for immunosuppressant drugs is very low, whereas that for amoxicillin is extremely high. Clinical use of drugs with a narrow therapeutic index has led to the monitoring of drug concentrations in patients – therapeutic drug monitoring – in which the plasma concentration of a drug is measured and the dose adjusted to achieve a desired therapeutic drug concentration. Generally defined as the range of drug concentrations associated with maximal efficacy and minimal toxicity, there is currently no standard defining

bone metabolism, and may contribute to an increased risk of infection [1,48].

**3. General principles of Therapeutic Drug Monitoring (TDM)**

intensity of both therapeutic and toxic effects.

**3.1. Therapeutic range**

The process of selecting the most appropriate dosage regimen to achieve concentrations in a relatively narrow range may be complicated by unpredictable intrapatient and interpatient variability in the drug's pharmacokinetics. A sophisticated application of pharmacokinetic principles, incorporating prior and subsequent measures of drug concentration and effects, can improve the quality of one's predictions. Although a single "best" approach to using drug concentrations does not exist for every drug, it is imperative to realize that without a systematic approach to therapeutic drug concentration monitoring, drug concentrations may be uninter‐ pretable, unhelpful and potentially harmful. It thus becomes essential to recognize the key elements of clinical pharmacokinetics and pharmacodynamics, and to develop strategies to perform and use them most effectively [52].

There are a number of advantages to therapeutic drug monitoring that provide the clinician with clinically useful information. Plasma drug concentrations in conjunction with a thorough assessment of the patient's clinical status and the therapeutic goals to be achieved provide a means of successfully and rapidly individualizing a patient's therapeutic regimen to assure optimal benefits con minimal risk. Therapeutic drug measuring is only one part of therapeutic drug monitoring that provides expert clinical interpretation of drug concentration as well as evaluation based on pharmacokinetic principles. Expert interpretation of a drug concentration measurement is essential to ensure full clinical benefit. Clinicians routinely monitor drug pharmacodynamics by directly measuring the physiological indices of therapeutic responses, such as lipid concentrations, blood glucose, blood pressure, and clotting [53].

Anyone involved in the utilization of information derived from TDM must always bear in mind that the interpretation of plasma drug concentration must always be carried out in conjunction with an assessment of the clinical status of the patient. Therapeutic ranges should more correctly be described as optimal concentrations. According to the definition mentioned above, the therapeutic range (optimal concentration) of a drug is that concentration of drug present in plasma or some other biologic fluid or tissue that provides the desired therapeutic response in most patients. The severity of the disease process determines the amount of drug necessary to achieve a given therapeutic effect. Thus, it is quite possible that a patient may achieve the desired therapeutic effect at a plasma concentration well below the optimal range. Conversely, some patients will not achieve the desired therapeutic effect even when plasma concentrations are elevated into the toxic range. If the desired therapeutic effect is achieved at suboptimal plasma concentrations, every attempt should be made to avoid the prescription of additional drugs simply to increase the plasma concentration into what is commonly referred to as the therapeutic range. Obviously, the interpretation of plasma drug concentration must take into account the various factors that can alter the steady state plasma concentrations achieved on a given dosage form [54].

conclusions about the result, and advising the physician who ordered the test how to optimize treatment. It is important to apply a uniform definition of TDM here, because different definitions have previously been used in cost-effectiveness studies and reviews of TDM. Consequently, comparisons have been made based on different approaches, which may influence the results. The International Association for Therapeutic Drug Monitoring and

Clinical Pharmacology and Therapeutic Drug Monitoring of Immunosuppressive Agents

http://dx.doi.org/10.5772/54910

321

*Therapeutic drug monitoring is defined as the measurement made in the laboratory of a parameter that, with appropriate interpretation, will directly influence prescribing procedures. Commonly the meas‐ urement is in a biologic matrix of a prescribed xenobiotic, but it may also be of an endogenous compound prescribed as replacement therapy in an individual who is physiologically or pathologically deficient in that compound*. This definition places TDM within the total therapeutic approach and should give not only more emphasis to the medication and patient-safety aspects of pharmacotherapy, but also more insight into why there are differences in efficacy among different patients. This definition implies that clinical pharmacologists have an active involvement in drug therapy,

For a drug to be a suitable candidate for therapeutic drug monitoring it must satisfy the

**2.** The drug should have a narrow therapeutic index; that is, the difference in the concen‐ trations exerting therapeutic benefit and dose causing adverse events should be small. **3.** There should be considerable between-subject pharmacokinetic variability and, therefore,

**4.** The pharmacological response of the drug should be difficult to assess or to distinguish

The most commonly used immunosuppressants require TDM because of their narrow therapeutic index and significant variability in blood concentrations between individuals. In transplant recipients, both supratherapeutics and subtherapeutics drug concentrations can have devastating results. At subtherapeutics drug concentrations, the transplant recipient is at risk for allograft rejection. At supratherapeutics drug concentrations, the patient is at risk for over-immunosuppression which can potentially lead to infection or drug specific side effects. It is it known that neurological and gastrointestinal side effects occur more frequently at higher concentrations of TRL [53]. Immunosuppressants display significant interindividual variability in plasma drug concentrations, which creates the demand for TDM when such

Immunosuppressants display significant interindividual variability in plasma drug concen‐ trations, which creates the demand for TDM when such drugs are used. It is appropriate to

**1.** There should be a clear relationship between drug concentration and effect.

a poor relationship between dose and drug concentration/response.

Clinical Toxicology has adopted the following definition:

something that is not yet realized in many countries [56].

*3.3.1. Why TDM for immunosuppressants?*

following criteria [55]:

form adverse events.

*3.3.2. Factors contributing to the variability*

drugs are used.

### **3.3. Therapeutic Drug Monitoring (TDM)**

Individualizing a patient's drug therapy to obtain the optimum balance between therapeutic efficacy and the occurrence of adverse events is the physician's goal. However, achieving this goal is not always straight forward, being complicated by within and between patient variability in both pharmacokinetics and pharmacodynamics. In the early 1960's new analyt‐ ical techniques became available allowing the measurement of the low drug concentrations seen in biological fluids during drug treatment. This offered the opportunity to reduce the pharmacokinetic component of variability by controlling drug therapy using concentrations in the body rather than by dose alone. This process became known as therapeutic drug monitoring [55].

The aim of TDM is to optimize pharmacotherapy by maximizing therapeutic efficacy, while minimizing adverse events, in those instances where the blood concentration of the drug is a better predictor of the desired effect(s) than the dose. The reasons why these principles have gained wide acceptance include the following: (1) although imperfect, a better relationship often exists between the effect of a given drug and its concentration in the blood than between the dose of the drug and the effect; (2) a thorough understanding of pharmacokinetics, i.e., the processes of drug absorption, distribution, metabolism, and drug excretion in individual patients and in patient populations is available; and (3) the development of reliable and relatively easy to use drug-monitoring assays. In addition, TDM can also be useful in cases in which compliance is in question, where it is not clear if the right drug is being taken, where dosage adjustment is required as a result of drug–drug or drug–food interactions, and where intoxication is suspected.

TDM is more than simply the analysis of a single drug concentration in the blood of a patient and a report of this number. It also comprises interpretation of the value measured using the mathematical (pharmacokinetic) principles mentioned above, drawing the appropriate conclusions about the result, and advising the physician who ordered the test how to optimize treatment. It is important to apply a uniform definition of TDM here, because different definitions have previously been used in cost-effectiveness studies and reviews of TDM. Consequently, comparisons have been made based on different approaches, which may influence the results. The International Association for Therapeutic Drug Monitoring and Clinical Toxicology has adopted the following definition:

*Therapeutic drug monitoring is defined as the measurement made in the laboratory of a parameter that, with appropriate interpretation, will directly influence prescribing procedures. Commonly the meas‐ urement is in a biologic matrix of a prescribed xenobiotic, but it may also be of an endogenous compound prescribed as replacement therapy in an individual who is physiologically or pathologically deficient in that compound*. This definition places TDM within the total therapeutic approach and should give not only more emphasis to the medication and patient-safety aspects of pharmacotherapy, but also more insight into why there are differences in efficacy among different patients. This definition implies that clinical pharmacologists have an active involvement in drug therapy, something that is not yet realized in many countries [56].
