A REVIEW ON APPLICATION OF PHARMACOKINETICS TO CLINICAL SITUATIONS

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About Authors:
V. KRISHNA KISHORE
M.Pharm, 2nd Sem (Pharmaceutics)
Roland Institute of  Pharmaceutical Sciences , Berhampur, Odisha.
Krishnakishorev58@gmail.com

1. Abstract:
Pharmacokinetics is currently defined as the study of the time course of drug absorption, distribution, metabolism, and excretion. Clinical pharmacokinetics is the application of pharmacokinetic principles to the safe and effective therapeutic management of drugs in an individual patient.
Primary goals of clinical pharmacokinetics include enhancing efficacy and decreasing toxicity of a patient's drug therapy. The development of strong correlations between drug concentrations and their pharmacologic responses has enabled clinicians to apply pharmacokinetic principles to actual patient situations.
A drug's effect is often related to its concentration at the site of action, so it would be useful to monitor this concentration. Receptor sites of drugs are generally inaccessible to our observations or are widely distributed in the body, and therefore direct measurement of drug concentrations at these sites is not practical. For example, the receptor sites for digoxin are believed to be within the myocardium, and we cannot directly sample drug concentration in this tissue. However, we can measure drug concentration in the blood or plasma, urine, saliva, and other easily sampled fluids.

Reference Id: PHARMATUTOR-ART-1534

The success of drug therapy is highly dependent on the choice of the drug and drug product and on the design of the dosage regimen. The choice of the drug and drug product, e.g., immediate release versus modified release, is based on the patient's characteristics and the known pharmacokinetics of the drug.
A properly designed dosage regimen tries to achieve a specified concentration of the drug at a receptor site to produce an optimal therapeutic response with minimum adverse effects. Individual variation in pharmacokinetics makes the design of dosage regimens difficult.

Therefore, the application of pharmacokinetics to dosage regimen design must be coordinated with proper clinical evaluation.

2. Individualization of Drug Dosage Regimens
Not all drugs require rigid individualization of the dosage regimen. Many drugs have a large margin of safety (i.e., exhibit a wide therapeutic window), and strict individualization of the dose is unnecessary. The U.S. Food and Drug Administration (FDA) has approved an over-the-counter (OTC) classification for drugs that the public may buy without prescription. In the past few years, many prescription drugs, such as ibuprofen, loratidine, omeprazole, naproxen, nicotine patches, and others, have been approved by the FDA for OTC status. These OTC drugs and certain prescription drugs, when taken as directed, are generally safe and effective for the labeled indications without medical supervision.

For drugs with a narrow therapeutic window, such as digoxin, aminoglycosides, antiarrhythmics, anticonvulsants, and some antiasthmatics, such as theophylline, individualization of the dosage regimen is very important. The objective of the dosage regimen design for these drugs is to produce a safe plasma drug concentration that does not exceed the minimum toxic concentration or fall below a critical minimum drug concentration below which the drug is not effective. For this reason, the dose of these drugs is carefully individualized to avoid plasma drug concentration fluctuations due to inter subject variation in drug absorption, distribution, or elimination processes. For drugs such as phenytoin that follow nonlinear pharmacokinetics at therapeutic plasma drug concentrations, a small change in the dose may cause a huge increase in the therapeutic response, leading to possible adverse effects.

The monitoring of plasma drug concentrations is valuable only if a relationship exists between the plasma drug concentration and the desired clinical effect or between the plasma drug concentration and an adverse effect. For those drugs in which plasma drug concentration and clinical effect are not related, other pharmacodynamic parameters may be monitored. For example, clotting time may be measured directly in patients on warfarin anticoagulant therapy [2].

3. Therapeutic Drug Monitoring
The usefulness of plasma drug concentration data is based on the concept that pharmacologic response is closely related to drug concentration at the site of action. For certain drugs, studies in patients have provided information on the plasma concentration range that is safe and effective in treating specific diseases Within this therapeutic range, the desired effects of the drug are seen. Below it, there is greater probability that the therapeutic benefits are not realized  above it, toxic effects may occur.

No absolute boundaries divide sub therapeutic, therapeutic, and toxic drug concentrations. A gray area usually exists for most drugs in which these concentrations overlap due to variability in individual patient response. Both pharmacodynamic and pharmacokinetic factors contribute to this variability in patient response [3].

Although my review focuses on pharmacokinetics, it is important to remember the fundamental relationship between drug pharmacokinetics and pharmacologic response. The pharmacokinetics of a drug determines the blood concentration achieved from a prescribed dosing regimen. It is generally assumed that after continued drug dosing, the blood concentration will mirror the drug concentration at the receptor site, and it is the receptor site concentration that should principally determine the intensity of a drug's effect. Consequently, both the pharmacokinetics and pharmacologic response characteristics of a drug and the relationship between them must be understood before predicting a patient's response to a drug regimen [4].

Theophylline is an excellent example of a drug whose pharmacokinetics and pharmacodynamics are fairly well understood. When theophylline is administered at a fixed dosage to numerous patients, the blood concentrations achieved vary greatly. That is, wide inter patient variability exists in the pharmacokinetics of theophylline. This is important for theophylline because subtle changes in the blood concentration may result in significant changes in drug response.
Many pharmacokinetic factors cause variability in the plasma drug concentration and, consequently, the pharmacologic response of a drug. Among these factors are:
a. Differences in an individual's ability to metabolize and eliminate the drug (e.g., genetics)
b. Variations in drug absorption
c. Disease states or physiologic states (e.g., extremes of age) that alter drug absorption, distribution, or elimination
d. Drug interactions
We could study a large group of patients by measuring the highest plasma drug concentrations resulting after administration of the same drug dose to each patient. For most drugs, the inter subject variability is likely to result in differing plasma drug concentrations.

This variability is primarily attributed to factors influencing drug absorption, distribution, metabolism, or excretion. Disease states (e.g., renal or hepatic failure) and other conditions (e.g., obesity and aging) that may alter these processes must be considered for the individualization of drug dosage regimens (dose and frequency of dosing).

Therapeutic drug monitoring is defined as the use of assay procedures for determination of drug concentrations in plasma, and the interpretation and application of the resulting concentration data to develop safe and effective drug regimens. If performed properly, this process allows for the achievement of therapeutic concentrations of a drug more rapidly and safely than can be attained with empiric dose changes. Together with observations of the drug's clinical effects, it should provide the safest approach to optimal drug therapy [5].
The major potential advantages of therapeutic drug monitoring include maximization of therapeutic drug benefits as well as minimization of toxic drug effects. Therapeutic drug monitoring may be used in designing safe and effective drug therapy regimens.

Some drugs lend themselves to clinical pharmacokinetic monitoring because their concentrations in plasma correlate well with pharmacologic response, for other drugs, this approach is not valuable. For example, it is advantageous to know the plasma theophylline concentration in a patient receiving this drug for the management of asthma. Because plasma theophylline concentration is related to pharmacologic effect, knowing that the plasma concentration is below the therapeutic range could justify increasing the dose. However, it is of little value to determine the plasma concentration of an antihypertensive agent, as it may not correlate well with pharmacologic effects and the end-point of treatment, blood pressure, is much easier to measure than the plasma concentration [3].

Therapeutic monitoring using drug concentration data is valuable when:
1. A good correlation exists between the pharmacologic response and plasma concentration. Over at least a limited concentration range, the intensity of pharmacologic effects should increase with plasma concentration. This relationship allows us to predict pharmacologic effects with changing plasma drug concentration.
2. Wide inter subject variation in plasma drug concentrations results from a given dose.
3. The drug has a narrow therapeutic index (i.e., the therapeutic concentration is close to the toxic concentration).
4. The drug's desired pharmacologic effects cannot be assessed readily by other simple means (e.g. blood pressure measurement for anti hypertensives).

The value of therapeutic drug monitoring is limited in situations in which:
1. There is no well-defined therapeutic plasma concentration range.
2. The formation of pharmacologically active metabolites of a drug complicates the application of plasma drug concentration data to clinical effect unless metabolite concentrations are also considered.
3. Toxic effects may occur at unexpectedly low drug concentrations as well as at high concentrations.
4. There are no significant consequences associated with too high or too low levels.

The therapeutic range for a drug is an approximation of the average plasma drug concentrations that are safe and efficacious in most patients [6]. When using published therapeutic drug concentration ranges, such as those in, the clinician must realize that the therapeutic range is essentially a probability concept and should never be considered as absolute values.

For example, the accepted therapeutic range for theophylline is 10–20 µg/ml. Some patients may exhibit signs of theophylline intoxication such as central nervous system excitation and insomnia at serum drug concentrations below 20 µg/ml (see, below) whereas other patients may show drug efficacy at serum drug concentrations below 10 µg/ml.

Table1: Therapeutic Range for Commonly Monitored Drugs.

               Amikacin

 20–30  µg/mL

  Carbamazepine

  4–12    µ g/mL

               Digoxin

  1–2      ng/mL

               Gentamicin

 5–10    µg/mL

               Lidocaine

 1–5      µg/mL

               Tobramycin

 5–10      µg/mL

               Valproic acid

 50–100   µ g/mL

               Vancomycin

20–40     µg/mL

In administering potent drugs to patients, the physician must maintain the plasma drug level within a narrow range of therapeutic concentrations. Various pharmacokinetic methods may be used to calculate the initial dose or dosage regimen. Usually, the initial dosage regimen is calculated based on body weight or body surface after a careful consideration of the known pharmacokinetics of the drug, the pathophysiologic condition of the patient, and the patient's drug history [4].

Because of inter patient variability in drug absorption, distribution, and elimination as well as changing pathophysiologic conditions in the patient, therapeutic drug monitoring (TDM) or clinical pharmacokinetic (laboratory) services (CPKS) have been established in many hospitals to evaluate the response of the patient to the recommended dosage regimen.

The improvement in the clinical effectiveness of the drug by therapeutic drug monitoring may decrease the cost of medical care by preventing untoward adverse drug effects.

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