Concepts in Clinical
`
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`Fifth Edition
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`Juseph T+ DiF'im, Pharm.D.
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`AMNEAL
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`EXHIBIT NO. 1057 Page 1
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` EXHIBIT NO. 1057 Page 1
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` AMNEAL
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`AMNEAL
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`EXHIBIT NO. 1057 Page 2
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`LESSON
`
`1
`Introduction to Pharmacokinetics
`and Pharmacodynamics
`
`C
`
`O B J E C T I V E S
`
`After completing Lesson 1, you should be able to:
`
`1.
`
`2.
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`3.
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`4.
`
`
`Define and differentiate between pharmacokinetics
`
`
`and clinical pharmacokinetics.
`Define
`
`pharmacodynamics and relate it to pharma-
`cokinetics.
`Describe the concept of the therapeutic concentra-
`tion range.
`Identify factors that cause interpatient variability in
`drug disposition and drug response.
`
`5.
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`6.
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`7.
`
`Describe situations in which routine clinical phar-
`macokinetic monitoring would be advantageous.
`List the assumptions made about drug distribution
`patterns in both one- and two-compartment models.
`Represent graphically the typical natural log of
`plasma drug concentration versus time curve for a
`one-compartment model after an
`intravenous
`dose.
`
`Pharmacokinetics is currently defined as the study of the
`
`time course of drug absorption, distribution, metabo-
`lism, 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 pharmacoki-
`netic 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 inac-
`cessible to our observations or are widely distributed in
`the body, and therefore direct measurement of drug con-
`centrations at these sites is not practical. For example, the
`
`receptor sites for digoxin are thought to be within the
`myocardium. Obviously 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 (Figure 1-1).
`Kinetic
` describes
`the predictable relationship
`homogeneity
`between plasma drug concentration and concentration at
`the receptor site where a given drug produces its thera-
`
`peutic effect (Figure 1-2).
`Changes in the plasma drug
`concentration reflect changes in drug concentrations at
`the receptor site, as well as in other tissues. As the con-
`centration of drug in plasma increases, the concentration
`of drug in most tissues will increase proportionally.
`Similarly, if the plasma concentration of a drug is
`decreasing, the concentration in tissues will also
`decrease. Figure 1-3 is a simplified plot of the drug con-
`centration versus time profile after an intravenous drug
`dose and illustrates this concept.
`
`1
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` EXHIBIT NO. 1057 Page 3
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`2
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`Concepts in Clinical Pharmacokinetics
`
`FIGURE 1-1.
`Blood is the fluid most often sampled for drug concentration
`determination.
`
`The property of kinetic homogeneity is important
`for the assumptions made in clinical pharmacokinet-
`ics. It is the foundation on which all therapeutic and
`toxic plasma drug concentrations are established. That
`is, when studying concentrations of a drug in plasma,
`we assume that these plasma concentrations directly
`relate to concentrations in tissues where the disease
`process is to be modified by the drug (e.g., the central
`nervous system in Parkinson’s disease or bone in
`osteomyelitis). This assumption, however, may not be
`true for all drugs.
`
`LINICAL
`
`ORRELATE
`
`䊑
` C
`C
`Drugs concentrate in some tissues because of physi-
`cal or chemical properties. Examples include digoxin,
`which concentrates in the myocardium, and lipid-
`soluble drugs, such as benzodiazepines, which con-
`centrate in fat.
`
`FIGURE 1-3.
`Drug concentration versus time.
`
`BASIC PHARMACODYNAMIC CONCEPTS
`
`Pharmacodynamics refers to the relationship between
`drug concentration at the site of action and the resulting
`effect, including the time course and intensity of thera-
`peutic and adverse effects. The effect of a drug present
`at the site of action is determined by that drug’s binding
`with a receptor. Receptors may be present on neurons in
`the central nervous system (i.e., opiate receptors) to
`depress pain sensation, on cardiac muscle to affect the
`intensity of contraction, or even within bacteria to dis-
`rupt maintenance of the bacterial cell wall.
`For most drugs, the concentration at the site of the
`receptor determines the intensity of a drug’s effect (Fig-
`ure 1-4). However, other factors affect drug response as
`well. Density of receptors on the cell surface, the mech-
`anism by which a signal is transmitted into the cell by
`second messengers (substances within the cell), or regu-
`latory factors that control gene translation and protein
`production may influence drug effect. This multilevel
`
`FIGURE 1-2.
`Relationship of plasma to tissue drug concentrations.
`
`FIGURE 1-4.
`Relationship of drug concentration to drug effect at the recep-
`tor site.
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` EXHIBIT NO. 1057 Page 4
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` AMNEAL
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`Lesson 1: Introduction to Pharmacokinetics and Pharmacodynamics
`
`3
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`FIGURE 1-6.
`Demonstration of tolerance to drug effect with repeated dosing.
`
`For some drugs, the effectiveness can decrease with
`continued use. This is referred to as
`
`tolerance. Tolerance
`may be caused by pharmacokinetic factors, such as
`increased drug metabolism, that decrease the concen-
`trations achieved with a given dose. There can also be
`pharmacodynamic tolerance, which occurs when the
`same concentration at the receptor site results in a
`reduced effect with repeated exposure. An example of
`drug tolerance is the use of opiates in the management
`of chronic pain. It is not uncommon to find these
`patients requiring increased doses of the opiate over
`time. Tolerance can be described in terms of the dose–
`response curve, as shown in Figure 1-6.
`To assess the effect that a drug regimen is likely to
`have, the clinician should consider pharmacokinetic
`and pharmacodynamic factors. Both are important in
`determining a drug’s effect.
`
`LINICAL
`
`ORRELATE
`
`䊑
` C
`C
`Tolerance can occur with many commonly used drugs.
`One example is the hemodynamic tolerance that occurs
`with continued use of organic nitrates, such as nitroglyc-
`erin. For this drug, tolerance can be reversed by inter-
`spersing drug-free intervals with chronic drug use.
`
`LINICAL
`
`ORRELATE
`
`䊑
` C
`C
`One way to compare potency of two drugs that are in
`the same pharmacologic class is to compare EC
`. The
`50
`drug with a lower EC
` is considered more potent.
`50
`
`FIGURE 1-5.
`Relationship of drug concentration at the receptor site to
`effect (as a percentage of maximal effect).
`
`regulation results in variation of sensitivity to drug
`effect from one individual to another and also deter-
`mines enhancement of or tolerance to drug effects.
`In the simplest examples of drug effect, there is a rela-
`tionship between the concentration of drug at the receptor
`site and the pharmacologic effect. If enough concentra-
`tions are tested, a maximum effect (E
`) can be deter-
`max
`mined (Figure 1-5). When the logarithm of concentration
`is plotted versus effect (Figure 1-5), one can see that there
`is a concentration below which no effect is observed and a
`concentration above which no greater effect is achieved.
`
`
`One way of comparing drug potency is by the concen-
`tration at which 50% of the maximum effect is achieved.
`
`
`
`This is referred to as the 50% effective concentration or EC
`.
`50
`When two drugs are tested in the same individual, the
`drug with a lower EC
` would be considered more potent.
`50
`This means that a lesser amount of a more potent drug is
`needed to achieve the same effect as a less potent drug.
`The EC
` does not, however, indicate other important
`50
`determinants of drug response, such as the duration of
`effect. Duration of effect is determined by a complex set
`of factors, including the time that a drug is engaged on
`the receptor as well as intracellular signaling and gene
`regulation.
`
` EXHIBIT NO. 1057 Page 5
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` AMNEAL
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`4
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`Concepts in Clinical Pharmacokinetics
`
`FIGURE 1-7.
`Relationship between drug concentration and drug effects for
`
`Source: Adapted with permission from
`a hypothetical drug.
`Evans WE, editor. General principles of applied pharmaco-
`kinetics. In:
`, 3rd ed. Vancouver, WA:
`Applied Pharmacokinetics
`Applied Therapeutics; 1992. pp.1–3.
`
`THERAPEUTIC DRUG MONITORING
`Therapeutic drug monitoring is defined as the use of
`assay procedures for determination of drug concentra-
`tions in plasma, and the interpretation and application
`of the resulting concentration data to develop safe and
`effective drug regimens. If performed properly, this pro-
`cess allows for the achievement of therapeutic concen-
`trations 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 pro-
`vide the safest approach to optimal drug therapy.
`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 infor-
`mation on the plasma concentration range that is safe
`and effective in treating specific diseases—the therapeu-
`tic range (Figure 1-7). Within this therapeutic range, the
`desired effects of the drug are observed. Below it, there is
`greater probability that the therapeutic benefits are not
`realized; above it, toxic effects may occur.
`No absolute boundaries divide subtherapeutic, thera-
`peutic, and toxic drug concentrations. A gray area usu-
`ally 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 vari-
`ous patients (Figure 1-8). This interpatient variability is
`primarily attributed to one or more of the following:
`
`• Variations in drug absorption
`• Variations in drug distribution
`
`FIGURE 1-8.
`Example of variability in plasma drug concentration among
`subjects given the same drug dose.
`
`• 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 pharmaco-
`logic 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 pre-
`dict pharmacologic effects with changing plasma
`drug concentrations (Figure 1-9).
`2. Wide intersubject variation in plasma drug concen-
`trations results from a given dose.
`
`FIGURE 1-9.
`When pharmacologic effects relate to plasma drug concentra-
`tions, the latter can be used to predict the former.
`
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`Lesson 1: Introduction to Pharmacokinetics and Pharmacodynamics
`
`5
`
`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 con-
`centration range.
`2. The formation of pharmacologically active metabo-
`lites 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.
`
`Theophylline is an excellent example of a drug in
`which significant interpatient variability in pharmacoki-
`netic properties exists. This is important from a clinical
`
`standpoint as subtle changes in serum concentrations
`may result in marked changes in drug response. Figure
`1-10 shows the relationship between theophylline con-
`centration (
`-axis, on a logarithmic scale) and its
`x
`pharmacologic effect, (changes in pulmonary function
`[
`
`y-axis]). This figure illustrates that as the concentration
`of theophylline increases, so does the intensity of the
`response for some patients. Wide interpatient variability
`is also shown.
`Figure 1-11 outlines the process clinicians may
`choose to follow in making drug dosing decisions by
`using therapeutic drug monitoring. Figure 1-12 shows
`the relationship of pharmacokinetic and pharmacody-
`namic factors.
`Examples of therapeutic ranges for commonly used
`drugs are shown in Table 1-1. As can be seen in this
`table, most drug concentrations are expressed as a unit
`of mass per volume.
`
`LINICAL
`
`ORRELATE
`
`䊑
` C
`C
`A drug’s effect may also be determined by the
`amount of time that the drug is present at the site of
`action. An example is with beta-lactam antimicrobials.
`The rate of bacterial killing by beta-lactams (the bac-
`terial cell would be considered the site of action) is
`usually determined by the length of time that the
`drug concentration remains above the minimal con-
`centration that inhibits bacterial growth.
`
`FIGURE 1-10.
`Relationship between plasma theophylline concentration and
`change in forced expiratory volume (FEV) in asthmatic patients.
`Source:
` Reproduced with permission from Mitenko PA, Ogilvie
`RI. Rational intravenous doses of theophylline.
`N Engl J Med
`1973;289:600–3. Copyright 1973, Massachusetts Medical
`Society.
`
`FIGURE 1-11.
`Process for reaching dosage decisions with therapeutic drug
`monitoring.
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`6
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`Concepts in Clinical Pharmacokinetics
`
`FIGURE 1-12.
`Relationship of pharmacokinetics and
`pharmacodynamics and factors that
`affect each.
`
`compartments needed to describe the drug’s behavior in
`the body. There are one-compartment, two-compart-
`ment, and multicompartment models. The compart-
`ments 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 (Figure 1-13).
`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 representa-
`tion 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 consid-
`ered as one compartment. The compartment that
`includes blood (plasma), heart, lungs, liver, and kidneys is
`usually referred to as the
`
`central compartment or the
` (Figure 1-14). The
`highly blood-perfused compartment
`other compartment that includes fat tissue, muscle tissue,
`
`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 concen-
`trations in tissues and fluids. Simplifications of body pro-
`cesses are necessary to predict a drug’s behavior 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. Com-
`partmental models are categorized by the number of
`
`TABLE 1-1.
`Therapeutic Ranges for Commonly Used Drugs
`
`Drug
`
`Digoxin
`
`Lidocaine
`
`Lithium
`
`Phenobarbital
`
`Phenytoin
`
`Quinidine
`
`Cyclosporin
`
`Valproic acid
`
`Carbamazepine
`
`Ethosuxamide
`
`Primidone
`
`Range
`
`0.5–2.0 ng/mL
`
`1.5–5.0 mg/L
`
`0.6–1.4 mEq/L
`
`15–40 mg/L
`
`10–20 mg/L
`
`2–5 mg/L
`
`150–400 ng/mL
`
`50–100 mg/L
`
`4–12 mcg/mL
`
`40–100 mg/L
`
`5–12 mg/L
`
`Source:
` Adapted with permission from Bauer LA. Clinical phar-
`macokinetics and pharmacodynamics. In: DiPiro JT, Talbert RL,
`Yee GC, et al., editors.
`Pharmacotherapy: a Pathophysiologic
` 7th ed. New York: McGraw-Hill; 2008. p. 10.
`Approach,
`
`FIGURE 1-13.
`Simple compartmental model.
`
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`Lesson 1: Introduction to Pharmacokinetics and Pharmacodynamics
`
`7
`
`FIGURE 1-15.
`One-compartment model.
`
`ment is represented by an enclosed square or rectangle,
`and rates of drug transfer are represented by straight
`arrows (Figure 1-15). The arrow pointing into the box
`simply indicates that drug is put into that compartment.
`And the arrow pointing out of the box indicates that
`drug is leaving the compartment.
`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. Common abbrevia-
`tions are shown in Figure 1-15.
`Some drugs do not distribute instantaneously to all
`parts of the body, however, even after intravenous
`bolus administration.
` means
`Intravenous bolus dosing
`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. Drug moves
`back and forth between these compartments to main-
`tain equilibrium (Figure 1-16).
`Figure 1-17 simplifies the difference between one-
`and two-compartment models. Again, the one-compart-
`ment model assumes that the drug is distributed to tissues
`very rapidly after intravenous administration.
`
`FIGURE 1-14.
`Typical organ groups for central and peripheral compartments.
`
`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 elimi-
`nation does not change over time.
`The value of any model is determined by how well it
`predicts drug concentrations in fluids and tissues. Gener-
`ally, 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 mod-
`els are often required to predict tissue drug concentrations.
`
`LINICAL
`
`ORRELATE
`
`䊑
` C
`C
`Drugs that do not extensively distribute into extravascu-
`lar tissues, such as aminoglycosides, are generally well
`described by one-compartment models. Extent of dis-
`tribution is partly determined by the chemistry of the
`agents. Aminoglycosides are polar molecules, so their
`distribution is limited primarily to extracellular water.
`Drugs extensively distributed in tissue (such as lipophilic
`drugs like the benzodiazepines) or that have extensive
`intracellular uptake may be better described by the
`more complex models.
`
`COMPARTMENTAL MODELS
`
`The one-compartment model
`is the most frequently
`used model in clinical practice. In structuring the
`model, a visual representation is helpful. The compart-
`
`FIGURE 1-16.
`Compartmental model representing transfer of drug to and
`from central and peripheral compartments.
`
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`8
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`Concepts in Clinical Pharmacokinetics
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`FIGURE 1-17.
`Drug distribution in one- and two-compartment
`models.
`
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`The two-compartment model can be represented as
`in Figure 1-18, where:
`
` = dose of drug
`
`X
`0
` = amount of drug in central compartment
`X
`1
` = amount of drug in peripheral compartment
`X
`2
`
`K = elimination rate constant of drug from central
`compartment to outside the body
`= elimination rate constant of drug from central
`K
`12
`compartment to peripheral compartment
` = elimination rate constant of drug from periph-
`K
`21
`eral compartment to central compartment
`
`drug in tissue and plasma, plasma concentrations
`decline less rapidly (Figure 1-19). The plasma would
`be the central compartment, and muscle tissue would
`be the peripheral compartment.
`
`Volume of Distribution
`) in
`Until now, we have spoken of the amount of drug (X
`
`a compartment. If we also consider the volume of the
`
`LINICAL
`
`ORRELATE
`
`䊑
` C
`C
`Digoxin, particularly when given intravenously, is an
`example of a drug that is well described by two-
`compartment pharmacokinetics. After an intravenous
`dose is administered, plasma concentrations rise and
`then rapidly decline as drug distributes out of plasma
`and into muscle tissue. After equilibration between
`
`FIGURE 1-18.
`Two-compartment model.
`
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`Lesson 1: Introduction to Pharmacokinetics and Pharmacodynamics
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`9
`
`TABLE 1-2.
`Approximate Volumes of Distribution
`of Commonly Used Drugs
`
`Drug
`
`Volume of Distribution (L/kg)
`
`Amlodipine
`
`Ganciclovir
`
`Ketorolac
`
`Lansoprazole
`
`Montelukast
`
`Sildenafil
`
`Valsartan
`
`16.0 ± 4
`
`1.1 ± 0.2
`
`0.21 ± 0.04
`
`0.35 ± 0.05
`
`0.15 ± 0.02
`
`1.2 ± 0.3
`
`0.23 ± 0.09
`
`Source: Brunton LL, Lazo JS, Parker KL (editors). The Pharma-
`cologic Basis of Therapeutics, 11th edition. New York: McGraw-
`Hill; 2006. pp. 1798, 1829, 1839, 1840, 1851, 1872, 1883.
`
`the body is primarily composed of water. To calculate
`the volume of the tank, we can place a known quantity
`of substance into it and then measure its concentration
`in the fluid (Figure 1-20). If the amount of substance (X)
`and the resulting concentration (C) is known, then the
`volume of distribution (V) can be calculated using the
`simplified equations:
`
`X C
`
`=
`
`V
`
`or
`
`X V
`
`=
`
`C
`
`=
`X VC
`
`or
`
`X = amount of drug in body
`V = volume of distribution
`C = concentration in the plasma
`As with other pharmacokinetic parameters, volume of
`distribution can vary considerably from one person to
`another because of differences in physiology or disease
`states. Something to note: The dose of a drug (X0) and
`
`FIGURE 1-20.
`The volume of a tank can be determined from the amount of
`substance added and the resulting concentration.
`
`FIGURE 1-19.
`Plasma concentrations of digoxin after an intravenous dose.
`
`compartment, we can describe the concept of drug con-
`centration. Drug concentration in the compartment is
`defined as the amount of drug in a given volume, such
`as mg/L:
`
`concentration
`
`=
`
`amount of drug in body
`volume in w
`hhich
`drug is distributed
`
`= X
`V
`
`䊕 1
`
`-1
`
`Volume of distribution (V) is an important indicator of
`the extent of drug distribution into body fluids and tis-
`sues. V relates the amount of drug in the body (X) to the
`measured concentration in the plasma (C). Thus, V is
`the volume required to account for all of the drug in the
`body if the concentrations in all tissues are the same as
`the plasma concentration:
`
`volume of distribution
`
`=
`
`amount of drug
`concentra
`ttion
`
`A large volume of distribution usually indicates that the
`drug distributes extensively into body tissues and fluids.
`Conversely, a small volume of distribution often indi-
`cates limited drug distribution.
`Volume of distribution indicates the extent of distri-
`bution but not the tissues or fluids into which the drug
`distributes. Two drugs can have the same volume of dis-
`tribution, but one may distribute primarily into muscle
`tissues, whereas the other may concentrate in adipose
`tissues. Approximate volumes of distribution for some
`commonly used drugs are shown in Table 1-2.
`When V is many times the volume of the body, the
`drug concentrations in some tissues should be much
`greater than those in plasma. The smallest volume in
`which a drug may distribute is the plasma volume.
`To illustrate the concept of volume of distribution, let
`us first imagine the body as a tank filled with fluid, as
`
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`10
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`Concepts in Clinical Pharmacokinetics
`
`Elimination
`
`FIGURE 1-21.
`Drug elimination complicates the determination of the “vol-
`ume” of the body from drug concentrations.
`
`FIGURE 1-22.
`One-compartment model.
`
`䊑 CLINICAL CORRELATE
`Drugs that have extensive distribution outside of
`plasma appear to have a large volume of distribu-
`tion. Examples include digoxin, diltiazem, imipramine,
`labetalol, metoprolol, meperidine, and nortriptyline.
`
`PLASMA DRUG CONCENTRATION
`VERSUS TIME CURVES
`With the one-compartment model (Figure 1-22), if we
`continuously measure the concentration of a drug in the
`plasma after an intravenous bolus dose and then plot
`these plasma drug concentrations against the times they
`are obtained, the curve shown in Figure 1-23 would
`result. Note that this plot is a curve and that the plasma
`concentration is highest just after the