Pharmacokinetic Of Drugs And Clinical Application

Pharmacokinetics is currently defined as the study of the time course of drug absorption, distribution, metabolism, and excretion (ADME). Clinical pharmacokinetics is the application of pharmacokinetic principles to the safe and effective therapeutic management of drugs in an individual patient. It is the process of applying pharmacokinetic principles to determine the dosage regimens of specific drug products for specific patients to maximize pharmacotherapeutic effects and minimize toxic effects.

Application of these principles requires an understanding of the ADME characteristics of specific drug products in specific diseases and patient populations. The development of patients’ individualized dosage regimens should be based on integrated findings from monitoring both the drug concentration-versus-time profiles in biological fluids and the pharmacologic responses to these drug products. Pharmacokinetic models the concentration-time profile using key parameters, such as volume of distribution, area under the curve, clearance, half-life, maximum concentration, and bioavailability. The development of strong correlations between drug concentrations and their pharmacologic responses has enabled clinicians to apply pharmacokinetic principles to actual patient situations.

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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. In the absence of drug concentration measurements, patient-specific characteristics and physiological markers should be used to provide clinical pharmacokinetic assessments and make dosage-regimen recommendations.

Pharmacokinetic

Pharmacokinetic Factors

The influence of factors such as age, sex, diet, pathophysiologic conditions, and concomitant use of other drug products must also be understood. 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. 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).

d. Drug interactions

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.

Goal Of Clinical Pharmacokinetic

Primary goals of clinical pharmacokinetics include enhancing efficacy and decreasing toxicity of a patient’s drug therapy.

Pharmacokinetic Parameters

Drug Absorption

Drugs can be absorbed into the circulation from numerous sites within the body, with the route of administration having a significant influence on the ability of a drug to accumulate at its site of action. There are four main routes of administration:

1. Ingestion through the digestive tract

2. Inhalation via the respiratory system

3. Dermal application to the skin or eye

4. Injection through direct administration into the bloodstream

Only injected compounds enter directly into the systemic circulation and results in 100% bioavailability. For drugs administered through ingestion, inhalation or dermal contact, the chemicals must cross a membrane before entering the bloodstream and will have reduced bioavailability. For instance, a drug that is ingested first undergoes metabolism during which some of the drug is excreted before entering the bloodstream.

Drug Distribution

Once in the circulation, the drug is transferred to the interstitial fluid and to the cells of the body. Some compounds move easily, while others do not. Factors such as blood flow, lipophilicity, tissue binding, and molecular size influence distribution. For a drug to transfer to its site of action, mechanisms must be available to allow the drug to traverse numerous biological membranes. These include passive diffusion, filtration, active transport, and endocytosis. These mechanisms are also important for the transfer of endogenous substances required for life.

Passive diffusion: When a molecule moves from an area of high concentration to an area of low concentration. This is the most common way a drug is absorbed.

Facilitated diffusion: When a molecule moves from an area of high concentration to one of low concentration with the help of carrier proteins in the membrane.

Active diffusion: An energy-dependent process during which a molecule requires energy in the form of ATP to cross a membrane. 

Endocytosis: When a larger drug is transferred through a membrane via invagination of the membrane.

Drug Metabolism

Drug metabolism is the biotransformation of a drug by organs or tissues (primarily the liver, kidney, skin or digestive tract) so that the drug can be excreted. To facilitate removal via feaces or urine, the drug compound is altered to become more water-soluble. There is an increased interest in the chemical changes in a drug once it enters the body. In most cases, these drug biotransformation reactions produce intermediates with less pharmacologic activity than the parent compound; however, some drug metabolites possess significant pharmacologic action. Furthermore, some metabolites are chemically reactive and capable of contributing to toxicity, mutagenesis, carcinogenesis, and birth defects.

Drug Excretion

Excretion is the process by which the metabolized drug compound is eliminated from the body. Researchers want to know how rapidly the drug is excreted and what pathway it takes to exit the body. Most drug excretion occurs as feaces or urine. Other excretion methods include through the lungs or in sweat through the skin. Molecular size and charge influence the excretion pathway. Not every drug compound is fully excreted. When the chemical or metabolic by-products bioaccumulate, adverse effects can occur. Lipid-soluble compounds are more prone to bioaccumulate compared to water-soluble compounds. The primary sites for drug excretion are the liver and kidney, although the skin, lungs, and bile and intestine may be sites for excretion as well.

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Some publications add release and elimination. Release is before adsorption. An active pharmaceutical ingredient (API) binds to its excipient. The drug is designed to be released at a particular place and time in the body. However, injections are immediately released. Elimination is a combination of distribution and excretion.

Pharmacokinetic Studies

Pharmacokinetic studies evaluate:

1. The rate that a chemical is absorbed and distributed

2. The rate and pathways of drug metabolism and excretion

3. The plasma concentration of a drug over time

Pharmacokinetic Models

The handling of a drug by the body can be very complex, as several processes (such as absorption, distribution, metabolism, and elimination) work to alter drug concentrations in tissues and fluids. Simplifications of body processes are necessary to predict a drug’s behaviour in the body. One way to make these simplifications is to apply mathematical principles to the various processes.

To apply mathematical principles, a model of the body must be selected. A basic type of model used in pharmacokinetics is the compartmental model. Compartmental models are categorisedized by the number of compartments needed to describe the drug’s behaviour in the body. There are one-compartment, two-compartment, and multicompartment models. The compartments do not represent a specific tissue or fluid but may represent a group of similar tissues or fluids. These models can be used to predict the time course of drug concentrations in the body.

Compartmental models are termed deterministic because the observed drug concentrations determine the type of compartmental model required to describe the pharmacokinetics of the drug. This concept will become evident when we examine one- and two-compartment models.

To construct a compartmental model as a representation of the body, simplifications of body structures are made. Organs and tissues in which drug distribution is similar are grouped into one compartment. For example, distribution into adipose tissue differs from distribution into renal tissue for most drugs. Therefore, these tissues may be in different compartments. The highly perfused organs (e.g., heart, liver, and kidneys) often have similar drug distribution patterns, so these areas may be considered as one compartment. The compartment that includes blood (plasma), heart, lungs, liver, and kidneys is usually referred to as the central compartment or the highly blood-perfused compartment. The other compartment that includes fat tissue, muscle tissue,and cerebrospinal fluid is the peripheral compartment, which is less well perfused than the central compartment.

Another simplification of body processes concerns the expression of changes in the amount of drug in the body over time. These changes with time are known as rates. The elimination rate describes the change in the amount of drug in the body due to drug elimination over time. Most pharmacokinetic models assume that elimination does not change over time.

The value of any model is determined by how well it predicts drug concentrations in fluids and tissues. Generally, it is best to use the simplest model that accurately predicts changes in drug concentrations over time. If a one-compartment model is sufficient to predict plasma drug concentrations (and those concentrations are of most interest to us), then a more complex (two-compartment or more) model is not needed. However, more complex models are often required to predict tissue drug concentrations.

Compartmental Models

The one-compartment model is the most frequently used model in clinical practice. This model is the simplest because there is only one compartment. All body tissues and fluids are considered a part of this compartment. Furthermore, it is assumed that after a dose of drug is administered, it distributes instantaneously to all body areas.

Some drugs do not distribute instantaneously to all parts of the body, however, even after intravenous bolus administration. Intravenous bolus dosing means administering a dose of drug over a very short time period. A common distribution pattern is for the drug to distribute rapidly in the bloodstream and to the highly perfused organs, such as the liver and kidneys.

Then, at a slower rate, the drug distributes to other body tissues. This pattern of drug distribution may be represented by a two-compartment model. Drugs move back and forth between these compartments to maintain equilibrium. Again, the one-compartment model assumes that the drug is distributed to tissues very rapidly after intravenous administration.

Pharmacist Responsibilities

Within the pharmaceutical care process, pharmacists’ clinical functions include appropriate and cost-conscious therapeutic drug monitoring and provision of clinical pharmacokinetic assessments. Clinical pharmacokinetic monitoring is a fundamental responsibility of all pharmacists providing pharmaceutical care. Clinical pharmacokinetic monitoring is an integral component of pharmaceutical care for selected patients based on their specific pharmacotherapy, disease states and related factors, and treatment goals. Clinical pharmacokinetic monitoring is essential to achieving positive outcomes for these patients across the continuum of care and in all practice settings of health systems. Examples of such outcomes include decreased mortality, decreased length of treatment, decreased length of hospital stay, decreased morbidity (either improved symptoms of disease or improved recuperation), and decreased adverse effects from drug therapy.

The following responsibilities should be part of clinical pharmacokinetic services or monitoring conducted by pharmacists:

1. Designing patient-specific drug dosage regimens based on the pharmacokinetic and pharmacologic characteristics of the drug products used, the objectives of drug therapy, concurrent diseases and drug therapy, and other pertinent patient factors (e.g., demographics, laboratory data) that improve the safety and effectiveness of drug therapy and promote positive patient outcomes.

2. Recommending or scheduling measurements of drug concentrations in biological fluids (e.g., plasma, serum, blood, cerebrospinal fluid) or tissues in order to facilitate the evaluation of dosage regimens.

3. Monitoring and adjusting dosage regimens on the basis of pharmacologic responses and biological fluid and tissue drug concentrations in conjunction with clinical signs and symptoms or other biochemical variables.

4. Evaluating unusual patient responses to drug therapy for possible pharmacokinetic and pharmacologic explanations.

5. Communicating patient-specific drug therapy information to physicians, nurses, and other clinical practitioners and to patients orally and in writing, and including documentation of this in the patient’s health record.

6. Educating pharmacists, physicians, nurses, and other clinical practitioners about pharmacokinetic principles and appropriate indications for clinical pharmacokinetic monitoring, including the cost-effective use of drug concentration measurements.

7. Developing quality assurance programme for documenting improved patient outcomes and economic benefits resulting from clinical pharmacokinetic monitoring.

8. Promoting collaborative relationships with other individuals and departments involved in drug therapy monitoring to encourage the development and appropriate use of pharmacokinetic principles in pharmaceutical care.

Pharmacists with specialised education, training, or experience may have the opportunity to assume the following additional responsibilities:

1. Designing and conducting research to expand clinical pharmacokinetic knowledge and its relationship to pharmacologic responses, exploring concentration–response relationships for specific drugs, and contributing to the evaluation and expansion of clinical pharmacokinetic monitoring as an integral part of pharmaceutical care.

2. Developing and applying computer programme and point-of-care information systems to enhance the accuracy and sophistication of pharmacokinetic modelling and applications to pharmaceutical care.

3. Serving as an expert consultant to pharmacists with a general background in clinical pharmacokinetic monitoring.

Therapeutic Drug Monitoring

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.

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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—the therapeutic range. Within this therapeutic range, the desired effects of the drug are observed. Below it, there is greater probability that the therapeutic benefits are not realised; above it, toxic effects may occur.

No absolute boundaries divide subtherapeutic, 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.

Numerous pharmacokinetic characteristics of a drug may result in variability in the plasma concentration achieved with a given dose when administered to various patients. This interpatient variability is primarily attributed to one or more of the following:

• Variations in drug absorption

• Variations in drug distribution

• Differences in an individual’s ability to metabolize and eliminate the drug (e.g., genetics)

• Disease states (renal or hepatic insufficiency) or physiologic states (e.g., extremes of age, obesity) that alter drug absorption, distribution, or elimination

• Drug interactions

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 concentrations.

2. Wide intersubject 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 antihypertensives).

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.

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. OTC drugs and certain prescription drugs, when taken as directed, are generally safe and effective for the labelled 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.

The therapeutic range for a drug is an approximation of the average plasma drug concentrations that are safe and efficacious in most patients. 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.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.

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 Functions Of A TDM Service

1. Select drug

2. Design dosage regimen

3. Evaluate patient response.

4. Determine need for measuring serum drug concentrations.

5. Assay for drug concentration in biological fluids.

6. Perform pharmacokinetic evaluation of drug concentrations.

7. Readjust dosage regimen, if necessary.

8. Monitor serum drug concentrations.

9. Recommend special requirements

The pharmacist may choose one drug over another based on cost, therapeutic, and pharmacokinetic considerations. Other factors include patient-specific information such as medical history, pathophysiologic states, concurrent drug therapy, known allergies, drug sensitivities, and drug interactions, all are important considerations in drug selection.

The overall objective of dosage regimen design is to achieve a target drug concentration at the receptor site. Certain factors must be met. First, the usual pharmacokinetics of the drug including its absorption, distribution, and elimination profile are considered in the patient. Second, the physiology of the patient, age, weight, gender, and nutritional status will affect the disposition of the drug and should be considered. Third, any pathophysiologic conditions, such as renal dysfunction, hepatic disease, or congestive heart failure, may change the normal pharmacokinetic profile of the drug, and the dose must be carefully adjusted. For some patients, the hidden effect of exposure to long-term medication or drug abuse is important. Personal lifestyle factors, such as cigarette smoking, alcohol abuse, and obesity are known to alter the pharmacokinetics of drugs.

The dosage form of the drug will affect drug bioavailability and the rate of absorption and thus the subsequent pharmacodynamics of the drug in the patient. The route of drug administration and the desired onset and duration of the clinical response will affect the choice of drug dosage form. In addition, the selection of an extended-release drug product instead of an immediate-release drug product may affect both the cost of the drug and patient compliance.

Factors that may affect patient compliance include the cost of the medication, complicated instructions, multiple daily doses, difficulty in swallowing, adverse drug reactions, and ambulatory versus institutionalized status. It is very important that the clinician or clinical pharmacist consider the patient's lifestyle and needs when developing a drug dosage regimen.

After the drug and drug product are chosen and the patient receives the initial dosage regimen, the practitioner should evaluate the patient's response clinically. If the patient is not responding to drug therapy as expected, then the drug and dosage regimen should be reviewed. The dosage regimen should be reviewed for adequacy, accuracy, and patient compliance to the drug therapy. In many situations, sound clinical judgement may preclude the need for measuring serum drug concentrations.

In some cases, the patient's response may not be related to the serum drug concentration. In many cases, a single blood sample gives insufficient information. Several blood samples are often needed to clarify the adequacy of the dosage regimen.

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In some cases, the clinical pharmacist may want an early-time sample that approximates the peak drug level, whereas a blood sample taken at three or four elimination half-lives will approximate the steady-state drug concentration.

If the pharmacist notices that the desired outcome is not achieved, the treatment plan can be readjusted and further analysis carried out as in the past.

Measure Of Pharmacokinetic Metrics

The following are the most commonly measured pharmacokinetic metrics:

1. Dose-Amount of drugs administered.

2. Dosing interval-Time between drug dose administrations.

3. Cmax-The peak plasma concentration of a drug after administration.

4. tmax-Time to reach Cmax.

5. Cmin-The lowest (trough) concentration that a drug reaches before the next dose is administered.

6. Volume of distribution-The apparent volume in which a drug is distributed (i.e., the parameter relating drug concentration in plasma to drug amount in the body).

7. Concentration-Amount of drug in a given volume of plasma.

8. Absorption half-life-The time required for 50% of a given dose of drug to be absorbed into the systemic circulation.

9. Absorption rate constant-The rate at which a drug enters into the body for oral and other extravascular routes.

10. Elimination half-‍life-The time required for the concentration of the drug to reach half of its original value.

11. Elimination rate constant-The rate at which a drug is removed from the body.

12. Infusion rate-Rate of infusion required to balance elimination.

13. Area under the curve-The integral of the concentration-time curve (after a single dose or in steady state).

14. Clearance-The volume of plasma cleared of the drug per unit time.

15. Bioavailability-The systemically available fraction of a drug.

16. Fluctuation-Peak trough fluctuation within one dosing interval at steady state.