'5‘
`
`215T EDITION
`
`Remington
`
`The Science and Practice
`
`of Pharmacy
`
`94% LIPPINCOTFWILLIAMS {4WILKINS
`
`
`
`'
`
`A Wolters Kluwer Company
`Philadelphia - Baltimore - New York - London
`Buenos Aires - Hong Kong - Sydney - Tokyo
`
`‘i—v—
`
`MYLAN INC. EXHIBIT NO. 1034 Page 1/
`/
`
`MYLAN INC. EXHIBIT NO. 1034 Page 1
`
`

`

`
`
`Editor: David B. Troy
`Managing Editor: Matthew J. Hauber
`Marketing Manager: Marisa A. O’Brien
`
`Lippincott Williams & Wilkins
`
`351 West Camden Street
`
`Baltimore, Maryland 21201-2436 USA
`
`530 Walnut Street
`
`Philadelphia, PA 19106
`
`All rights reserved. This book is protected by copyright. No part of this book may be reproduced in any form or by any means,
`including photocopying, or utilized by any information storage and retrieval system without written permission from the copy-
`right owner.
`
`The publisher is not responsible (as a matter of product liability, negligence or otherwise) for any injury resulting from any
`material contained herein. This publication contains information relating to general principles of medical care which should not
`be construed as specific instructions for individual patients. Manufacturer’s product information and package inserts should be
`reviewed for current information, including contraindications, dosages and precautions.
`
`Printed in the United States of America
`
`Entered according to Act of Congress, in the year 1885 by Joseph P Remington, in the Office of the Librarian of Congress, at
`Washington DC
`
`Copyright 1889, 1894, 1905, 1907, 1917, by Joseph P Remington
`
`Copyright 1926, 1936, by the Joseph P Remington Estate
`
`Copyright 1948, 1951, by the Philadelphia College of Pharmacy and Science
`
`Copyright 1956, 1960, 1965, 1970, 1975, 1980, 1985, 1990, 1995, by the Philadelphia College of Pharmacy and Science
`
`Copyright 2000, 2006, by the University of the Sciences in Philadelphia
`
`All Rights Reserved
`Library of Congress Catalog Card Information is available
`ISBN 0-7817-4673-6
`
`The publishers have made every effort to trace the copyright holders for borrowed material. If they have inadvertently overlooked
`any, they will be pleased to make the necessary arrangements at the first opportunity.
`
`The use of structural formulas from USAN and the USP Dictionary ofDrug Names is by permission of The USP Convention. The
`Convention is not responsible for any inaccuracy contained herein.
`
`Notice—This text is not intended to represent, nor shall it be interpreted to be, the equivalent of or a substitute for the official
`United States Pharmacopeia (USP) and / or the National Formulary (NF). In the event of any difference or discrepancy between the
`current ofi‘icial USP or NF standards ofstrength, quality, purity, packaging and labeling for drugs and representations of them
`herein, the context and effect of the official compendia shall prevail.
`
`To purchase additional copies of this book call our customer service department at (800) 638-3030 or fax orders to (301)
`824-7390. International customers should call (301) 714-2324.
`
`MYLAN INC. EXHIBIT NO. 1034 Page 2
`
`12345678910
`
`MYLAN INC. EXHIBIT NO. 1034 Page 2
`
`

`

`, A treatise on the theory
`_
`Remington: The Science and Practice of Pharmacy .
`and practice of the pharmaceuticai sciences, with essentiai
`information about pharmaceutical and medicinai agents, aiso, a
`guide to the professionai responsibitities of the pharmacist as the
`drug information speciaiist of the heaith team .
`.
`. A textbook and
`reference work for pharmacists, physicians, and other practitioners of
`the pharmaceuticai and medicai sciences.
`
`EDITORIAL BOARD
`
`Paul Beringer
`
`Pardeep K. Gupta
`
`Ara DerMarderosian
`
`John E. Hoover
`
`Linda Feiton
`
`Nicholas (3. Popovick
`
`Steven Gelone
`
`William J. Reiliy, Jr
`
`Alfonso R. Gennaro
`
`Randy Hendrickson, Chair
`
`AUTHORS
`
`The 133 chapters of this edition of Remington were written by
`
`the editors, by members of the Editorial Board, and by the au-
`
`thors listed on pages xi to xv.
`
`Director
`
`Philip P Gerbino 1995-2005
`
`Twenty-first Edition—2005
`
`Published in the 185th year of the
`PHILADELPHIA COLLEGE OF PHARMACY AND SCIENCE
`
`MYLAN INC. EXHIBIT NO. 1034 Page 3
`
`MYLAN INC. EXHIBIT NO. 1034 Page 3
`
`

`

`Clinical Pharmacokinetics and
`
`
`
`Pharmacodynamics
`
`Paul M Beringer, PharmD
`
`Michael E Winter, PharmD
`
`CHAPTER 59
`
`ii
`
`'5;
`
`
`In Chapter 58. the basic principles of pharmacokinetics were
`presented. Clinical pharmacokinetics is the discipline in which
`
`basic pharmacokinetic principles are applied to the develop—
`
`ment of rational dosage regimens. In this chapter, the concepts
`
`of pharmacokinctics are placed into perspective with thc devel-
`
`opment of individualized drug dosage regimens. The clinical
`
`significance of drug absorption, distribution. and elimination
`
`and influence ol‘diseasc states on these processes are empha—
`
`sized. Examples are given of the ways pharmacokinetic princi—
`
`ples can he applied in the calculation and adjustment oi'dosagc
`
`regimens designed to fit the pharmacokinetic and pharmacody-
`
`namic properties ofdrugs and specific disease states that alter
`
`drug disposition. The principles oftherapcutic drug monitoring
`
`and the rational use ofthis clinical science in the management
`ofpatients also are discussed.
`
`
`
`
`Overview of Clinical Pharmacokinetics
`
`The application of pharmacokinetic principles to patient care
`can aid the clinician in making rational drug Lise decisions.
`
`However, knowing the relationship between the time course of
`
`drug concentration and the pharmacologic effect
`is critical
`to the application ol‘pharmacokinetic principles and the inter—
`
`pretation of plasma drug concentrations in the patient care
`setting
`
`As a general rule traditional pharmacoltinetic research is
`
`an intensive study of'a limited number ol’subjects resulting in
`
`very precise pharmacokinctic and pharmacodynamic parame—
`ter estimates. Clinical pharmacoltinetics. on the other hand, is
`
`usually limited to very few and sometimes no plasma drug
`
`concentrations. requiring the clinician to make an educated
`
`guess about key elements ot‘drug disposition and the drug use
`
`process. In the research setting. it is common to obtain 10 or
`
`more samples for drug concentration measurements within
`
`a single dosing interval. In the clinical setting, it is uncom-
`
`mon to obtain more than two or three samples For a patient
`
`during a hospitalization or within a year for ambulatory care
`patients.
`
`Therefore. understanding the usual manner in which drugs
`are absorbed. distributed, and eliminated as well as the.
`
`known factors that alter drug disposition and which of these
`elements is most likely to be altered in the individual patient
`
`is key to the clinician‘s ability to effectively use pharmacoki—
`
`netics. A basic knowledge of pharmacokinctics provides guid—
`
`ance to the clinician when selecting a drug product, dosing
`
`regimen. the anticipated onset. ol‘drug effect. and determining
`
`an appropriate sampling strategy il'tlrug concentrations are. to
`he obtained.
`
`
`
`Drugs with Narrow Versus Wide
`Therapeutic Range
`The therapeutic range is a concentration range that is likely
`to result in the desired clinical or therapeutic response with
`an acceptable risk or likelihood of developing a toxic response.
`For every drug, there is a therapeutic range, but it is those
`drugs in which the minimum concentration that is likely to re-
`sult in the desired drug effect is relatively close to the higher
`drug concentration that is likely to result in a toxic response.
`The therapeutic index is the ratio of the maximum desired
`concentration relative to the minimum desired concentration.
`The application of pharmacokinetic principles may be limited
`in the use of some drugs. Drugs that have a wide therapeutic
`index may not require precise dose adjustments when drug
`disposition is altered and a simple approximation may be sat-
`isfactory to limit the probability of toxicity and assure efficacy.
`Other drugs may have a complex series of biological events
`that result in an obscure relationship between the pharmaco-
`logic effects and the drug dose or drug concentration making
`it difficult
`to apply the usual pharmacokinetic principles to
`the daily care of a patient.
`Drugs with a narrow therapeutic range, however. tend to
`lend themselves to careful dose adjustments and plasma drug
`concentration monitoring to help ensure optimal patient out-
`comes. For those drugs that are monitored with plasma drug
`concentrations, there is usually a Normal Therapeutic Range
`that attempts to define the drug,r concentrations where the. ben-
`efit to risk ratio is optimal {Fig 59-1}. While the Normal Thera-
`peutic Range is important, it is onlyr a guide, and it is the
`patient and not the drug concentration that is therapeutic or
`toxic. There are patients with an optimal clinical outcome
`whose plasma drug concentrations fall outside the usual range
`and others who develop unacceptable side effects or toxicities
`when drug concentrations are within or even below the usual
`Therapeutic Range.
`
`Plasma Protein Binding and the
`Therapeutic Range
`One potential [actor that can change the Normal Therapeutic
`Range is alterations in plasma protein binding. In most cases,
`clinical laboratories use assa)r procedures that measure and re-
`port the total plasma drug concentration, ie. the drug concen—
`tration thatis bound to plasma protein and the unbound plasma
`drug concentration. It is only the unbound drug in plasma that
`can cross into the tissue where the receptors are located.
`
`MYLAN INC. EXHIBIT NO. 1034 P211§84
`
`MYLAN INC. EXHIBIT NO. 1034 Page 4
`
`

`

`
`
`1192
`
`PART 6: PHARMACODYNAMICS AND PHARMACOKINETICS
`
`
`‘
`ii.-.r:ipeutie italics
`0.90 v
`
`
`
`
`
`
`1.00
`
`
`
`{Hill -
`
`[1.70 -
`
`ilfitl [-
`[J50
`
`one I—
`[Hill
`
`0.2L}
`0.10
`
`{Hit}
`
`r_
`
`‘0
`
`
`
`FractionalResponse
`
`Drug Concentration
`
`Figure 59-1. "Normal therapeutic range." The "normal therapeutic
`range" defines the region of drug concentrations where the probability
`of a positive therapeutic response is good and the risk for development
`at a Significant dose—related adverse effect is acceptable. For most agents
`the normal therapeutic range is quite Wider howcver. for certain agents
`there Is a relatively narrow therapeutic range and monitoring of drug
`concentrations may be necessary to maximize the potential tor efficacy
`and minimize the risk of tuiocitv
`
`Therefore. it is the unbound drug concentration th at. is propor-
`tional to the. tissue and receptor drug concentration and the
`pharmacodynamic response [Fig 59—2}. Any change in plasma
`protein binding would be expected to alter the potential for any
`plasma drug concentration. reported as both bound and un—
`bound drug, to result in a toxic or therapeutic response. Many
`drugs have significant binding to plasma proteins and the rela—
`tionship between the unbound drug concentration and the total
`drug concentration is referred to as the. free fraction or in.
`
`_
`Unbound Drug Concentration
`1” _
`Total Drug Concentration
`
`{1}
`
`Uf‘
`
`Unbound Drug Concentration =
`{fultTotal Drug Concentrationt
`
`:2}
`
`Any factor that alters plasma protein binding will result in an
`altered free. fraction ifu‘i. Therefore, when interpreting assayed
`drug concentrations with altered plasma binding. the clinician
`should make some type of adjustment when using the assayed
`drug concentration.
`One approach is to calculate a norma
`concentration:
`
`1 plasma binding drug
`
`Normal Plasma Binding
`Drug Concentration
`
`.
`i'
`= (iii
`
`Assayed Drug Concentration
`with
`Altered Plasma Binding
`
`‘3’
`
`aslna binding drug concentra—
`and then compare the normal pl
`[mate the drug's po—
`tion to the normal therapeutic range to eve
`tential for either efficacy or toxicity
`An alternative approach is to ca
`peutic range:
`
`lculate an adjusted thera-
`
`Adjusted
`_
`ILL
`__
`|
`.
`.
`Therapeutic Range — £11,] tNorinal Therapeutic Rangel
`
`_
`t4}
`
`peutic range to the assayed
`and compare this adjusted there
`luate the
`drug concentration with altered plasma binding to eva
`drug's potential for either efficacy or toxicity.
`
`In any case for drugs with high plasma binding. care should
`1‘ assayed drug concentration.
`be taken in the interpretation o
`Most weak acid drugs with high plasma binding leg, phenytoini
`most commonly
`are bound almost exclusively to albumin. The
`these
`encountered reasons for alterations in plasma binding for
`end stage renal Failure or dialysis
`drugs are hypoalhuniinemia,
`drugs. Basic compounds tend to
`and displacement by other
`have a more complex plasma-binding pattern and extensive
`bindingr to a number of plasma proteins including alpha-l-acid-
`glycoprotcio. other globulins and albumin is common.
`In addition to plasma binding alterations. clinical conditions
`can change a patient’s response to a given close or drug concen-
`tration. As an example. a change in renal function can change
`a patient’s ability to eliminate drugs whose route of elimination
`is via the. kidneys leg, ainiooglycoside antibiotics t. The addition
`ol'a new drug that either inhibits the elimination or metabolism
`tor, amiodarone when added to a patient receiving dignxinl
`or
`induces metabolism leg, carbamazepine inducing the
`metabolism of wartarint can alter the relationship between the
`drug dosing regimen and the resultant drug concentrations and
`drug effect. In addition, alterations in electrolyte or acid base
`balance [night alter the potential ofa drug to produce toxicity
`ieg, hypokalemia in a patient receiving digoxin}. While the nor-
`mal therapeutic range is usually thought ofas fixed upper and
`lower boundaries, there are many situations that require. the
`clinician to make adjustments in dosingr regimens and target
`drug concentrations. Knowing both the drug‘s pharmacokinetic
`and pharmacodynamic characteristics allow the clinician to tie
`sign drug regimens that have an optimal chance of producing a
`beneficial outcome for the patient.
`
`Absorption. Distribution. and Elimination
`In the application of pharmacokinetics to the clinical practice
`setting. the ability to estimate a patient‘s absorption, distrihuv
`tion. and elimination characteristics is an important step in ini-
`tiating drug therapy. For many drugs. clinicians simply learn
`the "usual" dose and use that close for all patients. In a number
`of situations, knowing the. principles behind the usual dose al—
`lows the clinician to make adjustments in drug therapy for
`those patients where therapeutic problems. toxicity or lack of
`efficacy. are likely to occur.
`
`Tissue
`
`
`C Non-Specific
`Binding |
`
`
`
`
`' C unbound
`
`
`
`C Receptor
`
`I
`
`
`Response
`
`Plasma
`
`C bound
`
`
`
`C unbound
`
`l
`
`Metabolism
`
`Elimination
`
`
`
`Figure 59-2. Note that it is the unbound drug concentration (C unbound:
`that is able to cross into the tissue and Equilibrate With the tissue binding
`sites and the drug receptor. While C bound may he a significant pet-
`centage of
`the plasma drug pool,
`in most cases very little drug is In
`plasma and theretore C bound represents relatively little of the total drug
`in the body.
`
`MYLAN INC. EXHIBIT NO. 1034 Page 5
`
`pro
`
`des
`drc
`ing-
`swi
`
`ver
`use.
`slot.
`in t.
`not.
`hou
`istr
`tlta
`dos-
`clin
`
`MYLAN INC. EXHIBIT NO. 1034 Page 5
`
`

`

`mug—r»
`
`G
`
`drug
`
`ptor
`
`IDSB
`
`.undl
`iding
`per-
`is in
`
`CHAPTER 59'. CLINICAL PHARMACGKINETICS AND PHARMACODYNAMICS
`
`1 193
`
`AbsorptionIBioavailabiIity
`The absorption of a drug is a key element in determining a
`drug—dosing regimen. The extent of absorption is referred to as
`bioavailability and is usually expressed as either a fraction {F}
`or percent of'an administered drug that is available to produce
`a pharmacologic effect. An F value ofl represent 1009}. ofan ad-
`ministered dose is bioavailable. Most drugs when given by the
`momentum route are assumed to be 1000? bioavailable {F of
`1.0!. Absorption by other routes of administration (oral. rectal.
`etc] may or may not be complete. A number of factors influence
`the bioavailability ofa drug.
`To be orally absorbed, drugs must have. a reasonable degree
`of water solubility so that they can dissolve in the gastroin-
`testinal {GI} fluids. In addition, they must also have some lipid
`solubility characteristics so that the drug can cross the lipid
`membranes ofthe cell wall in the GI tract and enter the general
`circulation and eventually cross the cell walls ofother tissues in
`the body. Aminoglycoside antibiotics are an example of a drug
`class whose water solubility is so high {lipid solubility very low!
`that they are not absorbed to any significant extent when ad—
`ministered by the oral route and must be given parents rally to
`achieve. systemic effects.
`Drugs that are unstable in the GI tract may have low
`bioovailability because they are broken down or decompose be-
`l'nrc they can be absorbed. The proton pump inhibitors leg,
`omcpraaolel are an example ofa drug class that is unstable in
`the gastric acid and are administered orallyr as an enteric-
`coated tablet. In addition. although some drugs are absorbed.
`they are metabolized by the enzymes in the gut wall or the liver
`prior to reaching the systemic circulation. Ioidocaine is an ex-
`ample ofa drug that is metabolized so extensively as it passes
`through the liver following oral absorption that effective sys-
`temic effects require parenteral administration. Extensive hep—
`atic metabolism following oral absorption is referred to as a
`First Pusa- Eflcct {see Chapter 58 Hepatic Clearance}. Recently
`a greater appreciation for the impact of drug transporters on
`oral bioavailability of a number of compounds has been real-
`ized. In particular. the xenohiotic transporter P-glyctiprotein
`has been shown to significantly affect the oral bioavailability of
`cyclosporine and other large hydrophobic compounds. Similar
`in the knowledge gained by studying the CYP450 enzymes re—
`sponsible for metabolism of commonly prescribed drugs, knowl—
`edge of the substrate specificity of P-glycoprotoin is integral to
`predicting the bioavailability of drugs that are substrates for
`this transporter.
`Bioavailability or F. refers only to the extent nfabsorption.
`The rate of' drug absorption can also be in important factor in
`drug administration. Extended release tablets and capsules are
`often designed for the drug to be slowly released from the
`dosage form so that drug absorption is relatively constant over
`the entire dosing interval. As a result. these types oi‘oral dosage
`limos tend to produce relatively little fluctuation in the plasma
`drug concentrations within a dosing interval. While this may be
`ideal for a drug with a narrow therapeutic. index. these drug
`products may not. be useful when relatively rapid drug onset is
`desired. in addition the drug release characteristics are usually
`designed to be consistent with a specific dosing interval. If a
`drug product is designed to be absorbed over 12 hours. extend—
`ing the doing interval to 24 hours may result in unacceptable
`swings in plasma concentrations.
`Patients with certain gastrointestinal diseases may have a
`very short gastrointestinal transit time and thereby limiting the
`use of seine extended release drug products. One example of a
`slowly absorbed drug with a limited bioavailability is phenytoin
`in the newborn. While not designed as an extended release procl-
`uct, phenytoin is so limited in its water solubility that several
`hours are required for complete absorption following oral admin—
`istration. The newborn child has such a short GI transit time
`that when infants are changed from parenteral to equal oral
`rinses ofphenytoin, the plasma concentrations almost always do-
`cline dramatically because of a limited oral bioavailability.
`
`Volume of Distribution (V)
`
`Following absorption, drugs distribute throughout the hotly.
`Each drug has its own characteristics that result. in an appar-
`ent volume ol'dislribution {V} and can be expressed mathemat-
`ically as:
`
`
`Amount of Drug in the Body
`Volume of Distribution —
`Plasma Concentration
`
`Ul'
`
`V _ Amount of Digg in the Body
`
`15!
`
`where V is the volume oi'distribution and C is the plasma drug
`concentration. As can be seen from the equation above. volume
`ol’distribution is the volume required to account fol-the drug as
`suming the tissues have the same concentration as plasma.
`Volume of distribution is an important. pharmacokinetic pa—
`rameter when calculating the loading dose required to rapidly
`increase the plasma drug concentration to some desired con-
`centration:
`
`THVI
`Loading Dose 2 lL_F__
`
`where C is the desired plasma concentration and F the bioavail—
`ability. In seine cases. there may be drug already present and
`only a partial or incremental loading dose is needed to achieve
`the desired [bl-um...
`
`Incremental = {C'I‘.ir|.;i-l — Cin.o.-.iliVl
`Loading Dose
`F‘
`
`{61
`
`In the above equation 0-1-1”... is the desired concentration fol—
`lowing and Cimli‘.” is the drug concentration just prior to the in‘
`cremental loading dose.
`
`Body Composition and Volume of
`Distribution
`
`Volume of distribution is most often reported as ng. The up-
`plicability of this Ulcg value assumes that the physical charac—
`teristics of the patient are similar to the study population. Pn—
`tients who are obese. emaciated. or have extensive third
`spacing offluid lascites or edema} may have an altered volume
`of distribution based on total body weight. Therefore some as-
`sessment of body composition is important when making initial
`estimates of V.
`OBESE VERSUS IDEAL BODY WEIGHT—When pa-
`tients are obese the most common approach is to calculate the
`patient's Ideal Body Weight i'IBWl:
`
`IBW..H.I*._. = 50 kg + 2.3[Height in inches 3 GDII
`
`IBWIemah... = 45 kg 1 2.3(Hcight in inches 3-“ 60b
`
`i7}
`
`[8]
`
`IBW in the above equations is in kg‘ and it is this weight that is
`generally assumed to represent a “non—obese" weight. When the
`volume of distribution is known to correspond best to ideal or
`non-obese weight, it is the IBW that should be used for obese pa-
`tients. As a practical approach, if a patient who weighs more
`than their IBW. most clinicians consider the patient to be clini—
`cally obese only ifthe patient. is greater than 120% ol‘thcir IBW:
`
`' Patients Weight
`Clinically Obese =[
`{BW
`
`lion
`
`120
`
`:91
`
`There are a few drugs that either part or all oi‘the excess adi—
`pose weight in the. clinically obese patient is used in calculating
`the apparent volume of distribution. Care should be taken to
`
`MYLAN INC. EXHIBIT NO. 1034 Page 6
`
`MYLAN INC. EXHIBIT NO. 1034 Page 6
`
`

`

`—___————
`
`1194
`
`PART 61PHARMACODYNAM1CS AND PHARMACOKINETICS
`
`carefullyr evaluate the patient‘s weight as well as the charac—
`teristics ofthe specific drug in question.
`EXCESS THIRD SPACE FLUID [EDEMA AND AS-
`CI'l‘ES}—-Somc patients have extensive edema or ascites, This
`fluid accumulates in the interstitial space between the vascula—
`ture and the intracellular compartment. or the peritoneal cav~
`ity. The degree to which a patient's vascular volume. andfor iu—
`tracellular volume can change is limited. Therefore. in most
`cases. significant. changes in body water occur in the intraperi-
`toneal and interstitial or third space. Depending on the drug‘s
`distribution characteristics the presence of third space fluid
`may alter how the apparent volume of distribution is calcu—
`lated. In most cases, the presence ofthird space lluid is evalu-
`ated by changes in weight, with 1 kg of weight gain represent.—
`ing 1 liter of third space fluid. Alternatively. an experienced
`clinician can often approximate in patients with ascites or
`edema the number of excess third space liters present.
`One. method that can be used to account for any third space
`fluid is to calculate the contribution that one would expect. for
`each liter tkgl of excess edema or ascites. The apparent V for
`each liter can be calculated by multiplying the. fraction of un-
`bound drug in plasma (1111 times the number of liters of excess
`third space fluid.
`l10l
`-= iquLiters of Excess 3"" Space Fluidl
`Viexcmm 5i.-_l.;,.i11.i‘|
`The units ofV are liters. The. liters ofexcessive third space fluid
`gain are usually estimated by subtracting the patients. current.
`weight from their usual weight in kilograms. Care should be
`taken to evaluate whether or not the. weight gain is in fact ex-
`cess third space fluid. Usually this is accomplished by deter—
`mining thc time course of the weight. gain. Muscle mass and
`adipose weight gain generally takes many months. but third
`space. weight gain can occur over weeks. days. or even a few
`hours. The presence of or change in the patient’s edema or as—
`cites is also a factor that should be. considered when estimating
`excess third space fluid weight. As an example. a patient who
`gains 10 kg of weight in 2 days may have. been initially dehy—
`drated and simply replaced a fluid deficit rather than have
`gained 10 L olicxccss third space iluid. On the other hand ifthe.
`patient has extensive edema before gaining the 10 kg. the
`amount of excess third space fluid may be much more than the
`most. recent 10 kg weight. gain would suggest.
`In most cases the amount of excess fluid gained is in the.
`range of 5 to 10 L and is seldom more. than 20 L. Because the
`contribution offi to 20 L is not significant for most drugs, the
`weight used in calculating the volume of distribution ne
`only consider the patient‘s usual weight. However. if the vol-
`ume ot‘distri'oution is small and plasma protein binding is low
`(in approaches 1:. then excess third spacing offluid should be
`considered in the calculation. rFhis would be accomplished by
`first. calculating the patient‘s weight without the excess third
`space weight and using the non-excess third spocc weight to
`calculate the patient‘s V in the usual way. In addition. Equa~
`tion 10 above can be used to determine the additional contri—
`bution of Vim...” 3rd film... mud. The sum of these two values
`would be the most reasonable value to use for the patient’s
`volume of distribution.
`Digoxin and aminoglycoside antibiotics are two drugs that
`represent the. extremes. Digoxin has a fu of approximately 0.9
`and a V of approximately 500 l. l? Uligl. if a patient accumu—
`lated 10 liters of excessive third space fluid, the increase in V
`would only be 9 I. lie, {0.9} {Liters of Excess 3rd Space Fluidll.
`This increase in V is less than 257: of the total volume of' distri—
`bution and therefore not clinically significant. it is important to
`note that. the patienl's weight without the. excess third space
`fluid should be used to calculate the volume of distribution for
`digoxin and most other drugs with a large volume of distribu—
`tion. Aminoglycoside antibiotics also have. a to ol'approxiinately
`0.9 but the usual V is approximately 15 to 20 liters. Therefore,
`the increase in V of 9 li associated with 10 liters of excess third
`space fluid would be significant and would be incorporated in
`the. calculation 01W".
`
`Two Compartment Volume Of Distribution
`While it is often useful to think of the body as a. single com—
`partment, in reality we are made of hundreds if not thousands
`of individual spaces into which a drug distributes. However,
`for most drugs the volume of distribution can be conceptual-
`ized into two individual compartments. An initial first volume
`[VII consisting of plasma and other rapidly equililtirating tis-
`sues and a second more slowly equilibrating volume W31 lFig
`59—3}.
`LOCATION OF TARGET ORGAN—The two—compart-
`ment model has two important clinical implications. First is rc~
`lated to the location of the target organ for clinical response
`{therapeutic or toxic}. Some. drugs have an end organ for clini-
`cal response tefficacy or toxicityl that equilibrates very rapidly
`with plasma. Therefore, large doses administered rapidly into
`the smaller first compartment will result in elevated drug con-
`centrations and have the potential for causing drug toxicity. h
`is also possible to give a smaller first dose that achieves an ini‘
`tial therapeutic concentration and response that is quickly lost
`as the. drug concentration declines during distribution into the
`larger volume. Drugs whose target organ respond as though it
`were located in the initial volume of distribution must be atl-
`ministcred in such a way as to avoid the transiently elevated
`drug concentrations during the administration process. This is
`most common when drugs are administered by the. intravenous
`route. Most. drugs have a maximum recommended rate ol‘infu-
`sion. Usually this rate is designed to allow drug distribution to
`take place. as the drug is being infused. Occasionally it is rec-
`ommended to divide a dose into portions that are administered
`at set intervals. again allowing for distribution to be completed
`before the next part of the. dose is administered. For some
`drugs. the intravenous administration rate has to be controlled
`because of an agent in the injectablc dosage form that has the
`potential for toxicity. As an example, penicillin is most com
`monly available as the potassium salt. While rapid injection of
`penicillin itself can be potentially harmful, it is the potassium
`that is probably the most dangerous and the reason for control-
`ling the infusion rate of IV potassium penicillin. When drugs
`
`n
`
` Drug
`logC ~k
`
`
`Ellmination
`
`
`0‘:
`
`Time
`
`Figure 59—3. Drug first enters the body IHLO V. The Il'llllal rapid (lEiIllde':
`In drug concentration in phase) IS prunarily due to drug moving 1f'lI'L'l tiic
`larger more slowly equilibiatinq V;
`the more slowly declining drug ton-
`centrauons {ii phase) are primarily due to drug being eliminated from the
`body.
`
`-
`
`MYLAN INC. EXHIBIT NO. 1034 Page 7
`
`g-
`
`MYLAN INC. EXHIBIT NO. 1034 Page 7
`
`

`

`
`
`Color Plate 1. Figure 34-32. The 3—dimensional molecular structure of d,|—proprano|o| hydrochloride provides information about the molecular con—
`formation and bonding whereas the its packing arrangement within the crystallographic unit cell is useful in understanding the physical properties of
`the crystalline form.
`
`
`
`
`
`IEDIOI' Pl!!! 2. Figure 34-35. The x—ray pOWder diffraction patterns of two polymorphic forms of d,l—propranolol hydrochloride indicate differences in
`molecular arrangements within their different crystal lattices.
`
`
`
`
`
`
`
`
`
`é+u+¢
`+9-rsilo:if?1
`t+ft¢+
`+fifilittdir¢l
`++++¢.
`+a¢aloo§++bi
`++f¢co
`¢+Ov¢+yi+§§l
`.
`v++¢ar
`s+c§++yi+i+j
`¢?f§l¢
`$+3!4s‘lfe‘f‘_
`v+9+¢+ ‘
`s+4v+vrete+1
`.-. Luau-Lu
`..:;'.~-.-1-LflnH
`
`
`+++++++++++4
`:
`a ++++o+++++4
`
`
`
`++HH+++++4
`444$wa
`
`
`t++¢++*H—H
`.
`--
`“
`I
`
`
`rPlltl 3. Figurl 34-44. Design for the crystallization process for polymorphic form screening demonstrates hot filtration of the crystallization so—
`_'
`'on and its transfer to three crystallization plates and two plates for soluleflemthC EXHIBIT N0 1034 Page 8
`
`
`
`
`MYLAN INC. EXHIBIT NO. 1034 Page 8
`
`

`

`LL]
`
`TI
`
`'1'.)
`
`05'P
`
`O
`
`O
`
`m
`
`'I'I
`
`6)
`
`I
`
`
`,J._
`
`he
`
`,L
`
`Lk
`
`Lu
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`III...I!-
`
`
`FFFFFre»
`Good Aqueous Solubility ' Gencml Rule of 5 compliance
`
`
`
`
`
`r
`Color Plate 4. Figure 34-45. Birefringence images and powder diffraction patterns collected lrom the everporatrve crystallizatton plate in the HTS of
`d,I-pr0pranolol hydroch onde indicates two polymorphic crystal forms and their lOCElIlOn within the 96-well plate, thus enabling correlation of crystal-
`lization chemistry with he crystal form obtained.
`
`Jib.
`
`
`
`General Characteristics
`
`
`II'-.__ ’ High mp, High crystal energy
`
`
`
`
`
`
`' Lipophilic or Less H—bonding
`' Less douse packing & Less l-i—bondtng
`' Higher Aq. Sol. or Less H-bondll‘lg
`' Lipop‘nilic or Moderate ll—bonding
`
`Color Plate 5. Figure 38-7. Possible and physiological—negative drug
`spaces.
`
`Color Plate 6. Figure 41—3. Multiple effect still (courtesy, Getinge).
`
`l
`
`MYLAN INC. EXHIBIT NO. 1034 Page 9
`___J._
`
`MYLAN INC. EXHIBIT NO. 1034 Page 9
`
`

`

`Color Plate 7. Figure 41-10. Example of an isolator (courtesy, LaCal-
`henel.
`
`Color Plate 8. Figure 41-12. Example of a three—bucket assembly used
`for sanitizing facilities (courtesy, Contec).
`
`
`
`High flow: 65-75 % porous
`Particles retained by
`
`r Sicving
`r Entrapment
`
`(tortuous pathway)
`
`r Adsorption
`(high internal area)
`
`
`
`membrane filters (courtesy, Mlllipore).
`Getinge USA).
`
`
` B
`
`Color Plate 10. Figure 41-19. Mechanisms of microbial retention on
`
`Color Plate 9. Figure 41-13. Rubber closure processors (courtesy,
`
`Color Plate 12. Figure 41-22 Vial filling mac hine distant and closeup
`Color Plate 11. Figure 41-21. Syringe filling machine (courtesy, BaXIEFMvaKNTNi/éaxteEXHIBIT N0 1034 Page 10
`
`MYLAN INC. EXHIBIT NO. 1034 Page 10
`
`

`

`
`
`Color Plate 13. Figure 41-27. Steam sterilizers (small and large) (comtesy. Getinge).
`
`Compressor (Back of Chamber}
`
`.
`
`_
`
`Computer
`Control
`Station
`
`.
`'.
`'
`
`.
`
`_
`
`.
`
`'
`
`_
`
`-
`
`__
`
`H_
`
`_
`g
`" '-
`
`Chamber
`and
`Shelves
`
`Sample Thief
`
`Vacuum Pump
`For Thief
`
`Vacuum Pump
`
`Condenser
`
`Color Plate 14. Figure 41-28. Example of a laboratory freeze—dryer (courtesy, Baxter).
`
`Temperature difference between chamber a