'51
`
`215T EDITION
`
`Remington
`
`
`
`The Science and Practice
`
`of Pharmacy
`
`é% LIPPINCOTTWILLIAMS a‘W[u<.IN5
`'
`A Wolters Kluwer Company
`'more - New York - London
`ng Kong - Sydney - Tokyo
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`A1\/[NEAL
`
`EXHIBIT N0. 1034 Page 1
`[[1
`
`

`
`
`
`Editor: David B. Troy
`Managing Editor: Matthew J. Hauber
`Marketing Manager: Marisa A. O’Brien
`
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`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
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`Copyright 2000, 2006, by the University ofthe Sciences in Philadelphia
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`All Rights Reserved
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`ISBN 0-7317-4673-6
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`any, they will be pleased to make the necessary arrangements at the first opportunity.
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`The use ofstructural formulas firom USAN and the USP Dictionary offlrug Names is by permission ofThe USP Convention. The
`Convention is not responsible for any inaccuracy contained herein.
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`Notioe—Tl1 is text is not intended to represent, nor‘ shall it be interpreted to be, the equivalent ofor a substitute for the ofiiciol
`United States Phorrnocopeio (USP) andIor the National Formulory (NF). In the event ofany difiizreiice or discrepancy between the
`current official USP or NF standards ofstrength, quality, purity, packaging and labeling for drugs and representations ofthern
`herein, the con text and efi"ect of the official compendia shall prevail.
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`Al\1NEAL
`
`EXHIBIT NO. 1034 Page 2
`
`12345678910
`
`

`
`. A treatise on the theory
`Remington: The Science and Practice-of Pharmacy. .
`and practice of the ,oharmaceuticai sciences, with essen tiai
`ihformation about pharmaceutical and medicinai agents,‘ also, a
`guide to the professional res,oonsibiIities of the pharmacist as the
`drug information specialist or‘ the health team .
`.
`.. A textbook and
`reference work for pharmacists, physicians, and other practitioners or
`the pharmaceu ticai and medicai sciences.
`
`EDITORIAL BOARD
`
`Paul Beringer
`
`Pardeep K. Gupta
`
`Ara Derlviarderosian
`
`John E. Hoover
`
`Linda Felton
`
`Steven Gelone
`
`Nicholas G. Popovick
`
`William J. Reilly, Jr
`
`Alfonso R. Gennaro
`
`Randy Hendritkson, 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—i'irst Edition—2005
`
`Published in the 185th year of the
`PHILADELPHIA COLLEGE OF PHARMACY AND SCIENCE
`
`AMNEAL
`
`EXHIBIT NO. 1034 Page 3
`
`

`
`
`
`clinical Fhaofinanokihetiics and
`Pharmacadynamicss
`
`Paul M Berinigen Ph_a'rmD
`Michael E wi'nte1r_, -Pha-rmo
`
`CHAPTER '59
`
`*3:
`
`In Chapter 58,. the basic principles of‘ pharmacokinctrics were
`presented. Clinical pharrnacokinetics is the discipline in which
`basic -pharmscokinetcic principles are applied to the develop-
`ment of rational dosage regimens. In this chapter, the concepts
`of pharmacokinetics are placed into perspective with the devel-
`cpment of individualized drug dosage regimens. The clinical
`significance of drug absorption. distribution, and elimination
`and influence of disease states on these processes are empha-
`sized. Examples are given of the ways pharmacokineiic princi-
`ples can he applied in the calculation and adjustment of dos age
`regimens designed to fit the pharmacolcinetic and pharmacody-
`namic properties of drugs and specific disease states that alter
`drug disposition. The principles oft!-ierapcutic drug monitoring
`and the rational use of this clinical science in the management
`of patients also are discussed.
`
`Overview of Clinical Pharrnacnkinetics
`
`'
`
`The application of pharrnacokinetic principles to patient care
`can aid the clinician in making rational drug use decisions.
`However. knowing the relationship between the time course of
`drug concentration and the phermacologic effect is critical
`to the application of pharmacokinetic principles and the inter‘
`pretation of plasma drug concentrations in the patient care
`setting-.
`As a general rule traditional pharmacolrinetic research is
`an intensive study of a limited number of subjects resulting in
`very precise pharmacokinetic and pharmacodynaniic parame—
`tor estimates. Clinical pharmacokinetics. 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‘ of drug disposition and the drug use
`process. In the research setting, it iscomnion 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 wl1.ich.d.r1J.ge
`-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 efiectively use pharrna.coki-
`notice. A basic knowledge of pharmacokiucfica provides guid-
`ance to the clinician when scler:ting- a drug product. dosing
`regimen, the anticipated onset of drug client, and determining
`suappropriate samplingstrategy if’ drug 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 minimuni desired concentration.
`The application of phannacokinetic principlw may be limited
`in the use of some drugs. Drugs that have a wide therapeutic
`"index may not require precise dose adjustrnents when drug
`disposition is altered and a simple approximation may he sat-
`isfactory to limit the probability of toxicity and assure sflicacy.
`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 thcrnsclvee to careful dose acliustrnents 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 concentrations where the hen-
`efit to risk ratio is optimal [Fig 59-1}. While the Normal Thera-
`peutic Range is important, it is only 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 Ra nge
`One potential factor that can change the Normal Therapeutic
`Range is alterations in plasma protein binding. In most cases,
`clinical laboratories use assay procedures that measure and re-
`port the total plasma drug concentration, ie. the drug concen-
`tration that ishoundto plasma protein andthe unboundplasrna.
`drug concentration. It. is only the unbound drug in plasma that
`can cross into the t'.'i'ssue where the receptors are located.
`
`ARINEAL
`
`1191
`EXHIBIT N0. 1034 Page 4
`
`

`
`
`
`themyw:;oo'-_e—e.-u
`
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`
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`
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`
`
`
`, care should
`In any case for clruge with high plasma hindi
`be taken in the interpretation of assayed drug concentration.
`Most weak acid dn_.lg‘a- with high plasma binding {BB3 Iahensrtoim
`are bound almost eztclueiveljr to a1humiu.Thc most commonly
`e:ocouut1erodreosI_m.c'l‘oralterations in p-lacuna binding for those
`drugs are hypoallz-uminan1.ia,_end -stage renal failure or-dialysis
`and displacement by other drugs. Basic c.ompot.n1cla tend to
`have a more complex plasma-binding pattern and extensive
`binding to a number cf_p1asma_proteins including alpha—1—.ecid-
`glycoprotein, o1'.l1e:‘.g'lnl:ru1ina and albumin ie common.
`In" a_ddit_ion to plahnia binding alterations, clinical conditions.
`can change a patience response to a given dose or drug concen-
`tration. As an example, a change in renal function can change
`a patieu’c"a' ability to eliminate drugs whose route -ofelimixiatinn
`is via thekidneys log. ominoglycueide antibiotics]. The addition
`oft-. new drug that either inhibits the eliminat'io:n or metabolism
`{egg autiodarune when -added to at patient receiving digoxinl
`or
`induces metabolism leg, carharoacepine -‘ind ucing the
`metabolism of warfarin‘: can alter the relationship between the
`drug closing regimen aodthe resultant-drug concentrations and
`drug efi'e'ct. In addition, alterations in electrolyte or acid base
`balance
`ht alter the potential of1: drug to produce toxicity
`(cg. hypoka emic in a patient receiving digoxinl. While the 1101-'7
`tool therapeutic range is ueuelly thought of as fixed upper and
`lower boundaries, there are many situations that require the
`clinician to make adjustments in closing reg1me.ns and target
`drug concentrations. Knowing both the drug's phormacckiuetic
`and pharmacodyrtaroic charaoteriatica allow the clinician to de-
`sign ‘drug-regimens that have an optimal chance oi'p't'od'uc1'og e
`beneficial outcome for the patient.
`
`Absorption, Distribution. and Elimination
`In the application of pharmocokiuetics to the clinical practice
`setting. the ability to estimate a patient‘s absorption. distribu-
`tion, and elimination characteristics is an important step in ini-
`tinting drug therapy-. For many drugs. clinicians simply learn
`the "tn.-cue!” dose and use that dose for all patients. Iii-a number
`of aituatiorm, knowing the principles. behind the usual dose oi»
`lows the clinician to make adjustroente in drug therapy for
`those patients where: therapeutic problems. toxicity or lack of
`efi.l_ca'c3-, are likelyto occur.
`
`.
`TISSUE
`
`Plasma
`
`C
`
`
`G unbound
`
`Meta-holtsm
`It
`-
`)
`Elumnatmn
`
`figure 59-1.No‘te that it is the unbound drug ccncentration {C Unbound]
`that}; ahle-to cross into the tissue and cquilicrate with thetissue binding
`sites and the drug receptor. While C hound may be a significant cer-
`cc-ntegc oi the plasma drug pool.
`Iri most case-syirery liltle drug is ill
`plasma and therefore C hound represents. relatively little of the total drug
`in tire hodv.
`
`ARINEAL
`
`EXHIBIT NO. 1034 Pag
`
` §
`
`1192
`
`PART 5: PHARMACODYNAMICS AND PHARMACOKINETECS
`
`1.00
`119%!
`
`Response
`Fractional
`
`Drug Concentration
`
`therapeutic range." The "normal therapeutic
`Figure 59-1. “Normal
`.range‘' defines the region of drug concentrations where the probability
`of a positive therapeutic response is good and the risk for development
`of a sigriiiica nt doserelated adverse elfecl LS acceptable. For mEi'5‘i agents
`the normal therapeutic range L5 Quite wide, howetret, for certain agents
`there is a relatively narrow thcI‘apeUti_I: range and monitoring of drug
`concentrations. may be necessary to rrtaximiie the potential for efficacy-
`and minimize the risk of to:u't:it5f.
`
`Therefore, it is the unbound drug concentration that ia propor-
`tional to the tissue and receptor drug concentration and the
`pharmacodynauuc rec once {Fig 59~2l. Any change in plasma
`prtiiflilt binding would E expected toalter the potential for any
`plaema. drug coucenisratioo, tuported as both bound and un-
`hctmd drug. to result’. in-a-toxic or therapeutic response. Many-
`droga have eign'ifi'ca,'ot binding to plasma proteins and the rela-
`tionship between the unbound drug concentration and the total
`drug concontratiouis referred to as. the free fi'o.oti'on.or fu.
`Unbound Drug Concentration
`Pu‘ = Total Drug Concentration
`
`(11
`
`or
`
`Unbound Drug Concentration =
`tfi.tlfTo'taI Drug Coocentrationl
`
`I2)
`
`Any factor that alters plasma protein binding will result in an
`altered free E:-action lfu'l. 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-ie to calculate a normal plasma binding drug
`coneen:ration 3
`
`Normal Plasma Binding
`Drug Concentration
`
`=
`
`A535.)-ed Drug"Canoe:-it;-etion)
`AlteredPlasma Binding
`
`with
`
`(33
`
`and then compare the normal plasma hindihg drug r:.ouce.ntra—
`tion to the normal therapeutic-range to evaluate the drugs po-
`tential for either efiicncy of toxicity
`An alternative app:-oaclr: is to calculate an adjusted there.-
`puutic range:
`
`Adjust-ad
`Therapeutic Range
`
`__
`
`(Normal Therapeutic Rangel
`
`(41
`
`and compare ‘this. odiuoted therapeutic range to the assayed
`-drug concentration tvith-altered plasma biudingto evaluate the
`drug's potential For either eflieacy or toxicity,
`
`

`
`-CHAPTER 59: Cl.lNfC£-‘AL PHARMa-’-.\COKiNE"|'fG A.NEt.FHARi'UlACODYNAM|CS
`
`1193
`
`Volume of Distribution (__V]
`
`Following absorption, drugs distribute throughout the body.
`Each drug has its own characteriatica that rES1lll:iIl.'31“l appar-
`ent volume of distribution {V} and can be exproaaod mathemat-
`ically as:
`
`Am‘
`f D
`'
`B
`Volume ofDistribution =
`
`0!’
`
`Am
`
`'
`cunt DfDfE3'_ln
`
`V :
`
`the Bod
`
`gr
`
`.
`[E5'
`
`where V is the volume ofdiatribution and C is the plasma drug
`concentration. As can he soon from the equation above, volume
`of‘ distribution is-the volume required to account forthe drug as‘-
`suming the tissues have the -same concentration as plasma.
`Volume of distribution is an important phatmaooltioctic pa-
`rameter when calculating the loading dose required to rapidly
`increase the plasma drug concentration to acme Iilcoired con-
`cenfiation:
`
`Loading Dose =
`
`iCllVI
`F
`
`wha1'-c'C.ic the desired plasma concentration and F the bioavai1-
`ability. In some cases, there may be drug alreadypreacnt and
`only a partial or incremental loading dose is needed to achieve
`tllfi
`C'rm-Egg.
`
`Incremental _ lC'l'l:fl_<t — C1uau.u.llV1
`Loading Dose
`5‘
`
`(61
`
`In the above equation C-1-,.,.g.,_ is the desired concentration fol-
`lowing anal Clllilllgl is the drug concentration just prior to the in-
`tzccmaotai loading duao.
`
`Body Composition and Volume of
`Distribution
`
`Volume of distribution is most often raportod as Ukg. The ap-
`plicability of this L/kg value assumes that the physical charac-
`teristics of t'l1c'pnlL'ienta.re ai1"n'ilar to the study population, Pa-
`tients who are obese, emaciated. or have extensive third
`spacing offluid lascitca or edema} may have an altered volume
`of distribution based on total body weight Therefore some as-
`aoaament of body composition is important when making initial
`oat_i1:oatea'ofV.
`OP-ESE VERSUSIDEAL BODY WEIGHT—When pa-
`tients are chose the moat common approach is to calculate the
`patients Ideal Body Weight IIBWI:
`
`[Bw,,,....,_ = 50 kg + 2'.3{Height in inches > am
`
`IBWp..m,;.5 = 45 kg + 2.3iI-{eight in inches :- GD)
`
`(71
`
`I8!
`
`IBW in the above equations is in kg‘. and it is this weight that is
`generally .aaaomad to represent a “non-obese” weight. When the
`1lOlIJ.111B of distribution is known to correspond heat to ideal or
`non-oboac weight. it it: tho IBW that ahoulcl ho mood for ohoac 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 iftlio patient is greatarthan 129% of their IBW:
`
`Clinically Obese =(
`
`Patientfa Weight
`IBW
`
`)mn :- 129
`
`on
`
`There are a few drugs l.l)8i. either part or all of the excess adi-
`pose weight "in the clinically obese patientia used in calculatiiig
`*1“ '=“'“"""'* '""'.1u1o of distribution. Care should be taken to
`
`ARINEAL
`
`EXHIBIT N0. 1034 Page 6
`
`-
`
`o‘l"E'}i-its.‘-.‘u"~'-‘.=Di'-"fl-"l'J~—-‘-""*““'"
`
`ptor
`
`-use
`
`I|.ll'l
`idi rig
`pot‘-
`is in
`drug
`
`
`
`AbsorptionffiinavailabiIity
`The absorption of a drug“ is a key claimant in determining a
`drug-dosing regimen. The extent of absorption ia referred to as
`biouvailability and is usually crxpret-mod as either a fraction {F}
`or percent of an administered drug that is available to produce
`apharmatologic eflcct. An F value of I represent 100% of an ad-
`ministered dose is bioavaflabla Moat drugs when given by the
`inbravcnuua route are assumed to be 100% bioa1.rai_lable- (F of
`1.53. Absorption by other routes of admiziistrati on (oral, rectal.
`etc] may o1"ma}.rt1ot be complete. A number of factors influence
`the hioavai1abi}ity' of a drug.
`To be orally absorbed. drugs must have a reasonable degree
`of water oolubflity so that they can dissolve in the gastroin-
`testinal ("Gil fluids. In addition, they must. also have some
`solubility characteristics so that the drug can cross the lipid
`membranes oftha cell wall in the Gltrarst and outer the general
`circulation and cvantually cross the cell walls of other tissues in
`tlic body. Aminoglycooido antibiotics are an example of a drug
`class who-so water solubility is so'higl1 (lipid solubility very low]
`that they are not absorbed to any significant extant when ud-
`otsiniatezred by the oral route and must be given parente-rally to
`ailiiavc ayotcmic cficcls.
`Drugs that are unstable in the GI tract may have low
`bioalrailability-because they are broken down "or decompose be-
`"fore they can be absorbed. The proton pump inhibitors tog,
`om-praaolcl are an example of El drugclaas that is unstable in
`the gastric acid and are atlmlniatorerl orally at an anterio-
`'.conted tablet. In addition, although some-drugs. are absorbed,
`they are metabolized by the enzyme-‘a in the gut wall or the liver
`"prior to reaching the systemic circulation. Litlocaino is an ex-
`llmple ofa drug that is metabolized to extensively as it passes
`through the liver following oral absorption that off‘-ecl:iv'o aya-
`tunic offsets require parenteral administration. Extensive hop-
`‘aiic metabolism following oral absorption-is referred to as a
`First Post: Effect (see Chapter 53 Hepatic Clcorocccl. Recently
`-a greater appreciation for the irnpac:..oFdr1'1g‘_ transporters on
`- Ural hioavailability of a numbor of compounds" has l5BE_§l1. mal-
`;iaecL In particular. the xanobiotic ttanapottcr F‘-glycoprotein
`' has be-enshown to significantly affect the oral hioavailabflity of
`I -tjmloapo1i.ne.and other large hydrophobic compounds. Siufilar
`to tho knowledge gained by studying the CYPEIEU enzymes ro~
`Qponaible for metabolism of commonly prescribed drugs, knowl-
`ifadge-of the substrate specificity of P-glyooprotain is integral to
`tho bioavailability of drugs that are substrates for
`transporter.
`Bioavailability or F, refers only to the extent of ab-B_orp‘|:.ion.
`- rate of drug absorption can also be in important factor in
`adtniniatration. Extended release tablets and capsules are
`n rles.i'gocd for tho drug to he alowlyrelcaaed from the
`;-.- flmn so that drug absorption is relatively constant over
`1-1119 entire dosing interval. As a roaultthoae typo-a oforal dosage
`' H
`- tend to produce relatively little fluctuation in the plasma.-
`gtom-aotrationa within a dosing interval. While this may be‘
`_ "all for a drug with a narrow therapeutic index. those drug
`.-I oducto may not be useful when relativaly rapid drug onset is
`__
`2'1.-d.lu addition the drug release clqaractaristica -are usually
`.-=u-:'_gned to be consistent with a specific dosing iotarval. If a
`' gpmduct is designed to be absorbed over 12. hours, extend-
`tho doing interval to 24 hours may result in unacceptable
`anga in plus ma concentrationa-.
`Patients with certain _gE1B'l?I"l3l1IlIB8l3lI1fll diseases may have a
`short gastrointestinal tran.£-it title and thereby
`the
`of some extended release drug products. One example of a
`131 absorbed drug with at limited bioavailability ia phonytoin
`‘Elia newborn. llfhilonot cloaigrted as an cxtomlad release prod-
`uhcnytoin is so limited in its water solubility that several
`ours are roquirod for complete absorption following oral admin-
`- tiou. The newborn child has such a short G1 transit time
`when infants art: changed from parenteral to equal oral
`lpbcoytoin, the plasma concontrafiona almost always do-
`ramatically because ofa limited oral bioatailabiiity.
`
`=--u
`
`T
`
`

`
` §
`
`1 19-!
`
`PART 6: PHARMACODYNANUG AND PHARMACGKJNEHCS
`
`carefially evaluate the patients weight as well as the charac-
`tenstics of the spatiflo drug in question.
`_
`EXCESS THIRD "SPACE FLUID {_EDE1flA AND AS-
`CITEB)-—Sorne patients have extensive edema or-ascites. This
`fluid accumulates in the interstitial space between the vascula-
`turn and the intracellular compartment or the peritoneal esc-
`ity. The degree to which a patio'nt's vascular volume audios’
`ti-acellulor volume can change is li1:uited=. ’I'h.erefcn"o_ {in most
`cases. simificant changes in body water occur in the‘ intrape_ri-
`toncal and interstitial or third space. Depending on the dmgla
`distribution characteristics the presence of third sprite fluid
`may alter how the apparent volume of distribution is colou-
`latpad. In most cases, the presence ofthird space fluid is evalu-
`ated by changes in weight. with 1 kg ofvveight gain represent-
`ing 1 liter of "third space fluid. Alternatively, an experienced
`clinician can often approximate in patients with ascites or
`edema..th number ofexpess third space liters present.
`One method that can be used to account for any third space-
`fluid is to calculate the coutribufion that-one would expect for
`each liter lkgl ofexoesscdenia or ascites- The apparent V‘ for
`each liter can be calculated. "by multiplying the fraction of un-
`hound drug in plasma (fut times the number of liters of excess
`third space fluid.
`3rd
`Of
`Vfiauwn ‘SH! ounce I'l-‘Hill =
`The units of‘! are ‘liters. The liters ofoxooesive third space fluid
`gain are usually estimated by subtracting the p_atient's 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 iluid. Usually this is accomplished by deter-
`mining the time course of the we‘ ht gain. Muscle mass and
`adipose wciglit 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 patients edema or as-
`cites '15 also a factorthat should be .consi.-dared when estimating
`excess third space fluid weight. As an exurople. rt Patient who
`gains 10 log ofweight in 2 days may have been initially dehy-
`drated and simply replaced a fluid deficit rather than have
`gained 10 L ofexccss third space fluid. On the other hand if the
`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 1.. Because the
`contribution o1'5 to 20 L is not significant for most drugs. the
`weight used in calculating the volume of distribution need
`only consider the patient’s- usual weight. However, if the vol-
`ume ofdistribution is small and plasma protein binding is low
`lfu approaches 1), than excess third spacing offluid should he
`considered in the calculation. This would be accomplished by
`fir-st calculating the patient’s weight without the excess third
`space weight and using the oouaccsss thirdspcce weight to
`calculate the patients V inthc ‘usual way. In addition. Equa-
`tion 10 above can be used to determine the additional contri-
`
`volunio of distribution.
`Digosin and aminoglyooside antibiotics are two dr1_.igs that
`represent the extremes. Digoxin "ha 3. fu of approximately-(E9
`and a V o!"approxirnatoly 500 L ('1 L.“Kgl. If a patient accumu-
`lated 10 liters of excessive third space fluid, the increase in V
`would only be 9 L [ie,.-(0.9) (Liters of Excess 3rd Space-Fluidl].
`This increase in V is less than 2% -of the total volume of distri-
`butinn and therefore not clinically Bignificatit.11.'.ia important to
`note that the patients weight without the excess third space
`fluid should he used to calculate the volume of distribution for
`
`with ‘Ill liters of oaitcess third
`the increase in V- f9 L assets:
`space fluid would be significant and would be incorporated‘ in
`the calculation of V.
`
`Two Compartment Volume Of Distribution
`While it is uflaan. useful to thin]: of the body as a single com-
`poxnnoot, in reality are are made oi"hu'ndr_e_ds_ if not thousands
`for roost drugs the volume of distribution can he conceptual-
`iced into two inidi_vi(l_us1 compartments. An initial first volume
`{V1lt'.Bn.'aisti11g' of pins:-on and other rapidly Iaquilibrating fis-
`eues and a second more slowly cquilibrating volume (V5; (Fig
`59-3).
`LOCATION BF TARGET OB.GAN—-The two—cunrpart-
`merit model has two important clinical implications. First is re-
`lated to the location of the target organ for clinical response
`(therapeutic or toxic). Some drugs have on and organ for clini-
`cal response (efficacy or toxicity) that equilibraoes very rapidly
`with plasma. Therefore, large doses ud'ministei-ed rapidly into
`the smaller first compartment will result in elevated drug con-
`centrations and have the potential for causing drug toxicity; It
`is -nlsopossihle to give "a smaller first dose that achieves an ini-
`tial therapeutic concentration and response that is quickly lost
`as thedrug concentration declines during distribution irito the
`larger volume. Drugs whose target organ respond as tlmugh it
`were located in the initial volume of dist-ribntion must be ad-
`ministered 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. Mostdrugs have a maximum recommended rate of info-
`sion. Usually this rate is designed to allow drug‘ distribution Ill
`take place as the drug is being. infused. Occasionally it is rec-
`ommended to divide a dose into portions that-are adlxliilistered
`atsot intervals, again allowing for distribution to be completed
`before the next part or the close is administered. For some
`dntgs, the intravenous adminis't:rsti'on rate has to be controlled
`because of an -agent in the injectable dosage form that has the
`poto_ntia1 for toxicity. As an eagample, penicillin is most com-
`monly available as the potassium salt. While rapid injection of
`penicillin "itself can be potentially hai-niful. it is the potassium
`that is probably the most dangerous and the reason for control-
`Iing the infusion rate of IN potassium penicillin. When drug:
`
`fig —o-
`
`V,
`
`Distribution
`
`V,
`
`Drug
`Elimination
`
`0!.
`
`log C
`
`[3
`
`Time
`
`
`
`Figure 59-3. -Drug first enters the body into on. The initial rapid decrease
`in drug concentration to phase) 15 primarily-dos to drug moving into the
`larger more slowly Equillbraiing V;,. the more slowly declining drug con
`controllers to phase} are primarily due to drug being elintfnsied-‘from the
`
`ARINEAL
`
`EXHIBIT NO. 1034 Pag
`
`

`
`Color Plate 1. Figure 34-32. The 3—dir'nensional molecular structure of -El,l-propranolol hydrochloride provides information about the molecular corr-
`fnrrnation and bonding whereas the its packing arrangement within the crystallographic unit cell is useful in understanding the physical properties of
`the crystalline form.
`
`Euler Hill 1. Figure 341-35. The Hay powder diffraction patterns of two polymorphic forms of d,I-propranolol hydrochloride indicate differences in
`molecular arrangements within their different crystal lattices.
`
`.
`.LIv-c-vb‘.
`
`.u$vLa_-cos».
`o--...--~a.-
`
`---.--vi-iv-ur
`....p¢--g...
`'.>+a..t.AL-
`
`
`..4!v
`
`‘Lie-in
`
`
`
`Master Pl. ate
`
`
`
`-nitivt-OI-6-f¢o<
`
`
`_¢.uc1'-u.-pg-go-eo-
`¢1o14-on-0&1
`-GO-J4--fie-+t1
`
`
`
`
`* 4-+-r-1» +-3+4he
`
`
`
`Ot-newt? ‘lo-0+».
`'.-.<-?'§vi-
`trio-rt
`
`
`4-¢o»so+4r¢v¢¢+4_
`§¢-0-2 O0-drf:-1|--S-#1
`++¢-++++.-:v+++<
`
`_ eooooovt-Qév-9-i
`
`
`
`
`.- H138 3- fiumefl-H. Design for the crystallization process for polymnrnhir tnrm vreeninfi demonstrates hot filtration of the crystallization so
`am and its transfer to three crystallization plates and two plates for solu
`Page 8
`
`
`
`,
`
`

`
`
`
`___a
`
`
`
`Color Plate 4. Figure 34-45. l‘_J.-:FCfIII3gL'_‘l"lCl" ||'Tlc'|g9S and powder cliflraciirin |'Ji'-'.I1Pf11‘- u:'n||s*rtPd
`dl-ri
`anolcl hydroqli nride iiiilicaies two p(_:I\.n'T‘.OrfJl1l(E.I'yS1€ll
`‘arms and ‘-.he:r lo-:a1.iaii1 ‘fl.-'|Lh
`Iizari
`hemisiry with lie crystal form obleiiried.
`
`l'fI I
`E5]
`
`-. <l[JU'El[|\'E' C-'3«'S1FllllZc|1iL‘.I11 plate in ilie HTS oi
`. plate. thus genablanq cor'r_-laiion of mafia!-
`
`-
`
`' Gciicml Rule 0l' 5 compliance
`
`General Cliaracteristics
`
`' High mp. High crystal CI'H.‘1'g3'
`
`
`
`' |.ipnphi|1'c'(1rI ta‘: |I—l1n|1(fi11g
`' I as: ilunsc packing &. Less H—bciiiii'mg
`' Highcr .-\q_ Sol. ur Less ll-bonding
`' Lipophiliu: oi Nlociuriin: ||—l:-ending
`
`Good Aquenus Solubility
`
`
`
`Color Piate 5. Figure 38-1‘. Possible and physsnlogical negative drug
`qiziritps
`
`AR/[NEAL
`
`EXHIBIT NO. 1034 Page"
`
`
`
`

`
`
`membrare fiiters (courtesy, Miiliporel.
`Getungc USA)
`
`
` B
`
`
`
`Color Plate 10. Figure 41-19. Mechanisms 01 mncroknal retenuon on
`
`Color Plate 9 Figure 41-18. Rubber closure processors (Courtesy,
`
`Color Plate ‘|1.Figure 41-21. Syriragta fi5|I'nr_.] rnm:,i1ine(LouI1e35.r] Baxter"
`
`CIDIOI Plate 12. Figure 41-22. Vial lilling machine, distant and close-up
`AMNEAL ““*’iixH[B1T N0. 1034 Page 10
`
`Color Ptate I. Figure 41'-1EI. Example of an nsolator icourtesy, LaCa|—
`hene-J.
`
`Colo: Plate 8. Figure 4-1-12. Example of a three—bucket assembly used
`for sanitizing Facilities (courtesy, Comet).
`
`High flow: 65-75% porous
`
`’:Irli-Isle.-a relnillcd by
`
`r Sicvirlg
`
`p Entrapment-
`Itortuous [)EltIlW£l_|H
`
`1' Adsorption
`[high internal area)
`
`

`
`
`
`
`
`
`
`Color Plate 13. Figure at-2?. Steam sterilizers (small and large) (courtesy, Getinge).
`
`Compressor [Back 01' Chamber]:
`
`
`
`_
`
`,.
`'.
`
`--
`
`C hamber
`and
`Shelves
`
`!
`
`co.-npuger
`Control ""'
`Station
`
`I
`
`Sample Thief
`
`'\'
`
`Vacuum Pump
`For Thief
`
`
`
`Vanuum Pump
`
`Condenser
`
`Color Plate 14. Figure 41-28. Example of a Laboratory freeze-dryer (courtesy, Baxter}.
`
`Temperature difference between chamber and condenser
`and pressure differential between solution in vials and
`vacuum pump drives ice out of trial and onto the condenser
`
`Conversion of solid
`
`AP
`
`‘R
`
`.g
`u:
`
`E E
`
`Q
`
`at
`9
`
`5. G
`
`
`Condenser
`
`Vacuum
`Pump
`Pressure gradient between
`sublimation front and chamber
`
`9'3’ ca”
`5”b”"”au°"' Frmt "W"
`Frozen Solution
`
`
`
`(ice) to vapor In
`chamber called
`sublimation
`
`_§
`E‘
`E
`§
`:1:
`
`
`
`control temperature in chamber
`
`Color Plate I5. Figure 41-29, I-leat and mass transfer in the lreezedryer.
`A1\/[NEAL
`EXHIBIT NO. 1034 Page
`
`

`
`
`
`Cc-|c..'
`
`.”r':1:'-
`
`;-i-."=..-:‘-:-
`
`?— '-;.’_ tr-(ample OI an Isolalor used lor st-Eriiity IeST.1I1g[f_'DLiflE.‘S‘y, Baxter).
`
`A1\/[NEAL
`
`EXHIBIT N0. 1034 Page 12
`
`

`
`EPITHELIUM
`BOWMAN'S
`MEM : FIANE
`
`‘
`
`-
`
`DE SCEMET'S
`MEMRANE
`
`ENDOTHELIUM
`
`PU