Jameson DRL EXHIBIT 1021 PAGE 1
`
`tebeese
`ae
`
`Hauser
`
`Longo
`
`16th Edition
`
`Kasper Braunwald=Fauci
`
`DRL EXHIBIT 1021 PAGE 1
`
`

`

`-
`
`TION 5
`f ~M-POSITIVE BACTERIA
`
`806
`
`814
`
`HARRISON
`PRINCIPLES OF
`Internal
`edic • 1ne
`
`823
`
`Editors
`
`DENNIS L. KASPER, MD
`William Ellery Channing Professor of Medicine,
`Professor of Microbiology and Molecular Genetics,
`Harvard Medical School; Director, Channing
`Laboratory, Department of Medicine, Brigham and
`Women 's Hospital, Boston
`
`ANTHONY S. FAUCI, MD
`Chief, Laboratory of Immunoregulation; Director,
`National Institute of Allergy and Infectious Diseases,
`National Institutes of Health, Bethesda
`
`DAN L. LONGO, MD
`Scientific Director, National Institute on Aging,
`National Institutes of Health ,
`Bethesda and Baltimore
`
`EUGENE BRAUNWALD, MD
`Distinguished Hersey Professor of Medicine,
`Harvard Medical School; Chairman, TIMI Study Group,
`Brigham and Women 's Hospital, Boston
`
`STEPHEN L. HAUSER, MD
`Robert A. Fishman Distingu ished Professor and Chai1man,
`Department of Neurology,
`University of California San Francisco, San Francisco
`
`J. LARRY JAMESON, MD, PHO
`Irving S. Cutter Professor and Chairnrnn ,
`Department of Medicine,
`Northwestern University Feinberg School of Medicine;
`Physician-in-Chief, Northwestern
`Memorial Hospital, Chicago
`
`McGraw-Hill
`MEDICAL PUBLISHING D IVI SION
`
`New York
`Mexico City
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`Chicago
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`San Francisco
`San Juan
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`Lisbon
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`
`London
`Singapore
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`Madrid
`Sydney
`
`Toronto
`
`DRL EXHIBIT 1021 PAGE 2
`
`

`

`.. Longo 's works as editors and authors were performed outside
`.i-Jloyment as U.S. government employees. These works represent their
`Jiessional views and not necessarily those of the U.S. government.
`
`Harrison's
`PRINCIPLES OF INTERNAL MEDICINE
`Sixteenth Edition
`
`Copyright © 2005 , 200 1, 1998, 1994, 1991 , 1987, 1983 , 1980, 1977, 1974, 1970, 1966, 1962, 1958 by The
`McGraw-Hill Companies, Inc. All rights reserved. Printed in the United States of America. Except as per(cid:173)
`mitted under the United States Copyright Act of 1976, no part of thi s publication may be reproduced or
`distributed in any form or by any means, or stored in a data base or retrieval system, without the prior written
`permission of the publisher.
`
`1234567890 DOWDOW 0987654
`
`ISB N 0-07-140235-7 (Combo)
`
`ISBN 0-07-1 39 140-1 (Set)
`ISBN 0-07-139141-X (Vol. I)
`ISBN 0-07-139142-8 (Vol. II)
`
`FOREIGN LANGUAGE EDITIONS
`Arabic (1 3e): McGraw-Hill Libri Italia srl
`(est. 1996)
`Chinese Long Form (15e): McGraw-Hill Inter(cid:173)
`national Enterprises, Inc., Taiwan
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`cation (Asia), Singapore
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`Paris, France
`German (l 5e): ABW Wissenschaftsverlagsge(cid:173)
`sellschaft mbH, Berlin, Gennany
`Greek (1 5e): Parissianos, S.A. , Athens, Greece
`Italian (15e): The McGraw-Hill Companies, Sri ,
`Milan, Italy
`Japanese (15e): MEDSI-Medical Sciences Inter(cid:173)
`national Ltd, Tokyo, Japan
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`Korean (15e): McGraw-Hill Korea, Inc. , Seoul ,
`Korea
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`bin, Poland (est. 2000)
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`do Brazil, Rio de Janeiro, Brazil
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`Bosnia & Herzegovina, Republic of Serbska
`Spanish (15e): McGraw-Hill Interamericana de
`Espana S.A. , Madrid , Spain
`Turkish (15e): Nobel Tip Kitabev leri, Ltd ., Is(cid:173)
`tanbul, Turkey
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`
`T his book was set in Times Roman by Progressive Information Technologies. The editors were Ma1tin
`Wonsiewicz and Mariapaz Ramos Englis. The production director was Robert Laffler. The index was pre(cid:173)
`pared by Barbara Littlewood. The text designer was Marsha Cohen/Parallelogram Graphics. Art director:
`Libby Pisacreta; cover design by Janice Bielawa. Medical illustrator: Jay McElroy, MAMS.
`
`R. R. Donnelley and Sons, Inc. , was the printer and binder.
`
`Cover illustrations courtesy of Raymond J. Gibbons, MD; George V. Kelvin; Robert S. Hillman, MD; and
`Marilu Gorno-Tempini, MD.
`
`Library of Congress Cataloging-in-Publication Data
`
`Harrison 's principles of internal medicine- 16th ed./editors, Dennis L. Kasper ... [et al.].
`Includes bibliographical references and index.
`ISBN0-07-139 141 -X (v. 1)-ISBN 0-07- 139142-8 (v . 2)- ISBN 0-07-
`ISBN 0-07-139140-1(set) -
`140235-7 (combo)
`1. Internal medicine. I. Title: Principles of internal medicine. II. Kasper, Dennis L. III. Harrison,
`Tinsley Randolph, 1900- Principles of internal medicine.
`[DNLM: 1. Internal Medicine. WB 115 H322 2005 ]
`RC46.H333 2005
`616-dc21
`
`p. cm.
`
`2004044931
`
`----··
`
`DRL EXHIBIT 1021 PAGE 3
`
`

`

`cine is practiced. One of the repeated admonitions of EBM pioneers
`has been to replace reliance on the local "gray-haired expert" (who
`may be often wrong but rarely in doubt) with a systematic search for
`and evaluation of the evidence. But EBM has not eliminated the need
`for subjective judgments ; each systematic review presents the inter(cid:173)
`pretation of an "expert," whose biases remain largely invisible to the
`consumer of the review. In addition, meta-analyses cannot generate
`evidence where there are no adequate randomized trials, and most of
`what clinicians face will never be thoroughly tested in a randomized
`trial. for the foreseeable future , excellent clinical reasoning skills and
`experience supplemented by well-designed quantitative tools and a
`keen appreciation for individual patient preferences will continue to
`be of paramount importance in the professional life of medical prac(cid:173)
`titioners.
`
`3 Principles of Clinical Pharmacology
`
`13
`
`FURTHER READING
`BALK EM et al: Con elation of quality measures with estimates of treatment
`effect in meta-analyses of randomized controlled trials. JAMA 287 :2973,
`2002
`NAYLOR CD: Gray zones of clinical practice: Some limits to evidence-based
`medicine. Lancet 345 :840, 1995
`POYNARD T et al: Truth survival in clinical research: An evidence-based req(cid:173)
`uiem? Ann Intern Med 136:888; 2002
`SACKEIT DL et al: Evidence-Based Medicine: Ho w to Practice and Teach
`EBM. 2d ed. London, Churchill Livingstone, 2000
`SCHULMAN KA et al: The effect of race and sex on physicians' recommen(cid:173)
`dations for cardiac catheterization. N Engl J Med 340:61 8, 1999
`
`3 PRINCIPLES OF CLINICAL PHARMACOLOGY
`
`Dan M. Roden
`
`Drugs are the cornerstone of modern therapeutics. Nevertheless, it is
`well recognized among physicians and among the lay community that
`the outcome of drug therapy varies widely among individuals. While
`this variability has been perceived as an unpredictable, and therefore
`inevitable, accompaniment of dmg therapy, this is not the case. The
`goal of this chapter is to describe the principles of clinical phanna(cid:173)
`cology that can be used for the safe and optimal use of available and
`new drugs .
`Drugs interact with specific target molecules to produce their ben(cid:173)
`eficial and adverse effects. The chain of events between administration
`of a drug and production of these effects in the body can be divided
`into two important components, both of which contribute to variability
`in drug actions. The first component comprises the processes that de(cid:173)
`te1mine drug delivery to, and removal from, molecular targets. The
`resultant description of the relationship between drug concentration
`and time is termed pharmacokinetics. The second component of vari(cid:173)
`ability in drug action comprises the processes that determine variabil(cid:173)
`ity in drug actions despite equivalent drug delivery to effector drug
`sites. This description of the relationship between drug concentration
`and effect is termed pharmacodynamics. As discussed further below,
`pharmacodynamic variability can arise as a result of variability in func(cid:173)
`tion of the target molecule itself or of variability in the broad biologic
`context in which the drug-target interaction occurs to achieve dmg
`effects.
`Two important goals of the discipline of clinical pharmacology are
`(1) to provide a description of conditions under which drug actions
`vary among human subjects; and (2) to determine mechanisms under(cid:173)
`lying this variability, with the goal of improving therapy with available
`drugs as well as pointing to new drug mechanisms that may be effec(cid:173)
`l!ve in the treatment of human disease. The first steps in the discipline
`were empirical descriptions of the influence of disease X on drug ac(cid:173)
`hon Y or of individuals or families with unusual sensitivities to adverse
`drug effects . These important descriptive fi ndings are now being re(cid:173)
`placed by an understanding of the molecular mechanisms underlying
`variability in drug actions . Thus, the effects of disease, drug coadmin(cid:173)
`istration, or familial factors in modulating drug action can now be
`remterpreted as variability in expression or function of specific genes
`~hose products determine phaimacokinetics and pharmacodynamics.
`. evenheless, it is the personal interaction of the patient with the phy(cid:173)
`~1.~tan or other health care provider that first identifies unusual varia(cid:173)
`c 1 1ty in drug actions; maintained alertness to unusual drug responses
`0~nues to be a key component of improving drug safety.
`. nusual drug responses, segregating in families, have been rec(cid:173)
`0
`ic:n~ed for decades and initially defined the field of pharmacogenet(cid:173)
`ac · ow, with an increasing appreciation of common polymorphisms
`ross the human genome, comes the opportunity to reinterpret de-
`
`scriptive mechanisms of variability in dru g action as a consequence of
`specific DNA polymorphisms, or sets of DNA polymorphisms, among
`individuals. This approach defines the nascent fi eld of pharmacogen(cid:173)
`omics , which may hold the opportunity of allowing practitioners to
`integrate a molecular understanding of the basis of disease with an
`individual's genomic makeup to prescribe personalized, highly effec(cid:173)
`tive, and safe therapies.
`
`INDICATIONS FOR DRUG THERAPY
`It is self-evident that the benefits of
`drug therapy should outweigh the risks. Benefits fall into two broad
`categories: those designed to alleviate a symptom, and those designed
`to prolong useful life. An increasing emphasis on the principles of
`evidence-based medicine and techniques such as large clinical trials
`and meta-analyses have defined benefits of drug therapy in specific
`patient subgroups. Establishing the balance between risk and benefit
`is not always simple: for example, therapies that provide symptomatic
`benefits but shorten life may be ente1tained in patients with serious
`and highly symptomatic diseases such as heart failure or cancer. These
`decisions illustrate the continuing highly personal nature of the rela(cid:173)
`tionship between the prescriber and the patient.
`Some adverse effects are so common, and so readily associated
`with drug therapy , that they are identified very early during clinical
`use of a drug. On the other hand, serious adverse effects may be suf(cid:173)
`ficiently uncommon that they escape detection for many years after a
`drug begins to be widely used. The issue of how to identify rare but
`serious adverse effects (that can profoundly affect the benefit-risk per(cid:173)
`ception in an individual patient) has not been satisfactorily resolved.
`Potential approaches range from an increased understanding of the
`molecular and genetic basis of variability in drug actions to expanded
`postmarketing surveillance mechanisms. None of these have been
`completely effective, so practitioners must be continuously vigilant to
`the possibility that unusual symptoms may be related to specific drugs,
`or combinations of drugs, that their patients receive.
`Beneficial and adverse reactions to drug therapy can be described
`by a series of dose-response relations (Fig. 3-1). Well-tolerated drugs
`demonstrate a wide margin, termed the therapeutic ratio , therape utic
`index , or therapeutic window, between the doses required to produce
`a therapeutic effect and those producing toxicity. In cases where there
`is a similar relationship between plasma drug concentration and ef(cid:173)
`fects, monitoring plasma concentrations can be a highly effective aid
`in managing drug therapy, by enabling concentJ·ations to be maintained
`above the minimum required to produce an effect and below the con(cid:173)
`centration range likely to produce toxicity. Such monitoring has been
`most widely used to guide therapy with specific agents, such as certain
`antiarrhythmics, anticonvulsants, and antibiotics. Many of the princi(cid:173)
`ples in clinical pharmacology and examples outlined below-that can
`
`DRL EXHIBIT 1021 PAGE 4
`
`

`

`14
`
`Part I Introduction to Clinical Medicine
`
`50
`
`0
`
`-
`-
`
`Desired effect
`Adverse effect
`
`A Dose-0
`
`IV
`
`t
`
`Elimination
`
`Time
`
`Wide
`therapeutic
`ratio
`
`Narrow
`therapeutic
`ratio
`
`(l) 100
`(/) c
`0 a.
`(/)
`~
`Ol
`::l
`-0
`cu
`0 100
`€
`Ei
`cu
`.0 e
`
`50
`
`0
`
`CL
`
`Dose or concentration - -
`
`FIGURE 3-1
`The concept of a therapeutic ratio. Each panel illustrates the relationship
`between increasing dose and cumulative probability of a desired or adverse drug effect.
`Top. A drug with a wide therapeutic ratio, i.e., a wide separation of the two curves.
`Bottom A drug with a narrow therapeutic ratio; here, the likelihood of adverse effects
`at therapeutic doses is increased because the curves are not well separated. Further,
`a steep dose-response curve for adverse effects is especially undesirable, as it implies
`that even small dosage increments may sharply increase the likelihood of toxicity.
`When there is a definable relationship between drug concentration (usually measured
`in plasma) and desirable and adverse effect curves, concentration may be substituted
`on the abscissa. Note that not all patients necessarily demonstrate a therapeutic re(cid:173)
`sponse (or adverse effect) at any dose, and that some effects (notably some adverse
`effects) may occur in a dose-independent fashion.
`
`be applied broadly to therapeutics-have been developed in these
`arenas .
`
`PRINCIPLES OF PHARMACOKINETICS
`The processes of absorption, distribution , metaboli sm, and elimina(cid:173)
`tion-collectively termed drug disposition- determine the concen(cid:173)
`tration of drug delivered to target effector molecules . Mathematical
`anal ysis of these processes can define specific, and clinically useful ,
`parameters that describe drug disposition. This approach allows pre(cid:173)
`diction of how factors such as disease, concomitant drug therapy , or
`genetic variants affect these parameters, and ho w dosages therefore
`should be adjusted. In this way, the chances of undertreatment due to
`low drug concentrations or adverse effects due to high drug concen(cid:173)
`trations can be minimized.
`
`BIOAVAI LABILITY When a drug is administered intravenously, each drug
`molecule is by definition available to the systemic circulation. How(cid:173)
`ever, drugs are often administered by other routes, such as orally,
`subcutaneously, intramuscularl y, rectally, sublingually, or directly into
`desired sites of action. With these other routes, the amount of drug
`actually entering the systemic circulation may be less than with the
`intravenous route. The fraction of drug available to the systemic cir(cid:173)
`culation by other routes is termed bioavailability. Bioavailability may
`be < 100% for two reasons: (1) absorption is reduced, or (2) the drug
`undergoes metabolism or elimination prior to entering the systemic
`circulation. Bioavailability (F) Is defined as the area under the time(cid:173)
`concentration curve (AUC) after a drug dose, divided by AUC after
`the same dose intravenously (Fig. 3-2A) .
`
`Absorption Drug administration by nonintravenous routes often in(cid:173)
`volves an absorptiori process characterized by the plasma level in(cid:173)
`creasing to a maximum value at some time after administration and
`then declining as the rate of drug elimination exceeds the rate of ab(cid:173)
`sorption (Fig. 3-2A). Thus, the peak concentration is lower and occurs
`later than after the same dose given by rapid intravenous injection.
`The extent of absorption may be reduced because a drug is incom(cid:173)
`pletely released from its dosage form , undergoes destruction at its site
`of administration, or has physicochemical properties such as insolu(cid:173)
`bility that prevent complete absorption.from its site of administration.
`The rate of absorption can be an important consideration for de(cid:173)
`termining a dosage regimen, especially for drugs with a narrow ther(cid:173)
`apeutic ratio. If absorption is too rapid, then the resulting high
`concentration may cause adverse effects not observed with a more
`slowly absorbed formulation. At the other extreme, slow absorption is
`
`Time
`
`FIGURE 3-2
`Idealized time-plasma concentration curves after a single dose of drug .
`A. The time course of drug concentration after an instantaneous intravenous (IV) bolus
`or an oral dose in the one-compartment model shown. The area under the time(cid:173)
`concentration curve is clearly less with the oral drug than the IV, indicating incomplete
`bioavailability. Note that despite this incomplete bioavailability, concentration after the
`oral dose can be higher than after the IV dose at some time points. The inset shows
`that the decline of concentrations over time is linear on a log-linear plot, characteristic
`of first-order elimination, and that oral and IV drug have the same elimination (parallel)
`time course. B. The decline of central compartment concentration when drug is both
`distributed to and from a peripheral compartment and eliminated from the central
`compartment. The rapid initial decline of concentration reflects not drug elimination
`but distribution.
`
`deliberately designed into "slow-release" or "sustained-release" drug
`formulations in order to minimize variation in plasma concentrations
`during the interval between closes, because the drug's rate of elimi(cid:173)
`nation is offset by an equivalent rate of absorption controlled by for(cid:173)
`mulation factors (Fig. 3-3).
`Presystemic Metabolism or Elimination When a drug is administered
`orally, it must transverse the intestinal epithelium , the portal venous
`system, and the liver prior to entering the systemic circulation (Fig. 3-
`4 ). At each of these sites, drug availability may be reduced; this mech(cid:173)
`anism of reduction of systemic availability is te1med presystemic elim(cid:173)
`ination, or first-pass elimination, and its efficiency assessed as
`extraction ratio. Uptake into the enterocyte is a combination of passive
`and active processes, the latter mediated by specific drug uptake trans(cid:173)
`port molecules . Once a drug enters the enterocyte, it may undergo
`metabolism, be transported into the portal vein, or undergo excretion
`back into the intestinal lumen . Both excretion into the intestinal lumen
`and metabolism decrease systemic bioavailability. Once a drug passes
`thi s enterocyte barrier, it may also undergo uptake (again often by
`specific uptake transporters such as the organic cation transporter or
`organic anion transporter) into the hepatocyte, where bioavailability
`can be further limited by metabolism or excretion into the bile.
`The drug transport molecule that has been most widely studied is
`
`t c
`
`0
`·~
`c (l)
`
`()
`c
`0 u
`
`Time -
`FIGURE 3-3 Concentration excursions between doses at steady state as a function
`of dosing frequency . With less frequent dosing (blue), excursions are larger; this is
`acceptable for a wide therapeutic ratio drug (Fig. 3-1). For narrower therapeutic ratio
`drugs, more frequent dosing (red) may be necessary to avoid toxicity and maintain
`efficacy. Another approach is use of a sustained-release formulation (black) that in
`theory results in very small excursions even with infrequent dosing.
`
`DRL EXHIBIT 1021 PAGE 5
`
`

`

`------------------------... ------
`
`3 Principles of Clinical Pharmacology
`
`15
`
`than those required intravenously. Thus , a typical intravenous dose of
`verapamil would be 1 to 5 mg, compared to the usual single oral dose
`of 40 to 120 mg. Even small variations in the presystemic elimination
`of very highly extracted drugs such as propranolol or verapamil can
`cause large interindividual variations in systemic availability and ef(cid:173)
`fect. Oral amiodarone is 35 to 50% bioavailable because of poor sol(cid:173)
`ubility. Therefore, prolonged administration of usual oral doses by the
`intravenous route would be inappropriate. Administration of low-dose
`aspirin can result in exposure of cyclooxygenase in platelets in the
`po11al vein to the drug, but systemic sparing because of first-pass de(cid:173)
`acylation in the liver. This is an example of presystemic metabolism
`being exploited to therapeutic advantage.
`
`FIRST-ORDER DISTRIBUTION AND ELI MINATION Most pharmacokinetic pro(cid:173)
`cesses are first order; i.e., the rate of the process depends on the amount
`of drug present. In the simplest pharmacokinetic model (Fig. 3-2A), a
`drug bolus is administered instantaneously to a central compartment,
`from which drug elimination occurs as a first-order process. The first(cid:173)
`order (concentration-dependent) nature of drug elimination leads di(cid:173)
`rectly to the relationship describing drug concentration (C) at any time
`(t) following the bolus:
`c = (dose/Ve) . eC-0.691/11 12)
`where Ve is the volume of the compartment into which drug is deliv(cid:173)
`ered and tv, is elimination half-life. As a consequence of this relation(cid:173)
`ship, a plot of the logarithm of concentration vs time is a straight line
`(Fig. 3-2A, inset). Half-life is the time required for 50% of a first-order
`process to be complete. Thus, 50% of drug elimination is accom(cid:173)
`plished after one drug elimination half-life; 75% after two; 87 .5% after
`three, etc. In practice, first-order processes such as elimination are
`near-complete after four to five half-lives.
`In some cases, drug is removed from the central compartment not
`only by elimination but also by distribution into peripheral compart(cid:173)
`ments. In this case, the plot of plasma concentration vs time after a
`bolus demonstrates two (or more) exponential components (Fig. 3-
`2B) . In general, the initial rapid drop in drug concentration represents
`not elimination but drug distribution into and out of peripheral tissues
`(also first-order processes) , while the slower component represents
`drug elimination; the initial precipitous decline is usually evident with
`administration by intravenous but not other routes. Drug concentra(cid:173)
`tions at peripheral sites are determined by a balance between drug
`distribution to and redistribution from peripheral sites, as well as by
`elimination. Once the distribution process is near-complete (four to
`five distribution half-lives) , plasma and tissue concentrations decline
`in parallel.
`Clinical Implications of Half-Life Measurements The elimination half-life
`not only determines the time required for drug concentrations to fall
`to near-immeasurable levels after a single bolus, but it is the key de(cid:173)
`te1minant of the time required for steady-state plasma concentrations
`to be achieved after any change in drug dosing (Fig. 3-5). This applies
`to the initiation of chronic drug therapy (whether by multiple oral
`doses or by continuous intravenous infusion) , a change in chronic drug
`dose or dosing interval, or discontinuation of drug. When drug effect
`parallels drug concentrations, the time required for a change in drug
`dosing to achieve a new level of effect is therefore determined by the
`elimination half-life.
`During chronic drug administration, a point is reached at which the
`amount of drug administered per unit time equals drug eliminated per
`unit time, defining the steady state. With a continuous intravenous
`infusion, plasma concentrations at steady state are stable, while with
`chronic oral drug administration, plasma concentrations vary during
`the dosing interval but the time-concentration profile between dosing
`intervals is stable (Fig. 3-5).
`DRUG DISTRIBUTION Distribution from central to peripheral sites, or
`from extracellular to intracellular sites, can be accomplished by pas(cid:173)
`sive mechanisms such as diffusion or by specific drug transport mech-
`
`Biliary canaliculus
`
`~-~~~f ~-. (-:
`~ :o~ e--
`···--------~_! __ r_ ___ : __ _
`
`lumen
`
`. "
`
`oo •
`"" Orally
`administered
`drug
`
`()
`
`Drug
`
`0
`Metabolite
`
`P-glycoprotein ©Other transporter
`
`FIGURE 3-4 Mechanism of presystemic clearance. After drug enters the enterocyte, it
`can undergo metabolism, excretion into the intestinal lumen, or transport into the portal
`vein. Similarly, the hepatocyte may accomplish metabolism and biliary excretion prior to the
`entry of drug and metabolites to the systemic circulation. [Adapted by permission from DM
`Roden, in DP Zipes, J Jalife (eds): Cardiac E/ectrophysiology: From Cell to Bedside, 4th ed.
`Philadelphia, Saunders, 2003. Copyright 2003 with permission from Elsevier.]
`
`P-glycoprotein, the product of the normal expression of the MDRJ
`gene. P-glycoprotein is expressed on the apical aspect of the enterocyte
`and on the canalicular aspect of the hepatocyte (Fig. 3-4); in both
`locations, it serves as an efflux pump, thus limiting availability of drug
`to the systemic circulation.
`Most drug metabolism takes place in the liver, although the en(cid:173)
`zymes accomplishing drug metabolism may be expressed, and hence
`drug metabolism may take place, in multiple other sites, including
`kidney, intestinal epithelium, lung, and plasma. Drug metabolism is
`generally conceptualized as "phase I," which generally results in more
`polar metabolites that are more readily excreted, and "phase II," during
`which specific endogenous compounds are conjugated to the drugs or
`their metabolites, again to enhance polarity and thus excretion. The
`major process during phase I is drug oxidation, generally accomplished
`by members of the cytochrome P450 (CYP) monooxygenase super(cid:173)
`family. CYPs that are especially important for drug metabolism (Table
`3-1) include CYP3A4 CYP3A5 CYP2D6 CYP2C9 CYP2Cl9
`CY
`'
`'
`'
`'
`'
`PlA2, and CYP2El, and each drug may be a substrate for one or
`more of these enzymes. The enzymes that accomplish phase II reac(cid:173)
`lions i 1 d
`nc u e glucuronyl- , acetyl-, sulfa- and methyltransferases. Drug
`~etabolites may exert important pharmacologic activity, as discussed
`Urther below.
`er ·
`inical Implications of Altered Bioavailability Some drugs undergo near-
`~o~plete presystemic metabolism and thus cannot be administered
`g~~/' L1docaine is an example; the drug is well absorbed but under(cid:173)
`lite near-complete extraction m the hver, so only hdocame metabo(cid:173)
`ad s .Cwhich may be toxic) appear in the systemic circulation following
`us:Inistration of the parent drug. Similarly , nitroglycerin cannot be
`syst orally because it is completely extracted prior to reaching the
`tran e~nic circulation. The drug is therefore used by the sublingual or
`~ ~rmal routes, which bypass presystemic metabolism.
`can t.
`r drugs undergo very extensive presystemic metabolism but
`st1 1 be ad
`. .
`d b
`.
`.
`mm1stere
`y the oral route, usmg much lugher doses
`
`1e
`
`n
`n
`oS
`JY
`or
`.ty
`
`is
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`DRL EXHIBIT 1021 PAGE 6
`
`

`

`TABLE 3-1 Molecular Pathways Mediating Drug Disposition"
`Molecule
`Substrates'
`
`CYP3A
`
`CY P2D6h
`
`CY P2C9•
`
`CYP2C J9h
`Thiopur ine S(cid:173)
`me thyltransferase''
`N-acetyl transferase•
`
`UGTlA l"
`Pseudochol inesterase"
`P-g lycoprmein
`
`Calcium channel bl ockers;
`an1iarrhytJ1m ics (lidocainc,
`quinidine, mexile1ine): HMG-CoA
`reducrase inhibitors C'sratins"; see
`text); cyclosporine, tacrolimus;
`indinavir, saqu.inavir, ritonavi r
`Timolol, metoprolol, carvedilol:
`phenformin; codeine; propafenon e,
`Hecainide; 1ricyclic a111idepressants;
`tluoxetine, paroxetine
`Warfarin; pheny1oin; gli pizide;
`losarran
`Omeprazole; mephenytoin
`6-Mercaptopurine, azath ioprine
`
`Tsoniazid ; procainamide; hydral azine;
`some sulfonamides
`Irin o1ecan
`Succinylcholine
`Digox in: HIV protease inhibitors;
`many CYP3A substrates
`
`Inhibitors'
`
`Am ioclarone; ketoconazole:
`itraconazole: erythromycin.
`clarilhromycin; ri1onavir
`
`Quinidine (even at ullralow doses);
`tricyclic antidepressants: lluoxetine.
`paroxetine
`
`Amiodarone; tluconazole; phenytoin
`
`Quin idine; amioclarone; verapamil ;
`cyclosporine; itraconazole;
`eryth romyci n
`
`" A li sting of CYP substrates, inhibitors, and inducers is maintained at h11p:llmedicine.i11p11i.ed11/flockhartlc/i11/ist.ht111/.
`" Clinicall y important genetics variants descri bed.
`' Inhibitors affect the molecular pathway and thus may affect substrate.
`
`dose and effect. A loading dose
`can be estimated from the desired
`plasma level (C) and the apparent
`volume of di stribution (V):
`Loading dose = C x V
`Alternatively,
`the
`loading
`amount required to achieve steady(cid:173)
`state plasma levels can also be
`detennined if the fraction of drug
`eliminated during the dosing in(cid:173)
`terval and the maintenance dose
`are known. For example, if the
`fraction of digoxin eliminated
`daily is 35 % and the planned main(cid:173)
`tenance dose is 0.25 mg daily,
`then the loading dose required to
`achieve steady-state levels would
`be (0 .25/0.35) = 0.75 mg.
`In congestive heart failure, the
`central volume of distribution of
`lidocaine is reduced. Therefore,
`lower-than-normal loading regi(cid:173)
`mens are required to achieve
`equi valent plasma drug concen(cid:173)
`trations and to avoid toxicity.
`
`anisms that are only now being defined at the molecular level. Models
`such as those shown in Fig . 3-2 allow deri vation of a volume term for
`each compartment. These vol umes rarely have any correspondence to
`actual physiologic volumes, such as plasma volume or total-body wa(cid:173)
`ter volume. For many drugs the central volume may be viewed con(cid:173)
`veniently as a site in rapid equilibrium with plasma. Central volumes
`and volume of distribution at steady state can be used to estimate tissue
`drug uptake and, in some cases , to adjust drug dosage in disease. In a
`typical 70-kg human, plasma volume is ~3 L, blood volume is ~5.5
`L, and extracellular water outside the vasculature is ~42 L. The vol(cid:173)
`ume of distribution of drugs extensively bound to plasma proteins but
`not to tissue components approaches plasma volume; warfarin is an
`example. However, for most drugs, the volume of distribution is far
`greater than any physiologic space. For example, the volume of dis(cid:173)
`tribution of digoxin and tricyclic antidepressants is hundreds of liters,
`obviously exceeding total-body vol ume. This indicates that these drugs
`are largely distributed outside the vascular system, and the proportion
`of the drug present in the plasma compartment is low. As a conse(cid:173)
`quence, such drugs are not readily removed by dialysis, an important
`consideration in overdose.
`Clinical Implications of Drug Distribution Digoxin accesses its cardiac site
`of action slowly, over a distribution phase of several hours. Thus after
`an intravenous dose, plasma levels fall but those at the site of action
`increase over hours. Only when distribution is near-complete does the
`concentration of digoxin in plasma reflect pharmacologic effect. For
`this reason, there should be a 6- to 8-h wait after administration before
`plasma levels of digoxin are measured as a guide to therapy .
`Animal models have suggested, and clinical studies are confirming,
`that limited drug penetration into the brain, the "blood-brain barrier,"
`often represents a robust P-glycoprotein-mediated efflux process from
`capillary endothelial cells in the cerebral circulation . Thus drug dis(cid:173)
`tribution into the brain may be modulated by changes in P-glycopro(cid:173)
`tein function .
`
`LOADING DOSES For some drugs, the indication may be so urgent that
`the time required to achieve steady-state concentrations may be too
`long. Under these conditions, administration of " loading" dosages may
`result in more rapid elevations of drug concentration to achieve ther(cid:173)
`apeutic effects earlier than with chronic maintenance therapy (Fig. 3-
`5). Nevertheless, the time required for true steady state to be achieved
`is still determined only by elimination half- life . This st