APPLIED
`BIDPHARMACEUTICS
`
`&PHARMACOK|NET|CS
`
`FIFTH EDITION
`
`LEON SHARGEL, PhD, RPh
`Vice President, Biopharmaceutics
`Eon Labs, Inc.
`Wilson, North Carolina
`
`Adjunct Associate Professor
`School of Pharmacy
`University of Maryland
`Baltimore, Maryland
`
`SUSANNA WU—PDNG PhD. RPh
`Associate Professor
`
`Department of Pharmaceutics
`Medical College of Virginia Campus
`Virginia Commonwealth University
`Richmond, Virginia
`
`ANDREW B.C. YU PhD. RPh
`Registered Pharmacist
`Gaithersburg, MD
`Formerly Associate Professor of Pharmaceutics
`Albany College of Pharmacy
`Present Affiliation: HFD—520, CDER, FDA*
`
`*The content of this book represents the personal views of the authors and not that of the FDA.
`
`McGraw-Hill
`
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`Page 1
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`

`
`The McGraw-Hill Companies
`
`Applied Biopharmaceutics and Pl1a1macokinefics, Fifth Edition
`
`Copyright © 2005 by The McGraw—Hill Companies, Inc. Copyright © 1999, 1993 by Appleton
`8c Lange; copyright © 1985, 1980 by Appleton~Century-Crofts. All rights reserved. Printed
`in the United States of America. Except as permitted under the United States copyright’
`Act of 1976, no part of this publication may be reproduced or distributed in any form or
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`mission of the publisher.
`
`23456'7‘?890 DOC/DOC 098765
`
`ISBN 0-07—l37550—3
`
`This book was set in New Baskerville by TechBooks.
`The editors were Michael Brown and Christie Naglieri.
`The production service was TechBool<s.
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`
`This book is printed on acid-free paper.
`
`Library of Congress Cataloging-in-Publication Data
`Shargel, Leon, 1941-
`Applied biopharmaceutics 8c pharmacokinetics/Leon Shargel, Susanna Wu-Pong,
`Andrew B.C; Yu. ;—-5th ed.
`p. ; cm.
`Includes bibliographical references and index.
`ISBN O-(J7-l 37550-3
`I. Title: Applied biopharmaceutics and
`2. Pharmacokinetics.
`‘* 1. Biopharmaceutics.
`pharmacokirieucs.
`ll. Wu-Pong, Susanna.
`III. Yu, Andrew B. C.,
`1945‘ IV. Title.
`
`2. Models, Chemical.
`1. Biopharrnaceutics.
`[DNLM:
`QV 38 S531a 2004] RM301.4.S52 2004
`615‘/7-dc22
`
`3. Pharmacokinetics.
`
`2004044993
`
`Please tell the authors and publisher what you think of this book by sending your
`comments to pharmacy@mcgraw—hill.com. Please put the author and title of the
`book in the subject line.
`
`Page 2
`
`

`
`RELATIONSHIP
`
`BETWEEN
`
`PHARMACOKINETICS
`AND
`
`PHARMACODYNAMICS
`
`PHARMACODYNAMICS AND PHARMACOKINETICS
`
`Previous chapters in this book have discussed the importance of using pharmaco-
`kinetics to develop dosing regimens that will result in plasma concentrations in the
`therapeutic window and yield the desired therapeutic or pharmacologic response.
`The interaction of a drug molecule with a receptor causes the initiation of a se-
`quence of molecular events resulting in a pharmacodynamic or pharmacologic
`response. ifhe term pha-rmacodynamics refers to the relationship between drug con-
`ccntrations at the site of action (receptor) and pharmacologic response, including
`the biochemical and physiologic effects that influence the interaction of drug with
`the receptor. Early pharmacologic research demonstrated that the pharmacody-
`namic response produced by the drug depends on the chemical structure of the
`drug molecule. Drug receptors interact only with drugs of specific chemical struc-
`ture, and the receptors were classified according to the type of pharmacodynamic
`response induced.
`Since most pharmacologic responses are due to noncovalent interaction between
`the drug and the receptor, the nature of the interaction is generally assumed to
`be reversible and conforms to the Law of Mass Action. One or several drug mole-
`cules may interact simultaneously with the receptor to produce a pharrnacologic
`response. Typically, a single drug molecule interacts with a receptor with a single
`binding site to produce a pharrnacologic response, as illustrated below.
`
`Page 3
`
`

`
`Page 4
`
`

`
`RELATIONSHIP l5L”l'WEEN PHARMACOKINETICS AND PHARMACQDYNAQAICS CHAPTER19.
`
`577
`
`Both theories are consistent with the observed saturation (siginoidal) drug—dose
`response relationships, but neither theory is sufficiently advanced to give a detailed
`description of the “locl<-and-key” or the more recent “induced-fit” type of drug in-
`teractions with enzymatic receptors. Newer theories of drug action are based on
`in-z/itro studies on isolated tissue receptors and on observation of the conforma-
`tional and binding changes with different. drug substrates. These in-vitro studies
`show that other types of interactions between the drug molecule and the receptor
`are possible. However, the results from the in—1/itro studies are dillicult to extrapo-
`late to in—v~ivo conditions. The pharmacologic response in drug therapy is often a
`product of physiologic adaptation to a drug response. Many drugs trigger the phar-
`macologic response through a cascade of enzymatic events highly regulated by the
`body
`Unlike pharmacokinetic modeling, pharmacodynamic modeling can be more
`complex because the clinical measure (change in blood pressure or clotting time)
`is often a surrogate for the drug’s actual pharmacologic action. For example, after
`the drug is systemically absorbed, it is then transported to site of action where the
`pharmacologic receptor resides. Drug—receptor binding may then cause a second-
`ary response, such as signal transduction, which then produces the desired elfect.
`Clinical measurement of drug response may only occur after many such biologic
`events, such as transport or signal transduction (an indirect effect), so pl1armacody-
`namic modeling must account for biologic processes involved in eliciting drug-
`induced responses.
`The complexity of the molecular events triggering a pharmacologic response is
`less difficult to describe using a pharmacokinetic approach. Pharmacokinetic mod-
`els allow very complex processes to be simplified. The process of pharmacokinetic
`modeling continues until a model is found that describes the real process quanti-
`tatively. The understanding of drug response is greatly enhanced when pharma-
`cokinetic modeling techniques are combined with clinical pharmacology, resulting
`in the development of pharmacokineticfiharmacodynanzic models. Pharmacol<inetiC—
`pharmacodynamic models use data derived from the plasma drug concentration-
`versus-time profile and from the time course of the pharmacologic effect to predict
`the pharmacodynamics of the drug. Pharmacokinetic—pharmacodynamic models
`have been reported for antipsychotic medications, anticoagulants, neuromuscular
`blockers, antihypertensives, anesthetics, and many antiarrhythmic drugs (the phar-
`macologic responses of these drugs are well studied because of easy monitoring).
`
`RELATION OF DOSE TO
`PHARMACOLOGIC EFFECT
`
`The onset, intensity, and duration of the pharmacologic effect depend on the dose
`and the pharmacokinetics of the drug. As the dose increases, the drug concentra-
`tion at the receptor site increases, and the pharmacologic response (effect) increases
`up to a maximum effect. A plot of the pharmacologic effect to dose on a linear
`scale generally results in a hyperbolic curve with maximum effect at the plateau
`(Fig. 19-1). The same data may be compressed and plotted on a log~linear scale
`and results in a sigmoid curve (Fig. 19-2).
`
`Page 5
`
`

`
`S78
`
`CHAPTER19. RELATIONSI-llP BETWEEN PHARM/\COl<lNEIICS7_AND PHARMACODYNAMICS
`
`response
`
`A small increase in
`response occurs by
`c: given dose change
`
`
`
`Pharmczcologicresponse
`
`A large increase in
`response occurs by
`0 given close change
`in this region
`
`DW9 ‘i059
`
`Figure 19-1. Plot of pharmacologic re
`sponse versus dose on a linear scale.
`
`For many drugs, the graph of log dose~response curve shows a linear relation-
`ship at a dose range between 20% and 80% of the maximum response, which typ-
`ically includes the therapeutic dose range for many drugs. For a drug that follows
`one-compartment pharmacokinetics, the Volume of distribution is constant; there-
`fore, the pharmacologic response is also proportional to the log plasma drug con-
`centration within a therapeutic range, as shown in Figure 19-3.
`Mathematically, the relationship in Figure 19-3 may be expressed by the follow-
`ing equation, where m is the slope, e is an extrapolated intercept, and E is the drug
`effect at drug concentration C:
`
`E = mlogC + e
`
`Solving for log C yields
`
`(j:
`log ,
`
`E—e
`
`m
`
`
`
`Phormcicologicelieci
`
`Log dose
`
`log dose versus
`Figure 19-2. Typical
`pharmacologic response curve.
`
`(19.1)
`
`
`
`Phcrmucologiceilecl
`
`Log drug concentration
`
`Figure 19-3. Graph of log drug con-
`centration versus pharmacologic effect.
`Only the linear portion of the curve is
`shown.
`
`Page 6
`
`

`
`RELATIONSHIP BETWEEN l’llARMACOKlNETlCS AND PHARMACODYNAMICS CHAPTER,
`
`579
`
`However, after an intravenous dose, the concentration of a drug in the body in a
`onecompartment open model is described as follows:
`kt
`logC“—’ logC0 — 23
`
`(19.3)
`
`By substituting Equation 19.2 into Equation 19.3, we get Equation 19.4, where
`E0 '—" effect at concentration C0:
`Eee
`m __E0-e
`m
`
`kt
`2.3
`
`E
`
`E0
`
`km
`2.3
`
`(19.4)
`
`The theoretical pharmacologic response at any time after an intravenous dose
`of a drug may be calculated using Equation l9/L. Equation 19.4 predicts that the
`pharmacologic effect will decline linearly with time for a drug that follows a one-
`compartment model, with a linear log dose—pharmacologic response. From this
`equation, the pharmacologic effect declines with a slope of km/2.3. The decrease
`in pharmacologic effect is affected by both the elimination constant k and the
`slope m. For a drug with a large m, the pharmacologic response declines rapidly
`and multiple doses must be given at short inteivals to maintain the pharmacologic
`effect.
`
`The relationship between pharmacokinelics and pharmacologic response can
`be demonstrated by observing the percent depression of muscular activity after an
`IV dose of (+)-tubocurarine. The decline of pharmaeologic effect is linear as a
`function of time (Fig. 19-4). For each dose and resulting pharmacologic response,
`the slope of each curve is the same. Because the values for each slope, which in-
`clude km (Eq. 19.4), are the same, the sensitivity of the receptors for (+)—tubocu—
`rarine is assumed to be the same at each site of action. Note that a plot of the log
`concentration of drug versus time yields a straight line.
`A second example of the pharmacologic effect declining linearly with time was
`observed with lysergic acid dicthylamide, or LSD (Fig. 196). After an IV dose of
`the drug, log concentrations of drug decreased linearly with time except for a brief
`distribution period. Furthermore, the pharmacologic effect, as measured by the
`performance score of each subject, also declined linearly with time. Because the
`
`Figure 19-4. Depression of normal muscle activity
`as a function of time after lv administration of O. l -0.2
`mg l+}—tubocurarine per kilogram to unanesthetized
`volunteers, presenting mean values of 6 experiments
`on 5 subjects. Circles represent head lift; squares,
`hand grip; and triangles, inspiratory flow.
`(Adapted from Johansen et al, 1964, with permission.)
`
`é (
`
`DO
`
`OO
`
`3:-0
`
`ix)0
`
`00
`
`15
`10
`5
`Time (minutes)
`
`20
`
`
`
`
`
`Depressionofnormalactivity(percent)
`
`Page 7
`
`

`
`580
`
`CHAPTER 19. RELATIONSHIP BETWIEEN l’HARMAL'()KlNljTlCS AND PMARMACODYNAMICS
`
`O
`
`i\)O
`
`
`
`Performance{percentofcontrol)> ooo~xx0O0
`
`
`
`
`
`PlasmaCOflCEfllVGlIO|"l(ng/mL)
`
`5
`
`()1
`
`—-to
`
`O
`
`A
`
`Time (hours)
`
`4
`
`Time (hours)
`
`Figure 19-5. Mean plasma concentrations of LSD and performance test scores as a function of time
`after IV administration of 2 pg LSD per kilogram to 5 normal human subjects.
`(Adapted from Aghajanian and Bing, I964, with permission.)
`
`slope is governed in part by the elimination rate constant, the pharmacologic effect
`declines mucl-.1 more rapidly when the elimination rate constant is increased as a
`result of increased metabolism or renal excretion. Conversely, a longer pharma»
`cologic response is experienced in patients when the drug has a longer halfilife.
`
`RELATIONSHIP BETWEEN DOSE AND DURATION
`
`OF ACTIVITY (teff), SINGLE IV BOLUS INJECTION
`
`The relationship between the duration of the pharmacologic effect and the dose
`can be inferred from Equation 19.3. After an intravenous dose, assuming a
`one—compartment model, the time needed for any drug to decline to a con-
`centration C is given by the following equation, assuming the drug takes effect
`immediately:
`
`2.3 1 re —1
`C
`
`z=_»9°52 0g )
`.1"
`,
`
`(19.5)
`
`Using Ceg to represent the minimum effective drug concentration, the duration of
`drug action can be obtained as follows:
`
`‘.3l
`
`1) V —l
`
`‘C
`
`lefi:
`
`(19_(;)
`
`Some practical applications are suggested by this equation. For example, a dou-
`bling of the dose will not result in a doubling of the effective duration of pharma—
`cologic action. On the other hand, a doubling of 231/2 or a corresponding decrease
`in k will result in a proportional increase in duration of action. A clinical situation
`is often encountered in the treatment of infections in which C53 is the bacteriocidal
`concentration of the drug, and, in order to double the duration of the antibiotic,
`a considerably greater increase than simply doubling the dose is necessary.
`
`Page 8
`
`

`
`581
`
`The minimum effective concentration (MEG) in plasma for a certain antibiotic is
`0.1 /veg/mL. The drug follows a one-compartment open model and has an apparent
`volume of distribution, VI), of 10 L and a first—order elimination rate constant of
`1.0 hr‘1.
`
`a. What is the Jeff for a single 100—mg IV dose of this antibiotic?
`b; What. is the new tag; or t’eg- for this drug if the dose were increased 10-fold, to
`1000 mg?
`i
`‘
`
`Solution 0
`a. The tcff for a 100-xiig dose is calculated as follows. Because VD = 10,000 mL,
`‘
`l00 mg
`=
`6° , 10,000 mL
`
`= 10
`
`L
`
`“g/I"
`
`For a lone-cornpartmem-model IV dose, C = C004“. Then
`0.1 = l0e“(1‘°"°”
`
`tdf
`
`hr
`
`téfffora}/1000-ing dose is calculated as follows.(prime refers to a new dose).
`Because V15 = 10,000 mL,
`’
`
`0
`
`.0- éfF§—,X.1cOO
`-
`teff '
`‘
`0,
`0
`_
`e "-6.91— .10
`entinc easefiri = L
`‘ -4 6146 L.>< 100
`7*Pe_rclente in reaseuin zeg %5o% 0
`0
`
`0
`
`am 1 shows hatac10¥foldincrease in the doseiinci~ease}Stl{1€s, agxramm of,‘
`rt.g;(:g;;>leil§ycie¢:11yji50%. *
`
`Page 9
`
`

`
`582
`
`CHAPTER 19. REL/\TliQNSHlP”l57ETWEEN PHARM/\COKlNETlCS AND PHARMACODYNAMICS
`
`\
`
`EFFECT OF BOTH DOSE AND ELIMINATION
`HALF-LIFE ON THE DURATION OF ACTIVITY
`
`A single equation can be derived to describe the relationship of dose (D0) and the
`elimination half—life (t1/2) on the effective time for therapeutic activity (tcff), This
`expression is derived below.
`
`ln Ccff -“ lnC0 —~ kteff
`
`Because C0 = D0/ VD,
`
`D
`
`ln(-9) ~ kleif
`
`Vn
`D
`
`ln<T/E) — ln Ce“
`1
`<D0/ VD)
`
`k
`
`Ct-eff
`
`Substituting 0.693/t1/2 for k,
`
`Arr
`
`):1.44 1 ——~
`
`51/2 n(VDCCff)
`
`(19.3)
`
`From Equation 19.8, an increase in £1/2 will increase the tsp; in direct propor-
`tion. However, an increase in the dose, D0, does not increase the teff in direct pro-
`portion. The effect of an increase in VD or Ceff can be seen by using generated
`data. Only the positive solutions for Equation 19.8 are valid, although mathemati-
`cally a negative tog can be obtained by increasing Ceff or VD. The effect of chang-
`ing dose on teff is shown in Figure 19-6 using data generated with Equation 19.8.
`A nonlinear increase in tcff is observed as dose increases.
`
`EFFECT OF ELIMINATION HALF—LIFE
`ON DURATION OF ACTIVITY
`
`Because elimination of drugs is due to the processes of excretion and metabolism,
`an alteration of any of these elimination processes will effect the t1/2 of the drug.
`In certain disease states, pathophysiologic changes in hepatic or renal function will
`
`Figure 19-6.
`
`Plot of reg versus dose.
`
`D059 ("'9/l<9l
`
`8
`
`12
`
`16
`
`Page 10
`
`

`
`RELATIONSHIP Btrwttn RHARMACOKINETICS AND PHARMACODYNAMICS CPTAPTERI9.
`
`583
`
`decrease the elimination ofa drug, as observed by a prolonged t1/2. This prolonged
`I1/2 will lead to retention of the drug in the body, thereby increasing the duration
`of activity of the drug (teff) as well as increasing the possibility of drug toxicity.
`To improve antibiotic therapy with the penicillin and cephalosporin antibi-
`otics, clinicians have intentionally prolonged the elimination of these’ drugs by
`giving a second drug, probenecid, which competitively inhibits renal excretion
`of the antibiotic. This approach to prolonging the duration of activity of antibi-
`otics that are rapidly excreted through the kidney has been used successfully for
`a number of years. Similarly, Augmentin is a combination of amoxicillin and
`clavulanic acid; the latter is an inhibitor of ,8-lactamase. This B—lactamase is a bac—
`terial enzyme that degrades penicillin-like drugs. The data in Table 19.1 illustrate
`how a change in the elimination ti/2 will affect the t,,n- for a drug. For all doses,
`a 100% increase in the m2 will result in a 100% increase in the teff. For example,
`for a drug whose I1/2 is 0.75 hour and that is given at a dose of 2 mg/kg, the tcff
`is 3.24 hours. If the tug is increased to 1.5 hours, the tcff is increased to 6.48 hours,
`an increase of 100%. However, the effect of doubling the dose from 2 to 4 mg/kg
`(no change in elimination processes) will only increase the teq to 3.98 hours, an
`increase of 22.8%. The effect of prolonging the elimination half—life has an
`extremely important effect on the treatment of infections, particularly in patients
`with high metabolism, or clearance, of the antibiotic. Therefore, antibiotics must
`be dosed with full consideration of the effect of alteration of the tug on the teff.
`Consequently, a simple proportional increase in dose will leave the patient’s blood
`concentration below the effective antibiotic level most of the time during drug
`therapy. The effect of a prolonged tefg is shown in lines a and c in Figure 19-7,
`and the disproportionate increase in teff as the dose is increased 10-fold is shown
`in lines a and b.
`
`1
`
`=
`
`*
`
`TABLE 19.1 Relationship between Elimination Ha1f»Life and Duration of Activity
`5 Dost-:50
`‘tj,"3 i=fo.7i15 hr
`“
`t”; = 1.5 hr
`(ma/K91
`1 mzihri ~
`tan ihri
`2.0
`3.24
`(3.48
`3.0
`3.67
`7.35
`4.0
`3.98
`7.97
`5.0
`4.22
`8.45
`6.0
`4.42
`8.84
`7.0
`4.59
`9.18
`8.0
`4.73
`9.47
`9.0
`4.86
`9.72
`10
`4.97
`9.95
`11
`5.08
`10.2
`12
`5.17
`10.3
`13
`5.26
`10.5
`14
`5.34
`10.7
`15
`5.41
`10.8
`16
`5.48
`11.0
`17
`5.55
`11.1
`18
`5.61
`11.2
`19
`5.67
`11.3
`20
`5.72
`11.4
`
`Page 11
`
`

`
`584
`
`CHAPTER 1‘). RELATIONSHIP BETWEEN PHARMACOKINETICS AND PHARMACODYNAMICS
`
`
`
`
`
`Logpiosrnoconcentration(1.19/mL)
`
`1 O
`
`I
`
`0,]
`
`00
`
`2
`
`A
`Time (hours)
`
`6
`
`Plasma |evel—time curves describing
`Figure 19-7.
`the relationship of both dose and elimination half—llfe
`on duration of drug action. Ceff = effective concentra-
`tion. Curve a= single lOO—mg IV injection of drug;
`k = 1.0 hr". Curve b = single lOOO—mg IV injection,‘
`k: 1.0 hr“. Curve C: single 100-mg lV injection;
`/<= 05 hr“? VD is 10 L.
`
`CW
`
`Pharmacokinetic/Pharmacodynamic Relationships
`and Efficacy of Antibiotics
`
`In the previous section, the time above the effective concentration, tag, was shown
`to be important in optimizing‘ the therapeutic response of many drugs. This con-
`cept has been applied to antibiotic drugs (Drusano, 1988; Craig, 1995; Craig and
`Andes, 1996; Scaglione, 1997). For example, Craig and Andes (1996) discussed the
`antibacterial treatment of otitis media. Using the minimum inhibitory antibiotic. con-
`centration (MIC) for the microorganism in serum, the percent time for the antibi-
`otic drug coiiceiitrationi to be above the MIC was calculated for several antibacterial
`classes, including cephalosporins, macrolides, and trimethoprim—sulfatnethoxazole
`(TMP/SMX) coinbination (Table 19.2). Although the drug concentration in the
`
`TABLE 19.2 Middle Ear F|uid—to—Serum Ratios for Common Antibiotics
`
`<
`
`Cephalosporins
`Cefaclor
`‘
`Cefuroxime
`Macrolide antibiotic
`Erythromycin
`Sulfa drug
`Sulfisoxazole
`
`From Craig and Andes (19%).
`
`0.184028
`0.22
`
`’
`
`0.49
`
`0.20
`
`Page 12
`
`

`
`
`
`
`
`Bocieriologiccure(percent)
`
`RELATIONSHIP BETWEEN7P7HKAi§r\/L/\COKlNETlCS AND PHARMACODYNAMICS CHAPTER19.
`
`585
`
`LEGEND:
`0 0 IHGCIGMS
`D I M°C”°”d9‘
`V ' WP/SMX
`
`60
`40
`Time above MIC (percent)
`
`80
`
`Figure 19-8. Relationship between the
`percent
`time above MlC9o of the dosing
`interval during therapy and percent of
`bacteriologic cure in otltis media caused by
`S. pneumoniae [open symbols) and ,8-
`lactamaseposltive
`and —negative
`H.
`inf/uenzae (closed symbols). (Circles, closed
`and open = ,8-lactams; squares, closed and
`open=macrolides;
`triangles, closed and
`open = TMP/SMX.}
`(From Craig and Andres,
`mission‘)
`
`I996, with per»
`
`middle ear fluid (MEF) is important, once the ratio (MEF/serum) is known, the
`serum drug level may be used to project MEF drug levels. The percent time above
`MIC of the dosing interval during therapy correlated well to the percent of bacte-
`riologic cure (Figure 19-8). An almost 100% Cure was attained by maintaining the
`drug concentration above the MIC for 60-70% of the dosing interval; an 80-85%
`cure was achieved with 40-50% of the dosing interval above MIC. When the per-
`cent of time above MIC falls below a critical value, bacteria will regrow, thereby
`prolonging the time for eradication of the infection. The pharmacokinetic model
`was further supported by experiments from a mouse infection model in which an
`infection in the thigh due to Pseudomonas aeruginosa was treated with ticarcillin and
`tobramycin.
`In another study, Craig (1995) compared the AUC/MIC, the time above MIC, and
`drug peak concentration over MIC and found that the best fit was obtained when
`colony-forming units (CFUS) were plotted versus time above MIC for cefotaxime in
`a mouse infection model (Fig. 19-9).
`Both Drusano (1988) and Craig (1995) reviewed the relationship of pharmaco-
`kinetics and pharmacodynamics in the therapeutic efficacy of antibiotics. For some
`antibiotics, such as the aminoglycosides and fluoroquinolones, both the drug con
`centration and the dosing interval have an influence on the antibacterial effect.
`For some antibiotics, such as the /3-lactams, vancomycin, and the macrolides, the
`duration of exposure (time-dependent killing) or the time the drug levels are main-
`tained above the MIC (tag) is most important for efficacy. For many antibiotics (cg,
`fluoroquinolones), there is a defined period of bacterial growth suppression after
`short exposures to the antibiotic. This phenomenon is known as the postantibiotic
`efiect (PAE). Other influences on antibiotic activity include the presence of active
`metabolite (s), plasma drug protein binding, and the penetration of the antibiotic
`into the tissues. In addition, the MIC for the antibiotic depends on the infectious
`microorganism and the resistance of the microorganism to the antibiotic. In the
`case of ciprofloxacin, a quinolone, the percent of cure of infection at Various doses
`was better related to AUIC, which is the product of area under the curve and the
`
`Page 13
`
`

`
`586
`
`CHAPTER19. RELA'l‘lONSHII’ BETWEEN PHARMACo1<iN_ET1cs AND Pl-MRMACODYNAMICST
`
`
`
`LogmCFUperlungat24hours
`
`l00 l000l0000
`l0
`Peak/MIC ratio
`
`l0 30 lOO 300l0OO3000
`24-Hour AUC/MIC ratio
`CFU = Colony-Forming unit
`
`0
`
`80 lO0
`60
`40
`20
`Time above MIC (percent)
`
`Figure 19-9. Relationship among three pharmacodynamic parameters and the number of K/ebsiel/a
`pneumoniae in the lungs of neurotroponic mice after 24-hour therapy with cefotaximc. Each point represents
`one mouse.
`
`(From Craig \)</A, i995, with permission.)
`
`211, 1993).
`reciprocal of minimum inhibition concentration, MIC (Forrest Ct
`Interestingly, quinolones inhibit bacterial DNA gyrase, quite different from the
`[3—lactam antibiotics, which involve darnage to bacterial cell walls.
`
`Relationship between Systemic Exposure and
`Response—Anticancer Drugs
`
`Plasma drug concentrations for drugs that have highly variable drug clearance
`in patients fluctuate widely even after intravenous infusion (Rodman and Evans,
`1991). For highly variable drugs, there is no apparent relationship between the
`therapeutic response and the drug dose. For example,
`the anticancer drug
`teniposide at three different doses give highly variable steady—state drug con-
`centrations and therapeutic response (Fig. 19-10). In some patients, single—point
`drug concentrations were variable and even higher with lower doses. Careful
`pharmacokinetic—pharmacodynarnic analysis showed that a graded response
`curve may be obtained when responses are plotted versus systemic exposure as
`
`(4)O
`
`ION)O01
`
`ou.oG
`
`
`
`Steady-stateconcentration
`
`OO
`O
`
`8
`
`LEGEND:
`0 Response
`g No response
`
`750
`600
`Dose level (mg/mzl
`
`Figure I9-10. Steady-state concentration and
`response after three levels of teniposide administered
`by intravenous infusion.
`(From Rodman and Evans, 1991, with permission.)
`
`Page 14
`
`

`
`RELATIONSHIP BETWEEN l’IlARMACOKlNETlC_S_ AND PHARlvtACODYN}§MlCS WCHAPTER19.
`
`587
`
`
`
`Responselpropofiion)
`
`Response
`(3/7)
`
`<5 500. 12oo—>18oo
`1200 1300
`I'M ' “W
`
`Figure 19-1 1. Relationship between systemic expo-
`sure for teniposide and toxicity and efficacy, shown as
`proportions of patients.
`{From Rodman and Evans, 199», with permission.)
`
`measured by “concentration >< time” (Fig. 19-11). This is one example showing
`that anticancer response may be better correlated to total area under the drug
`concentration curve (AUC), even when no apparent dose—response relation-
`ship is observed. Undoubtedly, the cytotoxic effect of the drug involves killing
`cancer cells with multiple-resistance thresholds that require different time ex-
`posures to the drug. The objective of applying pharmacokinetic—pharmacody—
`namic principles is to achieve therapeutic efficacy without triggering drug toxic-
`ity. This relationship is illustrated by the sigmoid curves for response and toxicity
`(Fig. 19-11), both of which lie close to each other and intensify as concentration
`increases.
`
`RATE OF DRUG ABSORPTION AND
`PHARMACODYNAMIC RESPONSE
`
`The rate of drug absorption influences the rate in which the drug gets to the re-
`ceptor and the subsequent pharmacologic effect. For drugs that exert an acute
`pharmacologic effect, usually a direct-acting drug agonist, extremely rapid drug ab-
`sorption may have an intense and possibly detrimental effect. For example, niacin
`(nicotinic acid) is a vitamin given in large doses to decrease elevated plasma cho-
`lesterol and triglycerides. Rapid systemic absorption of niacin when given in an im-
`mediate-release tablet will cause vasodilation, leading to flushing and postural hy-
`pertension. Exte_nded—release niacin products are preferred because the more
`slowly absorbed niacin allows the baroreceptors to adjust to the vasodilation and
`hypotensive effects of the drug. Phenylpropanolamine was commonly used as a
`nasal decongestant in cough and cold products or as an anorectant in weight-loss
`products. Phenylpropanolarnine acts as a pressor, increasing the blood pressure
`much more intensely when given as an immediate-release product compared to an
`extended-release product.
`
`Equilibration Pharmacodynamic Half-Life
`
`For some drugs, the half-time for drug equilibration has been estimated by ob-
`serving the onset of response. A list of drug half-times reported by Lalonde (1992)
`is shown in Table 19.3. The factors that affect this parameter include perfusion of
`
`Page 15
`
`

`
`S88
`
`CHAPTEl{19. REL/\TilONSl:l_lP BETWEEN PHARMACOKINETICS AND PH/\RMl\CODYNAMl7CS
`
`TABLE 19.3 Equllibration Half—Tlmes Deter/mined Using the Effect Compartment Method
`EOUILIBRATION
`PHARMACOLOGIC
`t,,2 (min)
`RESPONSE
`
`DRUG T
`
`d—Tubocurarine
`Dlsopyramide
`Ouinidine
`Digoxin
`Terbutaline
`Terhutaline
`Thcophylline
`Verapamil
`Nizatidine
`Thiopental
`Fentanyl
`Altentanil
`Ergotamine
`\/ercuronium
`/\l~/\cetylprocainamide
`
`From Lalonde ii992l,‘°\'lvith permission.
`
`4
`2
`8
`
`7 5
`
`1
`
`l
`2
`B3
`l.2
`6.4
`l
`l
`
`.
`
`Muscle paralysis
`OT prolongation
`OT prolongation
`LVET shortening
`FEV;
`Hypokalemia
`FFV.
`PR prolongation
`Gastric pH
`Spectral edge
`Spectral edge
`Spectral edge
`Vasoconstriction
`Muscle paralysis
`OT prolongation
`
`the effect compartment, blood—tissue partitioning, drug diffusion from capillaries
`to the effect compartment, protein binding, and elimination of thc drug from the
`effect compartment.
`
`Substance Abuse Potential
`
`The rate of drug absorption has been associated with the potential for substance
`abuse. Drugs taken by the oral route have the lowest abuse potential. For example,
`cocoa leaves containing cocaine alkaloid have been chewed by South American
`Indians for centuries (johanson and Fischman, i989). Cocaine abuse has become
`a problem as a result of the availability of cocaine alkaloid (“crack” cocaine) and
`because of the use of other routes of drug administration (intravenous, intranasal,
`or SII10klI1g,§‘_frtVl}§.>t allow a very rapid rate of drug absorption and onset of action
`(Gone, 1995); Studies on diazepam (deWit et al, 1993) and nicotine (Henningfield
`and Keenan, 1998) have shown that the rate of drug delivery correlates with the
`abuse liability of such drugs. Thus, the rate of drug absorption influences the abuse
`potential of these drugs, and the route of drug administrat.ion that provides faster
`absorption and more rapid onset leads to greater abuse.
`
`DRUG TOLERANCE AND PHYSICAL DEPENDENCY
`
`The study of drug tolerance and physical dependency is of particular interest in
`understanding the actions of abused drug substances, such as opiates and cocaine.
`Drug tolerance is a quantitative change in the sensitivity of the drug and is demon-
`strated by a decrease in pharmacodynamic effect after repeated exposure to the
`same drug. The degree of tolerance may vary greatly (Cox, 1990). Drug tolerance
`has been well described for organic nitrates, opioids, and other drugs. For example,
`
`Page 16
`
`

`
`Rl;'LATlONSlllP BETWEEN PHARMACOKINETICS AND PHARMACODYNAMICS CHAPTER 19.
`
`589
`
`the nitrates relax vascular smooth muscle and have been used for both acute angina
`(eg, nitroglycerin sublingual spray or transmucosal tablet) or angina prophylaxis
`(eg, nitroglycerin transdcrmal, oral controlled-release isosorbide dinitrate). VVell-
`controlled clinical studies have shown that tolerance to the vascular and antiangi—
`nal effects of nitrates may develop. For nitrate therapy, the use of a low nitrate or
`nitrate-free periods has been advocated as part of the therapeutic approach. The
`magnitude of drug tolerance is a function of both the dosage and the frequency
`of drug administration. Cross tolerance can occur for similar drugs that act on the
`same receptors. Tolerance does not develop uniformly to all the pharmacologic or
`toxic actions of the drug. For example, patients who show tolerance to the de-
`pressant activity of high doses of opiates will still exhibit “pinpoint" pupils and con-
`stipation.
`The mechanism of drug tolerance may be due to (1) disposition or pharmaco-
`kinetic tolerance or (2) pharmacodynamic tolerance. Pharmacakinetic tolerance is of-
`ten due to enzyme induction (discussed in earlier chapters), in which the hepatic
`drug clearance increases with repeated drug exposure. Pharmacodynawtic tolerance is
`due to a cellular or ‘receptor alteration in which the drug response is less than what
`is predicted in the patient given subsequent drug doses. Measurement of serum
`drug concentrations may differentiate between pharmacokinetic tolerance and
`pharmacodynamic tolerance. Acute tolerance, or taeltyphylaxifs, which is the rapid
`development of tolerance, may occur due to a change in the sensitivity of the re-
`ceptor or depletion of a cofactor after only a single or a few doses of the drug.
`Drugs that work indirectly by releasing norepinephrine may show tachyphylaxis.
`Drug tolerance should be differentiated from genetic factors which account for
`normal variability in the drug response.
`Physical dependency is demonstrated by the appearance of withdrawal symptoms af-
`ter cessation of the drug. Workers exposed to volatile organic nitrates in the work-
`place may initially develop headaches and dizziness followed by tolerance with con-
`tinuous exposure. However, after leaving the workplace for a few days, the workers
`may demonstrate nitrate withdrawal symptoms. Factors that may affect drug de-
`pendency may includc the dose or amount of drug used (intensity of drug effect),
`the duration of drug use (months, years, and peak use) and the total dose (amount
`of drug X duration). The appearance of withdrawal symptoms may be abruptly pre-
`cipitated in opiate-dependent subjects by the administration of naloxone (Narcan),
`an opioid antagonist that has no agonist properties.
`
`HYPERSENSITIVITY AND ADVERSE RESPONSE
`
`Many drug responses, such as hypersensitivity and allergic responses, are not fully
`explained by ph