`Textbookof Therapeutics
`
`
`
`
`
`Drug and Disease Management
`EIGHTH EDITION
`
`
`Richard A. Helms, PharmD, BCNSP
`Professor and Chair
`Department of Pharmacy
`College of Pharmacy
`Professor of Pediatrics
`University of Tennessee Health Sciences Center
`Memphis, Tennessee
`
`David J. Quan, PharmD, BCPS
`Assistant Clinical Professor
`School of Pharmacy
`University of California San Francisco
`Pharmacist Specialist
`UCSF Medical Center
`San Francisco, California
`
`Eric T. Herfindal, PharmD, MPH
`Professor Emeritus
`School of Pharmacy
`University of California
`San Francisco, California
`
`Dick R. Gourley, PharmD
`Professor and Dean
`College of Pharmacy
`University of Tennessee Health Sciences Center
`Memphis, Tennessee
`
`
`Kimberly A. Bergstrom / Paul M. Beringer /Ali J. Olyaei /
`W. Nathan Rawls / P. David Rogers / Timothy H.Self
`
`Joanna K. Hudson / Greta K. Gourley / Caroline S. Zeind
`G2. Lippincott Williams & Wilkins
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`

`

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`.LED-thy
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`Copyright © 2006 by Lippincott Williams & Wilkins
`Seventh edition © 2000 by Lippincott Williams & Wilkins
`
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`material contained herein. This publication contains information relating to general principles of medical care which should
`not be constructed as specific instruction for individual patients. Manufacturer’s product information should be reviewed
`for current information, including contraindications, dosages, and precautions.
`
`Printed in the United States of America
`
`Library of Congress Cataloging-in-Publication Data
`
`Textbook of therapeutics : drug and disease management. — 8th ed.
`/ editors, Richard A. Helms, David J. Quan.
`p.
`; cm
`Includes bibliographical references and index.
`ISBN 0-7817-5734-7
`1. Chemotherapy.
`2. Therapeutics.
`Il. Quan, David J.
`[DNLM:
`1. Drug Therapy.
`2006]
`RM262.C5 2006
`615.5’8—de22
`
`2. Therapeutics. WB 330 T3555
`
`I. Helms, Richard A.
`
`2005034101
`
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`

`
`
`Preface
`Contributors
`
`m SECTION |
`
`Section II Case Study Questions
`
`273
`
`SECTION ill
`m@
`Diseases of the Eye and Ear 275
`
`General
`
`1
`
`275
`12 Common Eye Disorders
`Andreas Katsoya Lauer and Ali J. Olyaei
`1=Clinical Pharmacodynamics and
`13 Glaucoma
`288
`Pharmacokinetics
`1
`J. Douglas Wurtzbacher and Dick R. Gourley
`Bernd Meibohm and William E. Evans
`
`2 Adverse Drug Reactions and Drug-induced
`Diseases
`31
`Candy Tsouronis
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`Drug Interactions 47
`Robert Keith Middleton
`
`Clinical Toxicology 73
`Wendy Klein-Schwartz
`
`Clinical Laboratory Tests and Interpretation
`91
`Charles F. Seifert and Beth H. Resman-Targoff
`
`Racial, Ethnic, and Sex Differencesin
`Response to Drugs
`116
`Hewitt W. Matthews and Jannifer L. Johnson
`
`Biotechnology 131
`Kimberly Bergstrom and Monique Mayo
`
`Patient Communication in Clinical Pharmacy
`Practice
`161
`Richard N. Herrier, Marie E. Gardner, and Helen
`Meldrum
`
`14 Common Ear Disorders 312
`Michael A. Oszko
`
`Section III Case Study Questions
`
`322
`
`mm
`SECTION IV
`Pediatric and Neonatal Therapy 325
`
`15 Pediatric and Neonatal Therapy 325
`Sherry A. Luedtke
`
`16 Pediatric Nutrition Support 340
`Emily B. Hak and Richard A. Helms
`
`Section IV Case Study Questions
`
`370
`
`m SECTION V
`
`OB/GYNDisorders 373
`
`17 Gynecologic Disorders 373
`Linh Khanh Vuong
`
`18 Contraception 411
`Shareen El-Ibiary
`
`Section I Case Study Questions
`
`176
`
`m@
`
`SECTION |l
`
`
`
`Skin Diseases 181
`
`9 Allergic and Drug-Induced Skin Diseases
`Kelly M. Smith
`
`181
`
`203
`10 Common Skin Disorders
`Rebecca Florez Boettger and Laurie H. Fukushima
`
`257
`11 Burns
`Ted L. Rice and Charles M. Karnack
`
`19 Drugs in Pregnancy and Lactation 434
`Beth Logsdon Pangle
`
`Section V Case Study Questions
`
`449
`
`@ SECTION VI
`
`
`
`Cardiovascular Disorders 451
`
`20 Hypertension 451
`L. Brian Cross
`
`21 Heart Failure 486
`Wendy Gattis Stough, Paul E. Nolan Jr., and Dawn
`G. Zarembski
`
`

`

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`

`

`2
`
`SECTION | & General
`
`not experience an adequate drug response or may experience
`drug-related toxicity.
`
`CLINICAL PHARMACOKINETICS
`
`fi
`
`tween-patient pharmacodynamic variability with the thera-
`peutic as well as toxic effects of a drug.It is importantto note
`that the therapeutic range should notbe considered in absolute
`terms as the limits for this probability range are oftentimes
`chosenarbitrarily. In addition, the therapeutic range is not well
`definedfor a large fraction of the drugsthatare used clinically.
`Theleft panelin Figure 1.1 (see color insert) showsa drug
`The utility of pharmacokinetics does notlie in diagnosing
`concentration-effect relationship. The probability of achiev-
`the diseaseor selecting the ‘‘drug of choice,”’ but in deciding
`ing the desired response is very low when drug concentrations
`the best way to administer a given drugto achieve its thera-
`are less than 5 mgperL,as is the chanceofobservingtoxicity.
`peutic objective. The manner in which a drug is taken is
`Asdrug concentrations increase from 5 to 20 mgperL, the
`referred to as the dosage regimen. The dosage regimentells
`probability of desired responseincreases significantly, while
`us “how much’’ and ‘‘how often’’ a drug must be taken to
`the probability of toxicity increases more slowly. One could
`achieve the desired result. It is these two questions (how
`select a therapeutic range of 10 to 20 mg per L, where the mini-
`much?, how often?) that form the basis for the discipline of
`pharmacokinetics.*°
`mum probability of a therapeutic responseis at least 50% and
`the probability oftoxicity is less than 10%. An optimal dosage
`Clinical pharmacokinetics is the application of pharmaco-
`regimen can be defined as onethat maintains the plasma con-
`kinetic principles in a patient care setting for the design of
`centration of the drug within the therapeutic range. The right
`optimum dosage regimensfor the individual patient. Proba-
`pane] in Figure 1.1 demonstrates this concept by comparing
`bly the most difficult aspect of clinical pharmacokinetics is
`two dosage regimens. The dosing interval (time between
`understandingthe full potential and practical limitations and
`doses; in this case 8 hours)is the same, but the discrete doses
`pitfalls of using specific pharmacokinetic models of drug
`givenin regimenBare twiceaslarge as those given in regimen
`disposition to attain target concentrations based on only a
`A. As shown, drug accumulates in the body during multiple
`limited number (usually 1~2) of drug concentration mea-
`dosing. Regimen A keeps the concentration-time profile
`surements. Although a good understanding of common phar-
`within the therapeutic range, which will result in the majority
`macokinetic concepts is crucial, the competentclinician will
`of patients with adequate therapeutic efficacy with only rare
`have knowledge of not only the mathematics of these con-
`occurrenceofundesired toxicity. Regimen B will likely result
`cepts, but also the principles, assumptions, and potential er-
`in mostpatients with only a marginal increase in efficacy com-
`rors underlying their application in a clinical setting. Further-
`pared toregimenA,but with a muchlargerlikelihood of unde-
`more, a broad therapeutic knowledge is also necessary
`sired toxicity. It should, however, be stressed, that despite
`because measured drug concentrations must be interpreted
`having plasma concentrations within the therapeutic range at
`with respect to the patient’s clinical condition and the phar-
`all times, some of the patients treated with regimen A may
`macodynamic profile of the therapeutic agent.
`
`40
`
`100
`
`
`
`Probability(%)
`
`50
`
`(mg/L)
`PlasmaDrugConcentration
`
`
`o4
`
`Toxicity Pus
`
`20 10
`
`Subtherapeutic
`
`Regimen A
`Regimen B
`
`48
`
`72
`
`96
`
`Drug Concentration (mg/L)
`
`Time (hr)
`
`FIGURE1.1 The concept of a therapeutic range. The left panel showsa relationship between
`the probability of achieving the desired response as well as the chance of observingtoxicity
`in relation to drug concentration in plasma, A therapeutic range of 10 to 20 mg/L could be de-
`fined as a rangeof concentration with relatively high probability of a therapeutic response
`but low probability of drug-related toxicity. The right panel demonstrates the application of
`the therapeutic range concept in designing multiple dose regimens. In the concentration-time
`plot, regimen A keeps drug concentrations within the therapeutic range, whereas regimen B
`results in concentrations exceeding the therapeutic range. RegimenBwill likely result in most
`patients with only a marginal increase in efficacy compared to regimen A, but with a much
`larger likelihood of drug-related toxicity.
`
`

`

`CHAPTER1 ® Clinical Pharmacodynamics and Pharmacokinetics
`
`3
`
`PRIMARY PHARMACOKINETIC PARAMETERS
`Pharmacokinetic parameters are characteristic for the dispo-
`sition and uptake of drug into the body of one specific drug
`in a specific patient. Pharmacokinetic parameters are usually
`not accessible for therapeutic manipulation by the clinician,
`but may be modulated by physiologic or pathophysiologic
`processesin the patient as well as concomitant drug therapy
`(drug-drug interactions) and environmental factors.
`The most
`important pharmacokinetic parameters are
`clearance (CL), volumeofdistribution (V), and bioavailabil-
`ity (F) (Fig. 1.2; see color insert). CL is reflective for the
`drug-eliminating capacity of the body, especially liver and
`kidneys, V refers to the distribution of drug within the body
`including uptake into specific organs and tissues as well as
`binding to proteins and other macromolecules. Based on
`these underlying physiologic processes, CL and V are inde-
`pendent of each other and are called primary pharmacoki-
`netic parameters. Bioavailability (F) refers to the extent of
`drug uptake into the systemic circulation. Although being
`at least partially dependent on hepatic CL via the so-called
`first-pass effect, bioavailability may also be considered as a
`primary parameter.
`Clearance. CL quantifies the elimination of a drug. It is
`the volume of body fluid, blood, or plasma that is cleared
`of the drug per time unit. Thus, it measures the removal of
`drug from the plasmaorblood. For simplicity, only plasma
`CLswill be consideredin the following. CL doesnot indicate
`
`how muchdrug is being removed, butit represents the vol-
`umeof plasma from which the drug is completely removed,
`or cleared, in a given time period. The unit of CL is volume
`per time, e.g., liters per hour or milliliters per minute. It
`may also be normalized to body size, e.g., L/hr/kg. CL is
`an independent pharmacokinetic parameter, and is the most
`important pharmacokinetic parameter because it determines
`the dosingrate.
`The overall total body CL is the sum of individual organ
`CLsthat contribute to the elimination of a drug:
`(1-1)
`CL = CLr + CLy + CLother
`CLp is the renal clearance representing elimination via
`the kidneys, CLy; hepatic clearance representing elimination
`via the liver, and CLother the clearance of other elimination
`organs(e.g., gastrointestinal tract, lungs) that contribute to
`the elimination of a specific drug.
`Organ CLs can be defined by a flow rate Q that represents
`the volume of plasmathat flows through the organ per time
`unit and the extraction ratio E, a measure of the extraction
`efficiency of the organ. E providesthe fraction of the volume
`of plasma that is completely cleared of drug per passage
`through the organ. The extraction ratio can be assessed as
`ratio of the difference between the drug concentration in
`the plasma entering (C;,) and leaving (Coy) the elimination
`organ compared to C;,. In other words, it gives the percent
`of Q that is completely cleared from the drug during passage
`
`through the organ.
`
`Dosage Regimen:
`How often ?
`
`Dosage Regimen:
`How much ?
`
`FIGURE1.2 Interrelationship of primary pharmacokinetic parameters (clearance, volumeofdis-
`tribution, and bioavailability) and their relevance for determining dosage regimens. (Modified
`from van de Waterbeemd H,Gifford E. ADMETin silico modelling: towards prediction para-
`dise? Nat Rev Drug Discov 2:192-—204, 2003.)
`
`

`

`4
`
`SECTION! B General
`
`Volumeof Distribution. V quantifies the extentofdistri-
`bution of a drug throughout the body. Drug distribution
`meansthe reversible transfer of drug from one location to
`another within the body. The concentration achieved in
`plasmaafter distribution depends on the dose and the extent
`of distribution. The V relates the amount of drugin the body
`to the plasma concentration. It is an apparent volume, which
`is calculated upon the simplifying assumption that
`the
`plasma concentration is present in all body compartments.
`The unit of V is volume,e.g., liter or milliliter. It may also
`be normalized to body size, e.g., liter per kilogram. The
`larger the V, the smallerthe fraction of the dose that resides
`in the plasma.
`Once drug has entered the vascular system, it becomes
`distributed throughout the various tissues and body fluids.
`However, most drugs do notdistribute uniformly throughout
`the various organs andtissues of the body. This heterogene-
`ous distribution is based on tissue-specific differences in rate
`and extent of drug uptake, including blood flow,i.e., the
`delivery of drug to the tissues, the ability for the drug to
`cross biomembranes, partitioning into the tissue, and drug
`bindingto tissue elements including binding to proteins and
`other macromolecules. As a consequence, V is an apparent
`volume that acts as a proportionality factor between drug
`amount in the body and measured concentration in plasma
`and can range between 3 L for a typical 70-kg subject repre-
`senting the plasma volume and up to valueslike 5,000 L for
`amiodarone,i.e., far in excess of the total body size.
`For most drugs, distribution throughout the body is not
`instantaneous, but a time-consuming process. Thus, the ini-
`tial drug distribution volumeafter intravenous (IV) bolus
`administration is frequently smaller than that after distribu-
`tion equilibrium throughout the body has been reached. The
`initial V is frequently referred to as the volumeofthe central
`compartment Vc, representing well-perfused organs andtis-
`sues for which drug distribution for a specific drug is nearly
`instantaneous. Differentiation between the postequilibrium
`V and the volumeof the central compartment Vc becomes
`especially important for loading dose calculations. Drugs
`with instantaneous and homogenousdistribution are referred
`to in the following as having one-compartmentdistribution
`characteristics, those with differences between Vc and the
`postequilibrium V as having multicompartmentdistribution
`characteristics.
`
`Bioavailability. Bioavailability commonly refers to the
`rate and extent of drug absorption into the systemic circula-
`tion. In the following, however, the term bioavailability (F)
`will be limited to the extent of absorption,i.e., the fraction
`of the administered dose that reaches the systemic circula-
`tion. By definition, F is 100% for intravascular administra-
`tions, e.g., IV dosing.
`Absolute bioavailability is the fraction (or percent) of
`a dose administered extravascularly which is systemically
`available as compared to an IV dose.If given orally, absolute
`bioavailability (F) is:
`
`Fm
`
`(1-2)
`
`
`AUCrai x Dry
`AUCy
`Dizas
`where AUC is the area-under-the-plasma-concentration-
`time curveafter oral or [V administration, respectively, and
`D is the administered dose (e.g., in milligrams) of the twO
`respective administration routes.
`Relative bioavailability does not compare an extravascu-
`lar with an IV administration, but two formulations given
`via extravascular routes. It is the fraction of a dose adminis-
`tered as a test formulation that is systemically available as
`compared to a reference formulation:
`Dreference
`F = A UCest formulation x
`Dtest formulation
`AUCreference
`Bioavailability can be viewed as the result of a combina-
`tion of processes that reduce the amountof extravascularly
`administered drug that reachesthe systemic circulation. Com-
`ponentsthat describe these processes for an oral dose adminis-
`tration include the fraction of drug that is absorbed from the
`gastrointestinal tract (F,), the fraction of drug that escaped
`presystemic gut wall metabolism (Fg), and the fraction of the
`drug that escaped hepatic first-pass metabolism (Fy).
`
`(1-3)
`
`F=F,X Fo X Fy
`
`(1-4)
`First-pass metabolism refers to the phenomenonthat drug
`absorbed in the gastrointestinal tract first undergoes trans-
`port throughthe portal vein, then passage through the capil-
`lary bed of the liver before it reaches the systemic circula-
`tion. Metabolism during this first
`liver passage may,
`depending on the drug, dramatically reduce thefraction of the
`administered dose that reachesthe systemic circulation. Fy is
`interrelated with CLy via the hepatic extraction ration Ej:
`
`Fy = 1
`
`CLy
`-—- Ey = 1-—=H
`
`(1-5)
`
`where Qy is the hepatic flow rate of plasma.
`
`INTERRELATIONSHIP BETWEEN PRIMARY
`PHARMACOKINETIC PARAMETERS AND THEIR
`EFFECT ON PLASMA CONCENTRATION-TIME
`PROFILES
`The primary pharmacokinetic parameters CL, V, and F are
`major determinants for the plasma concentration-time pro-
`file resulting from administration of a dosage regimen. The
`clinically most useful characteristics of the resulting concen-
`tration-time profile are the elimination half-life ty, as well
`as the average steady-state concentration C,,.., and the area
`under the plasma concentration-time curve AUC as mea-
`sures of systemic exposure (Fig. 1.2).
`Half-Life. Half-life (t,,) characterizes the monoexponential
`decline in drug concentration after drug input processes
`have been completed. Half-life is the time required for
`the plasma concentration to decrease by one-half. It is a
`transformation of the first-order elimination rate constant
`K that characterizes drug removal from the body if the
`elimination process follows first-order kinetics. Drug con-
`
`

`

`CHAPTER1 & Clinical Pharmacodynamics and Pharmacokinetics
`
`5
`
`centration C at any time t during a monoexponential de-
`crease can be described by
`
`C= Cp X e **!
`
`(1-6)
`
`where Co is the initial drug concentration at time t = 0
`hours. Half-life is then given.as
`
`or
`
`I
`
`tn =
`
`0.693
`hi al KK
`
`(1-7)
`
`(1-7b)
`
`The elimination rate constant K is the negative slope of
`the plasma concentration-timeprofile in a plot of the natural
`logarithm (/n) of the concentration versustime. Half-life can
`thus be calculated from two concentrations C, and C2 during
`the monoexponential decline of drug concentration via the
`relationship
`
`In (E2)C
`C)
`——_———
`57,
`
`K =
`
`(1-8)
`
`Half-life is a secondary pharmacokinetic parameterthat
`is defined by the primary parameters CL and V. The elimina-
`tion rate constant K as a transform of half-life can be seen
`as a proportionality factor between CL and V:
`
`CL=KxXV
`
`(1-9A)
`
`or
`
`CL
`K= v
`
`Thus, half-life is given by
`
`0.693 X V
`hp = <a
`
`(1-9B)
`
`(1-10)
`
`Because CL and V are determined by unrelated underly-
`ing physiologic processesas describedearlier, they are inde-
`pendent of each other. If V, for example is increased due
`to a pathophysiologic process, then CL remains unaffected.
`According to Equation 1-9A, change in V would result in
`a compensatory change in the elimination rate constant K
`without affecting CL. Vice versa, an increase or decrease in
`CL will only result in a corresponding change in the elimina-
`tion rate constant K, but V would remain unaffected.
`Half-life provides important information about specific
`aspects of a drug’s disposition, such as how longit will take
`to reach steady-state once maintenance dosingis started and
`how long it will take for ‘‘all’’ the drug to be eliminated
`from the body once dosing is stopped (usually considered
`five half-lives). Also, the relationship between half-life and
`dosing interval of a multiple dose regimen determines the
`fluctuation between peak and trough plasma concentration
`levels for this dosage regimen.
`
`Systemic Exposure. Exposure to drug in the systemic
`circulation is a time-integrated or time-averaged measure
`of drug concentration that is secondary to the administered
`dosage regimenandthe primary parameters CL andbioavail-
`ability (F).
`The area-under-the-concentration-time curve (AUC)is
`the integrated concentration over time as a measure of over-
`all exposure to a drug resulting from a specific dosage regi-
`men.It is given by
`
`AUC =
`
`
`FXD
`CL
`
`(1-11)
`
`where D is the administered dose.
`The average steady-state concentration C,,ay is the aver-
`age concentration over one dosing interval in a multiple dose
`regimen.It is related to CL and bioavailability (F) via
`
`
`FXD AUC
`Cssav = 7X CL f
`
`(1-12)
`
`whereT is the dosing interval between two consecutive doses
`of the multiple dose regimen. The ratio D/r is also referred
`to as dosing rate.
`As indicated in Eqs. 1-11 and 1-12, systemic exposure
`assessed as AUCorC,,.y is only dependenton the bioavaila-
`ble dose or dosing rate and CL, but not the extent of drug
`distribution as quantified by V. Table 1.1 summarizes the
`interrelationship between the primary pharmacokinetic pa-
`rameters CL, V, and F and the secondary parameters half-
`life, AUC, and C,,ay.
`
`
`PUROUCRMTUg ec fs
`
`UCR UCUCG
`Independent(primary)
`Dependent(secondary)
`Parameters
`Parameters
`
`
`
`AUC
`Gee
`tir
`F
`V
`CL
`L
`L
`1
`eo
`oe
`T
`T
`t
`tT
`o
`e&
`4
`o
`2
`T
`o
`Tt
`e
`o
`o
`L
`oe
`-
`o
`T
`tT
`o
`tT
`oe
`2
`L
`L
`o
`L
`o
`o
`:
`i.
`*
`o
`T
`T
`.
`L
`L
`e
`i
`+
`T
`T
`T
`oe
`T
`ab
`
`
`
`
`
`L & * tT1 T
`The ’*’ in the table indicates thatthe effect on the secondary
`parametercannotbe determined without knowing the extent of
`changesin CL,V, and F.
`T, increase; ©,little or no change; 1, decrease.
`
`

`

`6
`
`SECTION! & General
`
`THERAPEUTIC DOSAGE REGIMENS
`For a lot of drugs to be therapeutically effective, drug con-
`centrations of a certain level have to be maintained within
`the therapeutic range for a prolonged period of time (e.g.,
`B-lactam antibiotics, antiarrhythmics). To continuously
`maintain drug concentrations in a certain therapeutic range
`over a prolonged period of time, two basic approaches to
`administer the drug can be applied:
`
`1. Drug administration at a constant inputrate (i.e., a contin-
`uous, constant supply of drug; zero-order input)
`2. Sequential administration of discrete single doses (multi-
`ple dose regimens)
`
`concentration is the difference betweenthe input rate (infu-
`sion rate Ro) and the output rate (CL X concentration C)-
`At time t = 0 hours, whentheinfusionis started, the concen-
`tration and the output rate are both zero. Thus, the rate of
`change in plasma concentration has its maximum value-
`With increasing time, the outputrate increases as the plasma
`concentration C is rising while the input rate remains con-
`stant. Thus, the rate of change in drug concentration getS
`smaller with increasing time, but drug concentrations con-
`tinueto increaseas the rate of changeisstill positive. Finally,
`the plasma concentration has risen enough that the output
`rate is equal to the input rate. At this time, the so-called
`steady-state C,, has been reached, where the rate of change
`in drug plasma concentration is zero and a constant steady-
`state concentration C,, has been achieved. At steady-state,
`input rate is equal to outputrate.
`(1-13)
`Ro = CL X Cy
`Hence, the steady-state concentration C,, is only determined
`by the infusion rate Rp and the CL.
`
`Cys =
`
`Ro
`CL
`
`(1-14)
`
`Constant Input Rate Regimens. Administration of con-
`stant input rate regimenscanbevia intravascular orvia extra-
`vascular administration. Intravascular administration is most
`frequently accomplished by IV infusion of drug via a drip
`or an infusion pump. Although IV drug administration pro-
`vides a high level of control and precision,its major limita-
`tion is thatit is restricted primarily to clinical settings. Extra-
`vascular administration with a constant
`input rate has
`becomeavailable only recently and is now widely used in
`Anincrease in the infusion rate will result in a propor-
`constant release rate devices that deliver drug for an ex-
`tional
`increase in the steady-state concentration C,,, as
`tended period oftime at a constant rate. Best known exam-
`shownin Figure 1.4. For therapeutic purposes,it is often of
`ples for constant rate release devices are transdermal thera-
`critical importance to know howlongit will take after initia-
`peutic systems in patch format and oral therapeutic systems
`tion of an infusion to finally reach a targeted steady-state
`in capsule form. Here, absorption is an additional prerequi-
`concentration C,,. The rise in drug concentration during a
`site to attain effective plasma concentrations. An example
`constant rate infusion before steady-state is exponential in
`for the resulting concentration-time profile of such a dosage
`nature and is determined by the elimination process(elimina-
`form [oxybutynin chloride (OROS)] is given in Figure 1.3.
`tion rate constant K), not the infusion rate Ro:
`For understanding the principles involved in constant rate
`
`NE Ro —pgKxt
`regimens, administration by constantrelease rate devices in
`(1-15)
`the following are assumedto be equivalentto constant rate
`IV infusions.
`At any time during an infusion, the rate of change in
`the amount of drug in the body and subsequently the drug
`
`C= CL x (1
`
`e
`
`]
`
`After initiation of a constant rate infusion, it takes one
`elimination half-life to reach 50% of C,,, two elimination -
`half-lives to reach 75% of C,, and three elimination half-
`
`1s
`
`12
`
`
`
`
`
`PlasmaOxybutyninConcentration(ng/mL)
`
`
`
`—e-- IR Oxybutynin
`—f}-- OROS? oxybutynin chloride
`
`FIGURE1.3 Oral dosage form with constant input
`rate. Mean (SD) oxybutynin plasma concentrations
`in 13 subjects after oral administration of either 15
`mg OROSoxybutynin chloride once a day or 5 mg
`immediate release oxybutynin every 8 hours.
`OROSis an orally administered constant release
`rate dosage form. (From Gupta SK, Sathyan G.
`Pharmacokinetics of an oral once-a-day controlled-
`release oxybutynin formulation compared with im-
`mediate-release oxybutynin. J Clin Pharmacol 39:
`289-296, 1999.)
`
`

`

`CHAPTER 1 & Clinical Pharmacodynamics and Pharmacokinetics
`
`tz
`
`
`
`PlasmaAMP579Concentration(ng/mL) &
`
`v
`
`0
`
`1
`
`2
`
`3
`
`4
`
`$
`
`6
`
`7
`
`g
`
`9
`
`Ww H
`
`Time (hr)
`FIGURE1.4 Linear relationship between steady-state
`concentration and infusion rate. Mean AMP 579 con-
`centrations in six subjects after single intravenous
`infusions of 20, 50, 100, or 150 xg/kg AMP 579 ad-
`ministered as 6-hour constant rate infusions. AMP
`579 is an investigational adenosine agonist for the
`treatment of paroxysmal supraventricular tachycar-
`dia. (From Zannikos PN, Baybutt Rl, Boutouyrie BX,
`et al. Pharmacokinetics, safety, and tolerability of
`single intravenousinfusions of an adenosine ago-
`nist, AMP 579, in healthy male volunteers. J Clin
`Pharmacol! 39:1044-1052, 1999.)
`
`lives to reach 87.5% of C,,. Assuming for clinical purposes
`that a concentration of more than 95% of C,, is therapeuti-
`cally equivalent to the final steady-state concentration,it
`takes approximately five elimination half-lives (t,,) to reach
`steady-state after initiation of an infusion.
`The decline in drug concentration after cessation of an
`infusion can be described by Equation 1-6 where Cp is the
`concentration at the end of the infusion as determined by
`Equation 1-15 and t is the postinfusion time, the time incre-
`ment between end of infusion and‘the time of the observed
`plasma concentration C.
`During therapy it sometimes becomes necessary to
`change the input rate of a constant rate regimen,e.g., because
`of drug-related toxicity or inadequate therapeutic effect.
`After each change in the infusion rate it again takes five
`half-lives ty, before more than 95% of the change in the
`steady-state concentration C,, has occurred. An increase in
`the infusion rate Rp is best imagined by the sum of two
`independentinfusions. The first one has the same infusion
`rate as before the change in Rp. The second one has an
`infusion rate equal to the incremental increase in Ro. The
`resulting plasma concentration profile is the sum of the con-
`centrations independently produced by the two infusions
`(Fig. 1.5). Similarly, a decrease in the infusion rate Ro can
`be imagined as the result of two concomitant infusions of
`which one has been stopped.*
`
`Loading Dose and Maintenance Dose. Because the
`time to reach steady-state concentrations after initiation of
`a constant rate infusion is determined by the elimination
`half-life of the drug, depending on the drug’s half-life, it may
`
`
`
`Time (hr)
`
`FIGURE1.5 Increasein infusion rate. An increase in
`the infusion rate Ro is best imagined by the sum of
`two independent infusions, where a second infu-
`sion with the incremental infusion rate {in this case
`30 mg/hour)is initiated at the time of changein Ro.
`The resulting plasma concentrations(bo/d line) are
`the sum of the concentrations independently pro-
`ducedby the twoinfusions(dashed Jines).
`
`

`

`8
`
`SECTION | & General
`
`take a long time until the targeted steady-state concentration
`Crarget is reached. For a drug with an elimination half-life of
`8 hours, approximately 40 hours (5 X 8 hours) will be
`needed to reach more than 95% of C,,. Clinical situations
`sometimes demand that the Cyarger is reached more rapidly.
`A solution for this problem is to give a bolus dose and
`start an infusion at the same time. The resulting plasma con-
`centration is additive from the two modesof administration.
`The loading dose (LD)is supposed to immediately reach the
`desired target concentration Cyarger. It is administered as an
`IV bolus injection or, more frequently, as a short-term infu-
`sion. The maintenance dose (MD) is intended to sustain
`Crarget- It is administered as a constant rate infusion. When
`the LD and the MDare exactly matched, the concentrations
`of drug associated with LD and MD exactly complement
`each other(Fig. 1.6; see color insert). The gain in concentra-
`tion of MD offsets the loss of the concentration that was
`initially achieved with LD.In clinical practice, IV dosage
`regimens are often performed as a sequential combination
`of LD and MD.Butalso oral constant rate release systems
`often contain a LD to facilitate a more rapid achievement
`of therapeutic concentrations.
`The LD for a certain target concentration, Crarget for a drug
`with one-compartmentdistribution characteristics is solely
`determined by V.It has the unit of an amount, e.g., milli-
`grams.
`
`LD = Cyareet xv
`
`(1-16)
`
`The MD necessary to sustain the target concentration
`Crarget is solely determined by the CL.It has the unit of an
`amountper time, e.g., milligrams per hour:
`
`MD = Ro = Crarger X CL
`
`(1-17)
`
`Multicompartment Characteristics and Loading Dose-
`Whenapplyingclinical pharmacokinetics to design and opti-
`mize dosage regimensfor patients, it is generally assumed
`for practical purposes that the drug considered follows one-
`compartmentcharacteristics. In reality, however, most drugs
`show at least after IV administration multicompartment
`characteristics. For those drugs, plasma concentrations re-
`sulting from an LD based on the postequilibrium V are ini-
`tially always higher than predicted by a one-compartment
`model, which may lead to toxicity. The reason is that the
`volumeof the central compartment Vc in which the drug is
`initially distributed is always smaller than postequilibrium
`V. Approaches to overcomethis problem are to base the LD
`on Vc instead of V or to give a LD based on V as a short-
`term infusion rather than as bolusinjection.
`A patient shall be started on a combination dosing regi-
`menconsisting of a LD and a MD.A drug’s postequilibrium
`V in a patient is V = 50 L. ALD of 500 mgwascalculated
`to achieve a target plasma concentration of 10 m