, ·_·." • _,: , •• "' .. \tJ,i;;:c:}\ftsi~l"i~t3/Ji' .··
`
`\: -.t·:- •)',,., . <i.. .· .. • r: : >
`Textbook of Therapeutics
`Drug and Disease Managentent
`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
`
`· ITORS
`Joanna K. Hudson/ Greta K. Gourley/ Caroline S. Zeind
`®~ Lippincott Williams & Wilkins
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`Copyright © 2006 by Lippincott Williams & Wilkins
`Seventh edition © 2000 by Lippincott Williams & Wilkins
`
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`
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`
`The publisher is not responsible (as a matter of product liability, negligence or otherwise) for an injury resulting from any
`material contained herein. This publication contains information relating to general principles of medical care which should
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`for current information, including contraindications, dosages, and precautions.
`
`Printed in the United States of America
`
`Library of Congress Cataloging-in-Publication Data
`
`8th ed.
`
`Textbook of therapeutics : drug and disease management. -
`/ editors, Richard A. Helms, David J. Quan.
`p.; cm.
`Includes bibliographical references and index.
`ISBN 0-7817-5734-7
`1. Chemotherapy.
`2. Therapeutics.
`II. Quan, David J.
`[DNLM: 1. Drug Therapy. 2. Therapeutics. WB 330 T3555
`2006]
`RM262.C5 2006
`615.5'8-dc22
`
`I. Helms, Richard A.
`
`2005034101
`
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`10 9 8 7 6 5 4 3 2 1
`
`

`

`Preface
`Contributors
`
`11 SECTION I
`General 1
`
`1 Clinical Pharmacodynamics and
`Pharmacokinetics 1
`Bernd Meibohm and William E. Evans
`
`2 Adverse Drug Reactions and Drug-Induced
`Diseases 31
`Candy Tsouronis
`
`3 Drug Interactions 47
`Robert Keith Middleton
`
`4 Clinical Toxicology 73
`Wendy Klein-Schwartz
`
`5 Clinical Laboratory Tests and Interpretation
`91
`Charles F. Seifert and Beth H. Resman-Targoff
`
`6 Racial, Ethnic, and Sex Differences in
`Response to Drugs 116
`Hewitt W. Matthews and Jannifer L. Johnson
`
`7 Biotechnology 131
`Kimberly Bergstrom and Monique Mayo
`
`8 Patient Communication in Clinical Pharmacy
`Practice 161
`Richard N. Berrier, Marie E. Gardner, and Helen
`Meldrum
`
`Section I Case Study Questions 176
`
`11 SECTION II
`Skin Diseases 181
`
`9 Allergic and Drug-Induced Skin Diseases 181
`Kelly M. Smith
`
`10 Common Skin Disorders 203
`Rebecca Florez Boettger and Laurie H. Fukushima
`
`11 Burns 257
`Ted L. Rice and Charles M. Kamack
`
`Section II Case Study Questions 273
`
`■ SECTION Ill
`Diseases of the Eye and Ear 275
`
`12 Common Eye Disorders 275
`Andreas Katsoya Lauer and Ali J. Olyaei
`
`13 Glaucoma 288
`J. Douglas Wurtzbacher and Dick R. Gourley
`
`14 Common Ear Disorders 312
`Michael A. Oszko
`
`Section III Case Study Questions 322
`
`■ 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
`
`11 SECTION V
`OB/GYN Disorders 373
`
`17 Gynecologic Disorders 373
`Linh Khanh Vuong
`
`18 Contraception 411
`Shareen El-Ibiary
`
`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
`
`xxxi
`
`

`

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`SECTION I ■ GENERAL
`Clinical Pharinacodynantics and
`Phar111acokinetics
`Bernd Meibohm and William E. Evans
`
`1
`
`Therapeutic Range • 1
`Clinical Pharmacokinetics • 2
`Primary Pharmacokinetic Parameters • 3
`Interrelationship between Primary
`Pharmacokinetic Parameters and Their Effect
`on Plasma Concentration-Time Profiles • 4
`Therapeutic Dosage Regimens• 6
`Physiologic Variables Affecting Drug
`Clearance • 13
`Clinical Pharmacodynamics • 20
`Pharmacokinetic versus Pharmacodynamic
`Variability • 20
`
`Pharmacodynomic Models• 21
`Dosing Based on Pharmacokinetic and
`Pharmacodynamic Parameters • 23
`Hysteresis • 24
`Pharmacogenomics • 26
`Phormacogenetics Affecting Pharmocokinetic
`Processes • 26
`Polygenic Effects on Pharmocokinetics and
`Pharmacodynamics • 29
`Conclusion • 29
`Key Points• 29
`
`In applied pharmacotherapy, usage of medications is adjusted
`to the individual need of the patient to maximize efficacy and
`safety, i.e., to achieve the maximum therapeutic response with
`a minimum likelihood of adverse events. The rational use of
`drugs and the design of effective dosage regimens are facili(cid:173)
`tated by the appreciation of the relationships among the ad(cid:173)
`ministered dose of a drug, the resulting drug concentrations
`in various body fluids and tissues, and the intensity of pharma(cid:173)
`cologic effects caused by these concentrations. These rela(cid:173)
`tionships and thus the dose of a drug required to achieve a
`certain effect are determined by the drug's pharmacokinetic
`and pharmacodynamic properties. Thus, pharmacokinetic
`(PK) and phannacodynamic (PD) information form the scien(cid:173)
`tific basis of modem phannacotherapy .1
`2
`•
`Pharmacokinetics describes the time course of the con(cid:173)
`centration of a drug in a body fluid, preferably plasma or
`blood that results from the administration of a certain dosage
`regimen. In simple terms, pharmacokinetics is ''what the
`body does to the drug.'' Pharmacodynamics describes the
`intensity of a drug effect in relation to its concentration in
`a body fluid, usually at the site of drug action. It can be
`simplified to ''what the drug does to the body.'' 3
`The plasma concentration-time profile resulting from
`drug administration is determined by pharmacokinetic pa(cid:173)
`rameters and the administered dosage regimen. While the
`pharmacokinetic parameters are characteristic for the dispo(cid:173)
`sition or handling of a drug in a specific patient and thus
`usually cannot be altered during pharmacotherapy, the dos(cid:173)
`age regimen is the clinician's tool to affect drug concentra(cid:173)
`tions for maximum therapeutic benefit. For most drugs, ther(cid:173)
`apeutic response and/or
`toxicity are related
`to free
`concentration of the drug at the site of action. However, drug
`concentrations at the site of action (e.g., heart tissue for f3 1-
`blockers) often cannot be practically measured. Thus, drug
`concentrations in accessible body fluids such as plasma are
`
`often related to the observed effect under the assumption
`that the drug concentrations in the measured body fluid and
`at the site of action are in a constant relationship. Even
`though this assumption frequently is not accurate, it has
`proven to be a useful simplification that allows most drugs
`to achieve the desired effect levels via modulation of their
`plasma concentration, especially during prolonged pharma(cid:173)
`cotherapy with multiple dose regimens.
`
`THERAPEUTIC RANGE
`
`I
`The relationship between dosage regimen and effects of a
`drug, also known as the dose-concentration-response rela(cid:173)
`tionship, or exposure-response relationship, is not identical
`for all patients. Biologic variability in pharmacokinetics and
`pharmacodynamics as well as their modification by physio(cid:173)
`logic, pathophysiologic, and environmental factors result in
`different effect intensities when the same dosage regimen of
`a drug is given to different patients. Thus, different patients
`• may require different dosage regimens to achieve the same
`effect intensity. Factors that contribute to variability in the re(cid:173)
`lationship between dose and effect intensity include age,
`weight, ethnicity and genetics, gender, disease type and sever(cid:173)
`ity, concomitant drug therapy, and environmental factors.
`The variability in the relationship between dosage regimen
`and effect intensity is caused by pharmacokinetic variability,
`pharmacodynamic variability, or a combination of both.
`Knowledge about the variability in the plasma drug-concen(cid:173)
`tration-effect relationship allows establishing a drug-specific
`therapeutic range. A therapeutic range is a range of drug
`concentrations within which the probability of desired clini(cid:173)
`cal response in the considered patient population is rela(cid:173)
`tively high and the probability ofunacceptable toxicity is rela(cid:173)
`tively low. The therapeutic range approach combines be-
`,
`
`

`

`2
`
`SECTION I ■ General
`
`tween-patient pharmacodynamic variability with the thera(cid:173)
`peutic as well as toxic effects of a drug. It is important to note
`that the therapeutic range should not be considered in absolute
`terms as the limits for this probability range are oftentimes
`chosen arbitrarily. In addition, the therapeutic range is not well
`defined for a large fraction of the drugs that are used clinically.
`The left panel in Figure 1.1 (see color insert) shows a drug
`concentration-effect relationship. The probability of achiev(cid:173)
`ing the desired response is very low when drug concentrations
`are less than 5 mg per L, as is the chance of observing toxicity.
`As drug concentrations increase from 5 to 20 mg per L, the
`probability of desired response increases significantly, while
`the probability of toxicity increases more slowly. One could
`select a therapeutic range of 10 to 20 mg per L, where the mini(cid:173)
`mum probability of a therapeutic response is at least 50% and
`the probability of toxicity is less than 10%. An optimal dosage
`regimen can be defined as one that maintains the plasma con(cid:173)
`centration of the drug within the therapeutic range. The right
`panel in Figure 1.1 demonstrates this concept by comparing
`two dosage regimens. The dosing interval (time between
`doses; in this case 8 hours) is the same, but the discrete doses
`given in regimenB are twice as large as those given in regimen
`A. As shown, drug accumulates in the body during multiple
`dosing. Regimen A keeps the concentration-time profile
`within the therapeutic range, which will result in the majority
`of patients with adequate therapeutic efficacy with only rare
`occurrence ofundesired toxicity. Regimen B will likely result
`in most patients with only a marginal increase in efficacy com(cid:173)
`pared to regimen A, but with a much larger likelihood of unde(cid:173)
`sired toxicity. It should, however, be stressed, that despite
`having plasma concentrations within the therapeutic range at
`all times, some of the patients treated with regimen A may
`
`not experience an adequate drug response or may experience
`drug-related toxicity.
`
`CLINICAL PHARMACOKINETICS
`
`I
`
`The utility of pharmacokinetics does not lie in diagnosing
`the disease or selecting the ''drug of choice,'' but in deciding
`the best way to administer a given drug to achieve its thera(cid:173)
`peutic objective. The manner in which a drug is taken is
`referred to as the dosage regimen. The dosage regimen tells
`us "how much" and "how often" a drug must be taken to
`achieve the desired result. It is these two questions (how
`much?, how often?) that form the basis for the discipline of
`pharmacokinetics.4
`•5
`Clinical pharmacokinetics is the application of pharrnaco(cid:173)
`kinetic principles in a patient care setting for the design of
`optimum dosage regimens for the individual patient. Proba(cid:173)
`bly the most difficult aspect of clinical pharmacokinetics is
`understanding the full potential and practical limitations and
`pitfalls of using specific pharmacokinetic models of drug
`disposition to attain target concentrations based on only a
`limited number (usually 1-2) of drug concentration mea(cid:173)
`surements. Although a good understanding of common phar(cid:173)
`macokinetic concepts is crucial, the competent clinician will
`have knowledge of not only the mathematics of these con(cid:173)
`cepts, but also the principles, assumptions, and potential er(cid:173)
`rors underlying their application in a clinical setting. Further(cid:173)
`more, a broad therapeutic knowledge is also necessary
`because measured drug concentrations must be interpreted
`with respect to the patient's clinical condition and the phar(cid:173)
`macodynamic profile of the therapeutic agent.
`
`Response
`
`J 40 - , - - - - - - - - - - - - - - - - - - - ,
`
`r
`
`100
`
`~
`:a
`_& 50 e D.
`
`0
`
`10
`
`Regimen B
`0 -f_-,---,--.,--.,--.,--.,--....-~;:::::::;::::::;;::::::;:=:;:=:;=;:~
`96
`24
`48
`72
`0
`Time (hr)
`
`Drug Concentration (mg/L)
`FIGURE 1.1 The concept of a therapeutic range. The left panel shows a relationship between
`the probability of achieving the desired response as well as the chance of observing toxicity
`in relation to drug concentration in plasma. A therapeutic range of 10 to 20 mg/L could be de(cid:173)
`fined as a range of 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. Regimen B will 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.
`
`

`

`CHAPTER 1 ■ Clinical Phannacodynarnics and Pharmacokinetics
`
`3
`
`PRIMARY PHARMACOKINETIC PARAMETERS
`Pharmacokinetic parameters are characteristic for the dispo(cid:173)
`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
`processes in the patient as well as concomitant drug therapy
`(drug-drug interactions) and environmental factors.
`The most important pharmacokinetic parameters are
`clearance (CL), volume of distribution (V), and bioavailabil(cid:173)
`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(cid:173)
`pendent of each other and are called primary pharmacoki(cid:173)
`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 plasma or blood. For simplicity, only plasma
`CLs will be considered in the following. CL does not indicate
`
`how much drug is being removed, but it represents the vol(cid:173)
`ume of 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 dosing rate.
`The overall total body CL is the sum of individual organ
`CLs that contribute to the elimination of a drug:
`CL = CLR + CLn + CLorher
`(1-1)
`CLR is the renal clearance representing elimination via
`the kidneys, CLH 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 plasma that flows through the organ per time
`unit and the extraction ratio E, a measure of the extraction
`efficiency of the organ. E provides the 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;n) and leaving (C0ut) the elimination
`organ compared to C;n. In other words, it gives the percent
`of Q that is completely cleared from the drug during passage
`through the organ.
`
`Dosage Regimen:
`Dosage Regimen:
`How much?
`How often?
`FIGURE 1.2 Interrelationship of primary pharmacokinetic parameters (clearance, volume of dis(cid:173)
`tribution, and bioavailability) and their relevance for determining dosage regimens. (Modified
`from van de Waterbeemd H, Gifford E. ADMET in silico modelling: towards prediction para(cid:173)
`dise? Nat Rev Drug Discov 2:192-204, 2003.)
`
`

`

`4
`
`SECTION I ■ General
`
`Volume of Distribution. V quantifies the extent of distri(cid:173)
`bution of a drug throughout the body. Drug distribution
`means the reversible transfer of drug from one location to
`another within the body. The concentration achieved in
`plasma after distribution depends on the dose and the extent
`of distribution. The V relates the amount of drug in 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 smaller the 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 not distribute uniformly throughout
`the various organs and tissues of the body. This heterogene(cid:173)
`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
`binding to 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(cid:173)
`senting the plasma volume and up to values like 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(cid:173)
`tial drug distribution volume after intravenous (IV) bolus
`administration is frequently smaller than that after distribu(cid:173)
`tion equilibrium throughout the body has been reached. The
`initial V is frequently referred to as the volume of the central
`compartment V c, representing well-perfused organs and tis(cid:173)
`sues for which drug distribution for a specific drug is nearly
`instantaneous. Differentiation between the postequilibrium
`V and the volume of the central compartment V c becomes
`especially important for loading dose calculations. Drugs
`with instantaneous and homogenous distribution are referred
`to in the following as having one-compartment distribution
`characteristics, those with differences between V c and the
`postequilibrium V as having multicompartment distribution
`characteristics.
`
`Bioavailability. Bioavailability commonly refers to the
`rate and extent of drug absorption into the systemic circula(cid:173)
`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(cid:173)
`tion. By definition, Fis 100% for intravascular administra(cid:173)
`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:
`
`(1-2)
`
`F = AUCoral X DIV
`AVCIV
`Doral
`where AUC is the area-under-the-plasma-concentration(cid:173)
`time curve after oral or IV administration, respectively, and
`Dis the administered dose (e.g., in milligrams) of the two
`respective administration routes.
`Relative bioavailability does not compare an extravascu(cid:173)
`lar with an IV administration, but two formulations given
`via extravascular routes. It is the fraction of a dose adminis(cid:173)
`tered as a test formulation that is systemically available as
`compared to a reference formulation:
`F = AVCtestformulation X Dreference
`AVCreference
`Diestformulation
`Bioavailability can be viewed as the result of a combina(cid:173)
`tion of processes that reduce the amount of extravascularly
`administered drug that reaches the systemic circulation. Com(cid:173)
`ponents that describe these processes for an oral dose adminis(cid:173)
`tration include the fraction of drug that is absorbed from the
`gastrointestinal tract CFa), the fraction of drug that escaped
`presystemic gut wall metabolism (Fa), and the fraction of the
`drug that escaped hepatic first-pass metabolism (FH).
`
`(1-3)
`
`(1-4)
`
`First-pass metabolism refers to the phenomenon that drug
`absorbed in the gastrointestinal tract first undergoes trans(cid:173)
`port through the portal vein, then passage through the capil(cid:173)
`lary bed of the liver before it reaches the systemic circula(cid:173)
`tion. Metabolism during this first liver passage may,
`depending on the drug, dramatically reduce the fraction of the
`administered dose that reaches the systemic circulation. PH is
`interrelated with CLH via the hepatic extraction ration EH:
`CLH
`FH = 1 - EH = 1 - QH
`
`(l-5)
`
`where QH is the hepatic flow rate of plasma.
`
`INTERRELATIONSHIP BETWEEN PRIMARY
`PHARMACOKINETIC PARAMETERS AND THEIR
`EFFECT ON PLASMA CONCENTRATION-TIME
`PROFILES
`The primary pharmacok:inetic parameters CL, V, and F are
`major determinants for the plasma concentration-time pro(cid:173)
`file resulting from administration of a dosage regimen. The
`clinically most useful characteristics of the resulting concen(cid:173)
`tration-time profile are the elimination half-life t ½, as well
`as the average steady-state concentration Css,av and the area
`under the plasma concentration-time curve AUC as mea(cid:173)
`sures of systemic exposure (Fig. 1.2).
`Half-Life. Half-life (ty,) 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-
`
`

`

`CHAPTER 1 ■ Clinical Pharmacodynamics and Pharmacokinetics
`
`S
`
`centration C at any time t during a monoexponential de(cid:173)
`crease can be described by
`C = Co X e-K x t
`
`(1-6)
`
`where C0 is the initial drug concentration at time t = 0
`hours. Half-life is then given-as
`
`or
`
`in 2
`1112 = K
`
`0.693
`t112 = --Y-
`
`(1-7a)
`
`(1-7b)
`
`The elimination rate constant K is the negative slope of
`the plasma concentration-time profile in a plot of the natural
`logarithm (In) of the concentration versus time. Half-life can
`thus be calculated from two concentrations C1 and C2 during
`the monoexponential decline of drug concentration via the
`relationship
`
`(1-8)
`
`Half-life is a secondary phannacokinetic parameter that
`is defined by the primary parameters CL and V. The elimina(cid:173)
`tion rate constant K as a transform of half-life can be seen
`as a proportionality factor between CL and V:
`
`CL= K X V
`
`(1-9A)
`
`or
`
`K = CL
`V
`
`Thus, half-life is given by
`
`0.693 X V
`1112 = __ C_L __
`
`(l-9B)
`
`(1-10)
`
`Because CL and V are determined by unrelated underly(cid:173)
`ing physiologic processes as described earlier, they are inde(cid:173)
`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(cid:173)
`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 long it will take
`to reach steady-state once maintenance dosing is 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 regimen and the primary parameters CL and bioavail(cid:173)
`ability (F).
`The area-under-the-concentration-time curve (ADC) is
`the integrated concentration over time as a measure of over(cid:173)
`all exposure to a drug resulting from a specific dosage regi(cid:173)
`men. It is given by
`
`FXD
`AUC = CL
`
`(1-11)
`
`where D is the administered dose.
`The average steady-state concentration Css.av is the aver(cid:173)
`age concentration over one dosing interval in a multiple dose
`regimen. It is related to CL and bioavailability (F) via
`
`(1-12)
`
`where 'Tis the dosing interval between two consecutive doses
`of the multiple dose regimen. The ratio D/'T is also referred
`to as dosing rate.
`As indicated in Eqs. 1-11 and 1-12, systemic exposure
`assessed as ADC or Css,av is only dependent on the bioavaila(cid:173)
`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(cid:173)
`rameters CL, V, and F and the secondary parameters half(cid:173)
`life, ADC, and Css,av·
`
`!Effect of Changes in Primary Pharmacok· r ,,,
`iParameters_ on Sec'ondciry,P(!rameters
`. .
`.
`
`Independent (primary)
`Parameters
`
`Dependent (secondary)
`Parameters
`
`CL
`i
`j,
`
`H
`
`H
`
`H
`
`H
`t
`t
`j,
`
`j,
`
`V
`
`H
`
`H
`i
`j,
`
`H
`
`H
`t
`i
`t
`i
`
`F
`
`H
`
`H
`
`H
`
`H
`t
`j,
`
`H
`
`H
`
`H
`
`H
`
`t,12
`j,
`t
`i
`j,
`
`H
`
`H
`
`*
`i
`t
`*
`
`Cssav*
`
`AUC
`
`j,
`t
`H
`
`H
`t
`j,
`J,
`i
`i
`t
`
`j,
`t
`H
`
`H
`t
`j,
`i
`j,
`i
`i
`
`The '*' in the table indicates that the effect on the secondary
`parameter cannot be determined without knowing the extent of
`changes in CL, V, and F.
`i, increase; H, little or no change; -1., decrease.
`
`

`

`6
`
`SECTION I ■ General
`
`THERAPEUTIC DOSAGE REGIMENS
`For a lot of drugs to be therapeutically effective, drug con(cid:173)
`centrations of a certain level have to be maintained within
`the therapeutic range for a prolonged period of time (e.g.,
`(3-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 input rate (i.e., a contin(cid:173)
`uous, constant supply of drug; zero-order input)
`2. Sequential administration of discrete single doses (multi-
`ple dose regimens)
`
`Constant Input Rate Regimens. Administration of con(cid:173)
`stant input rate regimens can be via intra vascular or via extra(cid:173)
`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(cid:173)
`vides a high level of control and precision, its major limita(cid:173)
`tion is that it is restricted primarily to clinical settings. Extra(cid:173)
`vascular administration with a constant input rate has
`become available only recently and is now widely used in
`constant release rate devices that deliver drug for an ex(cid:173)
`tended period of time at a constant rate. Best known exam(cid:173)
`ples for constant rate release devices are transdermal thera(cid:173)
`peutic systems in patch format and oral therapeutic systems
`in capsule form. Here, absorption is an additional prerequi(cid:173)
`site to attain effective plasma concentrations. An example
`for the resulting concentration-time profile of such a dosage
`form [oxybutynin chloride (OROS)] is given in Figure 1.3.
`For understanding the principles involved in constant rate
`regimens, administration by constant release rate devices in
`the following are assumed to be equivalent to 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
`
`15
`
`concentration is the difference between the input rate (infu(cid:173)
`sion rate R0) and the output rate (CL X concentration C).
`At time t = 0 hours, when the infusion is started, the concen(cid:173)
`tration and the output rate are both zero. Thus, the rate of
`change in plasma concentration has its maximum value.
`With increasing time, the output rate increases as the plasma
`concentration C is rising while the input rate remains con(cid:173)
`stant. Thus, the rate of change in drug concentration gets
`smaller with increasing time, but drug concentrations con(cid:173)
`tinue to increase as the rate of change is still 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 ss has been reached, where the rate of change
`in drug plasma concentration is zero and a constant steady(cid:173)
`state concentration Css has been achieved. At steady-state.
`input rate is equal to output rate.
`Ro = CL X Css
`(1-13)
`Hence, the steady-state concentration C ss is only determined
`by the infusion rate Ro and the CL.
`
`(1-14)
`
`An increase in the infusion rate will result in a propor(cid:173)
`tional increase in the steady-state concentration C ss , as
`shown in Figure 1.4. For therapeutic purposes, it is often of
`critical importance to know how long it will take after initia(cid:173)
`tion of an infusion to finally reach a targeted steady-state
`concentration Css. The rise in drug concentration during a
`constant rate infusion before steady-state is exponential in
`nature and is determined by the elimination process (elimina(cid:173)
`tion rate constant K), not the infusion rate R0 :
`
`C = ~r X (