A REVIEW ON APPLICATION OF PHARMACOKINETICS TO CLINICAL SITUATIONS

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.

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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.

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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4. 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.

i.    Drug Selection
The choice of drug and the drug product is made not only on the basis of therapeutic consideration, but also based on cost and therapeutic equivalency. Pharmacokinetics and pharmacodynamics are part of the overall considerations in the selection of a drug for inclusion into the drug formulary (DF). New pharmacokinetic and pharmacodynamic data are periodically reviewed and updated by Institutional Pharmacy and Therapeutic Committees (IPTCs).

Drugs with similar therapeutic indications may differ in dose and pharmacokinetics. 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.

ii.    Dosage Regimen Design
The overall objective of dosage regimen design is to achieve a target drug concentration at the receptor site. Once the proper drug is selected for the patient, a number of factors must be considered when designing a therapeutic dosage regimen. First, the usual pharmacokinetics of the drug including its absorption, distribution, and elimination profile are considered in the patient. Some patients have unusual first-pass metabolism and bioavailability may be reduced. 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.

Optimal dosing design can greatly improve the safety and efficacy of the drug, including reduced side effects and a decrease in frequency of therapeutic drug monitoring and its associated costs. For some drugs, TDM will be necessary because of the unpredictable nature of their pharmacodynamics and pharmacokinetics. Changes in drug or drug dose may be required after careful assessment by the pharmacist of the patient, including changes in the drug's pharmacokinetics, drug tolerance, cross sensitivity, or history of unusual reactions to related drugs [1].

iii.    Pharmacokinetics of the Drug
Various popular drug references list pharmacokinetic parameters such as clearance, bioavailability, and elimination half-life. The values for these pharmacokinetic parameters are often obtained from small clinical studies. Therefore, it is difficult to determine whether these reported pharmacokinetic parameters are reflected in the general population or in specific patient groups. Differences in study design, patient population, and data analysis may lead to conflicting values for the same pharmacokinetic parameters. For example, values for the apparent volume of distribution and clearance can be estimated by different methods.

Ideally, the target drug concentration and the therapeutic window for the drug should be obtained, if available. In using the target drug concentration in the development of a dosage regimen, the clinical pharmacist should know whether the reported target (effective) drug concentration represents an average steady state drug concentration, a peak drug concentration, or a trough concentration [3]

iv.    Drug Dosage Form (Drug Product)
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.

v.    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. Institutionalized patients may have very little choice as to the prescribed drug and drug dosage form. Moreover, patient compliance in institutions is dictated by the fact that medication is provided by the medical personnel. Ambulatory patients must remember to take the medication as prescribed to obtain the optimum clinical effect of the drug. Therefore, it is very important that the clinician or clinical pharmacist consider the patient's lifestyle and needs when developing a drug dosage regimen.

vi.    Evaluation of Patient's Response
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 judgment may preclude the need for measuring serum drug concentrations.

vii.    Measurement of Serum Drug Concentrations
Before blood samples are taken from the patient, the practitioner needs to determine whether serum drug concentrations in the patient need to be measured. In some cases, the patient's response may not be related to the serum drug concentration. For example, allergy or mild nausea may not be dose related. In other cases, the response of a drug may be related to its chronopharmacology.A major assumption made by the practitioner is that serum drug concentrations relate to the therapeutic and/or toxic effects of the drug. For many drugs, clinical studies have demonstrated a therapeutically effective range of serum concentrations. Knowledge of the serum drug concentration may clarify why a patient is not responding to the drug therapy or why the drug is having an adverse effect. In addition, the practitioner may want to verify the accuracy of the dosage regimen. When ordering serum drug concentrations to be measured, a single serum drug concentration may not yield useful information unless other factors are considered.

For example, the dosage regimen of the drug should be known, including the size of the dose and the dosage interval, the route of drug administration, the time of sampling (peak, trough, or steady state), and the type of drug product (e.g. immediate release or extended release)

In many cases, a single blood sample gives insufficient information. Several blood samples are often needed to clarify the adequacy of the dosage regimen. In practice, trough serum concentrations are easier to obtain than peak or C ∞ av samples under a multiple-dose regimen. In addition, limitations in terms of the number of blood samples that may be taken, total volume of blood needed for the assay, and time to perform the drug analysis may exist. Has suggested that blood sampling times for therapeutic drug monitoring should be taken during the post distributive phase for loading and maintenance doses, but at steady state for maintenance doses. After distribution equilibrium has been achieved, the plasma drug concentration during the post distributive phase is better correlated with the tissue concentration and, presumably, the drug concentration at the site of action. 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. The practitioner who orders the measurement of serum concentrations should also consider the cost of the assays, the risks and discomfort for the patient, and the utility of the information gained.

viii.    Assay for Drug
Drug analyses are usually performed by either a clinical chemistry laboratory or a clinical pharmacokinetics laboratory. A variety of analytic techniques are available for drug measurement, including high-pressure liquid chromatography, gas chromatography, spectrophotometry, fluorometry, immunoassay, and radio isotopic methods. The methods used by the analytic laboratory may depend on such factors as the physicochemical characteristics of the drug, target concentration for measurement, amount and nature of the biologic specimen (serum, urine), available instrumentation, cost for each assay, and analytical skills of the laboratory personnel. The laboratory should have a standard operating procedure (SOP) for each drug analysis technique and follow good laboratory practices. Moreover, analytic methods used for the assay of drugs in serum should be validated with respect to specificity, linearity, sensitivity, precision, accuracy, stability, and ruggedness.

Because of cost and equipment constraints, most clinical pharmacokinetic services routinely analyze drugs by immunoassay. Various immunoassay methods are currently available that may differ in assay specificity for the drug, the cost of analyses, and the time to perform the assay and obtain the results. The Abbott TDx system is a fluorescence polarization immunoassay (FPI), which measures most of the anti arrhythmics and amino glycosides and other drugs of abuse (). TDx FLx is a newer system that allows flexible handling of samples. Other dedicated systems routinely used in hospitals include the Auto carousel (Syva Corp., which markets many EMIT test kits for many drugs). Other makers of instruments or kits for drug testing include Syntex, Eastman Kodak, Hoffman-La Roche, and Miles Laboratories.

Table 3: Common Drugs Monitored in Hospitals

ix.    Monitoring Serum Drug Concentrations
In many cases, the patient's pathophysiology may be unstable, either improving or deteriorating further. For example, proper therapy for congestive heart failure will improve cardiac output and renal perfusion, thereby increasing renal drug clearance. Therefore, continuous monitoring of serum drug concentrations is necessary to ensure proper drug therapy for the patient. For some drugs, an acute pharmacologic response can be monitored in lieu of actual serum drug concentration. For example, prothrombin clotting time might be useful for monitoring anticoagulant therapy and blood pressure monitoring for hypotensive agents.

x.    Special Recommendations
At times, the patient may not be responding to drug therapy because of other factors. For example, the patient may not be following instructions for taking the medication (patient noncompliance). The patient may be taking the drug after a meal instead of before, or may not be adhering to a special diet (e.g. low salt). Therefore, the patient may need special instructions that are simple and easy to follow [3].

5. Pharmacokinetic Evaluation [1].
After the serum or plasma drug concentrations are measured, the pharmacokineticist must evaluate the data. Most laboratories report total drug (free plus bound drug) concentrations in the serum. The pharmacokineticist should be aware of the usual therapeutic range of serum concentrations from the literature.The assay results from the laboratory may show that the patient's serum drug levels are higher, lower, or similar to the expected serum levels. The pharmacokineticist should evaluate these results while considering the patient and the patient's pathophysiologic condition. Lists a number of factors the pharmacokineticist should consider when interpreting drug serum concentration. Often, other data, such as a high serum creatinine and high blood urea nitrogen, may help verify that an observed high serum drug concentration in a patient is due to lower renal drug clearance because of compromised kidney function. Therefore, the clinician or pharmacokineticist should evaluate the data using sound medical judgment and observation. The therapeutic decision should not be based solely on serum drug concentration.

Table 4:Pharmacokinetic Evaluation of Serum Drug Concentrations

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i.    Dosage Adjustment
From the serum drug concentration data and patient observations, the clinician or pharmacokineticist may recommend an adjustment in the dosage regimen. Ideally, the new dosage regimen should be calculated using the pharmacokinetic parameters derived from the patient's serum drug concentrations. Although there may not be enough data for a complete pharmacokinetic profile, the pharmacokineticist should still be able to derive a new dosage regimen based on the available data and the pharmacokinetic parameters in the literature that are based on average population data.

ii.    Monitoring Serum Drug Concentrations
In many cases, the patient's pathophysiology may be unstable, either improving or deteriorating further. For example, proper therapy for congestive heart failure will improve cardiac output and renal perfusion, thereby increasing renal drug clearance. Therefore, continuous monitoring of serum drug concentrations is necessary to ensure proper drug therapy for the patient. For some drugs, an acute pharmacologic response can be monitored in lieu of actual serum drug concentration. For example, prothrombin clotting time might be useful for monitoring anticoagulant therapy and blood pressure monitoring for hypotensive agents [6].

iii.    Design of Dosage Regimens
Several methods may be used to design a dosage regimen. Generally, the initial dosage of the drug is estimated using average population pharmacokinetic parameters obtained from the literature. The patient is then monitored for the therapeutic response by physical examination and, if necessary, by measurement of serum drug levels. After evaluation of the patient, adjustment of the dosage regimen using the patient's individual pharmacokinetic parameters may be indicated, with further therapeutic drug monitoring.
Many versions of clinical pharmacokinetic software are available for dose calculations of drugs with narrow therapeutic index (e.g. Data Kinetics [ASHSP], and the Abbott base pharmacokinetic system). The dosing strategies are based generally on basic pharmacokinetic principles that have been estimated manually. Computer automation and pharmacokinetic software packages improve the accuracy of the calculation, make the calculations "easier,'' and have an added advantage of maintaining proper documentation.

The most accurate approach to dosage regimen design is to calculate the dose based on the pharmacokinetics of the drug in the individual patient. This approach is not feasible for calculation of the initial dose. However, once the patient has been medicated, the readjustment of the dose may be calculated using pharmacokinetic parameters derived from measurement of the serum drug levels from the patient after the initial dose. Most dosing programs record the patient's age and weight and calculate the individual dose based on creatinine clearance and lean body weight [2].

iv.    Dosage Regimens Based on Population Averages
The method most often used to calculate a dosage regimen is based on average pharmacokinetic parameters obtained from clinical studies published in the drug literature. This method may be based on a fixed or an adaptive model.
The fixed model assumes that population average pharmacokinetic parameters may be used directly to calculate a dosage regimen for the patient, without any alteration. Usually, pharmacokinetic parameters such as absorption rate constant k a, bioavailability factor F, apparent volume of distribution V D, and elimination rate constant k, are assumed to remain constant. Most often the drug is assumed to follow the pharmacokinetics of a one-compartment model. When a multiple-dose regimen is designed, multiple-dosage equations based on the principle of superposition are used to evaluate the dose. The practitioner may use the usual dosage suggested by the literature and then make a small adjustment of the dosage based on the patient's weight and/or age [7].

The adaptive model for dosage regimen calculation uses patient variables such as weight, age, sex, body surface area, and known patient pathophysiology, such as renal disease, as well as the known population average pharmacokinetic parameters of the drug. In this case, calculation of the dosage regimen takes into consideration any changing pathophysiology of the patient and attempts to adapt or modify the dosage regimen according to the needs of the patient. The adaptive model generally assumes that pharmacokinetic parameters such as drug clearance do not change from one dose to the next. However, some adaptive models allow for continuously adaptive change with time in order to simulate more closely the changing process of drug disposition.

v.    Dosage Regimens Based on Partial Pharmacokinetic Parameters
For many drugs, the entire pharmacokinetic profile for the drug is unknown or unavailable. Therefore, the pharmacokineticist needs to make some assumptions in order to calculate the dosage regimen. For example, a common assumption is to let the bioavailability factor F equal 1 or 100%. Thus, if the drug is less than fully absorbed systemically, the patient will be under medicated rather than overmedicated. Some of these assumptions will depend on the safety, efficacy, and therapeutic range of the drug. The use of population pharmacokinetics (discussed later in this chapter) uses average patient population characteristics and only a few serum drug concentrations from the patient. Population pharmacokinetic approaches to therapeutic drug monitoring have increased with the increased availability of computerized databases and the development of statistical tools for the analysis of observational data.

vi.    Empirical Dosage Regimens
In many cases, the physician selects a dosage regimen for the patient without using any pharmacokinetic variables. In such a situation, the physician makes the decision based on empirical clinical data, personal experience, and clinical observations. The physician characterizes the patient as representative of a similar well-studied clinical population that has used the drug successfully.

vii.    Conversion from Intravenous Infusion to Oral Dosing
After the patient's dosing is controlled by intravenous infusion, it is often desirable to continue to medicate the patient with the same drug using the oral route of administration. When intravenous infusion is stopped, the serum drug concentration decreases according to first-order elimination kinetics. For most oral drug products, the time to reach steady state depends on the first-order elimination rate constant for the drug. Therefore, if the patient starts the dosage regimen with the oral drug product at the same time as the intravenous infusion is stopped, and then the exponential decline of serum levels from the intravenous infusion should be matched by the exponential increase in serum drug levels from the oral drug product [9].

The conversion from intravenous infusion to a controlled-release oral medication given once or twice daily has become more common with the availability of more controlled-release drug products, such as theophylline and quinidine. Computer simulation for the conversion of intravenous theophylline (aminophylline) therapy to oral controlled-release theophylline demonstrated that oral therapy should be started at the same time as intravenous infusion is stopped. With this method, minimal fluctuations are observed between the peak and trough serum theophylline levels.

viii.    Determination of Dose
The drug dose is estimated to deliver a desirable (target) therapeutic level of the drug to the body. The dose of a drug is estimated with the objective of delivering a desirable therapeutic level of the drug in the body. For many drugs, the desirable therapeutic drug levels and pharmacokinetic parameters are available in the clinical literature. However, the literature in some cases may not yield complete drug information, or the information available may be partly equivocal. Therefore, the pharmacokineticist must make certain necessary assumptions in accordance with the best pharmacokinetic information available.
For a drug that is given in multiple doses for an extended period of time, the dosage regimen is usually calculated so that the average steady-state blood level is within the therapeutic range. The dose can be calculated with Equation 20.4, which expresses the C ∞ av in terms of dose (D 0), dosing interval, volume of distribution (V D), and the elimination half-life of the drug. F is the fraction of drug absorbed and is equal to 1 for drugs administered intravenously.

ix.    Effect of Changing Dose and Dosing Interval on C ∞ max, C ∞ min, and C ∞ avg
During intravenous infusion, C SS may be used to monitor the steady-state serum concentrations. In contrast, when considering therapeutic drug monitoring of serum concentrations after the initiation of a multiple-dosage regimen, the trough serum drug concentrations or C ∞ min may be used to validate the dosage regimen. The blood sample withdrawn just prior to the administration of the next dose represents C ∞ min. To obtain C ∞ max, the blood sample must be withdrawn exactly at the time for peak absorption, or closely spaced blood samples must be taken and the plasma drug concentrations graphed. In practice, an approximate time for maximum drug absorption is estimated and a blood sample is withdrawn. Because of differences in rates of drug absorption, C ∞ max measured in this manner is only an approximation of the true C ∞ max.

The C ∞ av is used most often in dosage calculation. The advantage of using C ∞ av as an indicator for deciding therapeutic blood level is that C ∞ av is determined on a set of points and generally fluctuates less than either C ∞ max or C ∞ min. Moreover, when the dosing interval is changed, the dose may be increased proportionally, to keep C ∞ av constant. This approach works well for some drugs. For example, if the drug diazepam is given either 10 mg TID (three times a day) or 15 mg BID (twice daily), the same C ∞ av is obtained. In fact, if the daily dose is the same, the C ∞ av should be the same. However, when monitoring serum drug concentrations, C ∞ av cannot be measured directly but may be obtained from AUC/ during multiple-dosage regimens. As discussed in, the C ∞ av is not the arithmetic average of C ∞ min and C ∞ min because serum concentrations decline exponentially.

The dosing interval must be selected while considering the elimination half-life of the drug; otherwise, the patient may suffer the toxic effect of a high C ∞ max or sub therapeutic effects of a low C ∞ min even if the C ∞ av is kept constant. For example, using the same example of diazepam, the same C ∞ av is achieved at 10 mg TID or 60 mg every other day. Obviously, the C ∞ max of the latter dose regimen would produce a C ∞ max several times larger than that achieved with 10-mg-TID dose regimen. In general, if a drug has a relatively wide therapeutic index and a relatively long elimination half-life, then flexibility exists in changing the dose or dosing interval, , using C ∞ av as an indicator. When the drug has a narrow therapeutic index, C ∞ max and C ∞ min must be monitored to ensure safety and efficacy.

As the size of the dose or dosage intervals change proportionately, the C ∞ av may be the same but the steady-state peak, C ∞ max, and trough, C ∞ min, drug levels will change. C ∞ max is influenced by the size of the dose and the dosage interval. An increase in the size of the dose given at a longer dosage interval will cause an increase in C ∞ max and a decrease in C ∞ min. In this case C ∞ max may be very close or above the minimum toxic drug concentration (MTC). However, the C ∞ min may be lower than the minimum effective drug concentration (MEC). In this latter case the low C ∞ min may be sub therapeutic and dangerous for the patient, depending on the nature of the drug.

6. Determination of Frequency of Drug Administration
The size of a drug dose is often related to the frequency of drug administration. The more frequently a drug is administered, the smaller the dose must be to obtain the same C ∞ av. Thus, a dose of 250 mg every 3 hours could be changed to 500 mg every 6 hours without affecting the average steady-state plasma concentration of the drug. However, as the dosing intervals get longer, the size of the dose required to maintain the average plasma drug concentration gets correspondingly larger. When an excessively long dosing interval is chosen, the large dose may result in peak plasma levels that are above toxic drug concentration, even though C ∞ av will remain the same.

In general, the dosing interval for most drugs is determined by the elimination half-life. Drugs such as the penicillin’s, which have relatively low toxicity, may be given at intervals much longer than their elimination half-lives without any toxicity problems. Drugs having a narrow therapeutic range, such as digoxin and phenytoin, must be given relatively frequently to minimize excessive "peak-and-trough'' fluctuations in blood levels. For example, the common maintenance schedule for digoxin is 0.25 mg/day and the elimination half-life of digoxin is 1.7 days. In contrast, penicillin G is given at 250 mg every 6 hours, while the elimination half-life of penicillin G is 0.75 hour. Penicillin is given at a dosage interval equal to 8 times its elimination half-life, whereas digoxin is given at a dosing interval only 0.59 times its elimination half-life.

The toxic plasma concentration of penicillin G is over 100 times greater than its effective concentration, whereas digoxin has an effective concentration of 1–2 ng/ml and a toxicity level of 3ng/ml. The toxic concentration of digoxin is only 1.5 times effective concentration. Therefore, a drug with a large therapeutic index (i.e. a large margin of safety) can be given in large doses and at relatively long dosing intervals.

Table 5: Maintenance dose of theophylline when the serum concentration is not measured*