`Parmacokineticl
`Pharmacodynamic
`Correlation
`
`Eafifed Z33;
`
`Harmut Derendorf, Ph. D.
`
`Giinter Hochhaus, PhD.
`
`Uf?fZ?E2‘Sff3; of Ffamfin
`GfEfI€€SI’?f§f.£?,
`}.4‘?o;'frfr2
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`I,.ibI‘aI‘}‘ 0!’ Congress Catzilogiiig-in«Pubiitatiim Data
`
`Hzizidizouk of pli:mmicok‘mtic/pi1:xrtmc<>dynamic correlmioii I edited by Hzirtmm Deremlorf. Giimlier E-Inclihalis,
`p. Cm.
`Includes bibliogrziphiczsl refrsrences and index.
`{SEN l}~8493—‘§303—X
`l. Pliminzicakiiietics. 2. Dmgs»Physlr;>lligieii1effect.
`I. Dei‘end01'f, Harliiiut.
`II. Hochiimis, Gi'nitlier.
`LDNLM: I. P}iai'iimc0kii1eti{:s. 2, Pharma<:<3«]<3gy. 3. D<>s;<:~Resp0i1sn: Relationship. Drug.
`QR’ 38 H2365 1995}
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`|nnoPharma Exhibit 1027.0002
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` —wm« A
`
`Table of Contents
`
`
`Clmptex‘ I
`PharmacokinetiC~Pharmeuzodynamic Modeling of Rcvr:-:1‘sib1e Drug Efi’»::cts ................................. .. I
`J1"trg<2n ‘afelaitz
`
`Chaptrsr 2
`Pha1'l1'12tc0kinctic:~Ph21rma<:<)d§;11ami<; Mutielilig of I1‘x'e*.-'et'sihl<: Drug Elfilzcls
`Steven C. Ebert
`
`CE1z1pte1' 3
`P11ax*:m1c<skim:Iic—Phzmnacociynaniixz Ma:-deling in Dung Dc-ax-*e1<:ep:11ez11:
`Comments and Applicz/1ti0ns .......................................................................................................... .5’?
`.I0sep12 C. I4‘IeEshaker and James .1. I*‘erry
`
`Chapter 4
`Dose Opiimizaticm Based on Phzu‘mac<:«kix1etic-VP}:a1'macod3,*n2m1ic MocI<:Ii:1g
`Gimther Hucitlaetus and Hartmut D(3!‘€l3{1(}I‘f
`
`Ci1apte° 5
`Pha1*1mv;:£:1;in=::tic—Phzumacczdjymimic Correlations of x—\z1es;th<:iic
`V’i:*gi13‘a D. Sciumith and Keith T. Viuir
`
`121
`
`Chapter 6
`P11311112(20%;inetic«Phzmnztcodymrmic C‘()1'1*eIa1i0ns of;—X:1z1£g::sics ...................................
`Jtldith Walker
`
`......... .. 1&1}
`
`Chapta“ 7’
`P1”téit‘I‘11Z cokEnetic—Pharmz1c0dy:1:1mit: C(m'r:1z1£i011:~; of B<:m:<}cEi21;:<:§:inc.s
`Satnir K. Gupta and Everett H. EHEIW.-‘{)(}lEl
`
`W1
`
`Cimpte’ 8
`Pbzmnzscokinericffllzmnacorciyzmmic Comzlatioals tn“ ;3m1’irc.::«11vulsz»111£:»s ....................................... ,. I85
`I\=I<:in<fi<:rt Dmthof and RM; A. Vmslztrjgl
`
`Chapter 9
`PlxmmztctokinctiC—PhzumztcodynzmiEC Re12\ti<m.~;11ip.~; of {‘.::1‘dim*as;c1:i;u‘ D1'ug.~; ........................... .. 192?
`Ritshzml L. 1_.aI<m<Ie
`
`|nnoPharma Exhibit 1027.0003
`
`

`

`IO
`C11aptr21‘
`Pha1'ma<:{::l<instiCXP11armacodymxmic Correlaticans of Selectecl Vasodi1at~::1's ............................. "22?
`Tsang-Bin Tzeng and I‘Io«Leung Fang
`
`Chapter’ 11
`Phazmacodjmzaznics of Antimagulams ........................................................................................ .241
`Dennis Mlmgall and Richard H. White
`
`Chaizeter £2
`Pharrnacokineti<:~Pha11nac0dynami<: C{)l‘!'f:1‘c1iiOI1&$ of Aniihixtatniixcs ........................................ \V2,?S
`Eric Snoeck, Achiel Van Peer, and J03 Heykanis
`
`Chapter 13
`{33—Ag0nist:;: Ttzrbuialimz, Albuierol, and F<3I1(}I€iI'O1
`Giinfher Ilcrcirhaus and Hclmut Miillmsamz
`
`.................................................................. .299
`
`C11apter 14
`Phzmm1<:0kimeIicmPham1ac:od}mamic: Correlations of C0r'tic0stez'0ids ........................................ .323
`Hehnut Méilimamx, Stefan Balhach, Giinther Hochhaus,
`Jiit‘ge12 Barth, and Hartmut Derendmf
`
`Clmpter I5
`Pha1*mac0k.inetic,?P11a1*:nacoclynamit: Mociding of Antibiotics;
`Arno Nolting and Hartmuf Derendorf
`
`Clxapter 16
`Clinical P11a1'mac0s:i;matnics of Anticzmcer Drugs ..................................................................... .389
`Howard L. McLeod and Winiam E. Evans
`
`Chapter 1?
`COI':1p1J.’[6I' App1i:;:atir:>ns in Clinical PE121m1ac:o1<ineticéa and Pha1'11121c:0:i§=:121rniCs ........................ "415
`Dennis Mtzizgali, Joe Heissler, and Matthieu Kaitenhach
`
`Inciex ............................................................................................................................................ . . 465
`
`|nnoPharma Exhibit 1027.0004
`
`

`

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`Chapter 2
`
`PI-IARMAC()KINETIC-PHARMACODYNAMIC MODELING
`OF IRREVERSIBLE DRUG EFFECTS
`
`Steven C. Ebert
`
`INTRODUCTION
`
`The mathematical relationship hetween drug ceneentratien and response generaliy assumes drug
`binding to it given population of receptors. Greater ecettpzttien of these receptors will resuit in 21
`greater ei‘f'e<;t, and vice vet'Sa. The t=*z1t‘iahility in t‘ecept0t‘ amiiity accounts for the nottlineat‘ t’et21ti0n-
`ship izetween eeneeutration and effect.
`l\v’l()Sl reseztrelt imtel‘~.-‘ed in the Clt21t‘E1CE€i1’iZétttOI1 of phamiaeetiiynarnie vztriahles has heen ( one with
`(;lt'LtgS exhibiting reversible et't'eets~;. With reversible drug et‘t'e<:ts, the number and drug 21 Tinity of‘
`reeepters remain l’Cl2tti\’(:l}’ constant, aliewi g 1‘epr0duCihle etifects with repeztted drug (3><p()St3:‘<i1£«;. In
`certain instzmees, seitsitizatien 0:‘ i<)lt3E'altt:C to the drug effect tmt}-= occur.
`In eentmstt the goal of antimicrobial therapy is It; etiminztte the ’-sery target at whieit ti e tttrttg is
`directed,
`i.e., the “receptors” are actualty he pztthegenie orgzmisms. The de.°.ired ettee of drug
`therztpy,
`the death of pathogens,
`is there ‘ere i1’I"3\‘€;i1‘§$il}l€.
`The repliezttiott of ()i‘gE?t§’3lf»1‘m§§, with
`subsequent replenishment of the “receptor” t!l1ti)Ct‘t11€t}‘ occur, ltewever, and result in an 21 uparentiy
`1‘evet':~;ihle effect as mea.<;tt1‘ed by the total number of ergztnisttts. In this sysitetn, the development oi’
`telerztnee er frank resistzmce of the remztinhg “reeepters" is more likely t(}'()Ct1t31’, since the mest
`susceptible C)t‘gE1ttiSmS are killed. Therei'01‘e,
`it W€}ttl(l he expected that Stifiiatintltl expo}; ire to an
`2mtit‘ni<.:t‘0hial wotiid result in it gradtlally di nini:~;hing effect over time, unless E1 sufficient drttg-free
`period exists to enabie the €}!'g€tItlS!‘£1
`poputzttim to fully recover its susctmtihility.
`Figure 1 shows the relzttienship between l1Z11‘I‘tl£1C0i{tt‘t€itiC \:ariahte:;, pharmzieodyaminie Tl(:2tSlI!‘{;i§L
`of E1tttimi<'.I:’()i)t£1i ztetiviiy, and drug ettect. Intuitivety, i1”tCl‘€E1Stttg the {lose of an atitimicr<:»bitt1 shotzid
`iIt<3!’C£1S€
`its effect. By t1t1(l€E‘S{E1t‘ttitI1g
`the pliarmaeedynamie features et’ at given elites ef :1 ‘tti]t1iC!‘()~
`hiztts, one t1’tE1}’, lmwexrer, be able to l111'ther enhance {)tlEC()mt3 by rttettifyiuig dosing pztrztme ers other
`than time size, e._g.t dosing fI‘€3(}tt€I1C}*. The plitztrma<:(>ttynmnic properties; of 2t!}itI‘ttiC1'(}l.>i£1l$ 1113;‘ be
`estimztted ex: t-'!‘1'(), W‘i}{3l‘tZ2tS for other drug etasses, response must be estimated in vivo. This eltztpter
`wiit address the plttmtitteekinetie and pha:“Inae0{1yn21tt“:ie properties: of ztntimierebiztis wifeit iettt1~
`enee drug z‘e:;1:)ett'::e, witl <;l12t:'z1cteri;:e tirttg et't’eet;»;, and wit] then exztmine teehnittues that have been
`used to link these [}i‘1{3fi{)lTt€i1tt.
`
`PHARMACOKlNI§’t‘fC VARIABLES
`
`The ph211‘m2te0i<inetic varizthies: of :1 drug (ietermitte the time t2()!.It'St3 of drug Cc:meentr2tti=:>n in
`serum amt, uttimately, at the site of infection. Twodit't‘ere11tcategories et‘ pitamzeeottittetie varizthies
`exisi. Some pi12t1'tnaeel<ine1ie vztriahles‘.
`{"3121}? be altered by atijusting the dosing regimen, wheretts
`othera; resttlt from the eitettiieztl pa‘0pe:'ties of 21 pttttietttztt‘ itrtlg, Elhti are minimally intitttenced t.>y
`dosing regimen. In the etittieai setting, tmtdifictttiert of regimeti-ttepentient ‘>2'E11‘i2tblCS is the gent <31’
`phztrmae<)l<i1teti<: therapeutic drug menitet'in_t_z, in ertiier to achieve the desired ceateetttmtien pro»
`file.“
`
`I{EGIMEN-DEI’ENDENT V’ARIAI3IJ1?<§S
`
`Meet zmtimiemhizitz; are adinieistereci itttermittently, i.e., :1 givett total deity dese is divittetl and
`the fi‘a<:ti<m:; given at
`t’i><.ed itttewals. The three pht11‘mz1t:0ki:teti<: varizthles that may he used tee
`
`
`It :,rxn§§t)
`l‘}‘)5 by (‘RC i’n:>:t lIIi:.
`
`|nnoPharma Exhibit 1027.0005
`
`

`

`36
`
`Hczzzcfbook off"Plies3'112a(:()!<i:2efin/P}2c:i':1zaca({)!::amit Czmelaiioit
`
`Pl1£!IlI1£IC{)l<ll}f3iiC Parameiers
`
`Dose R<:gimen~Rek1ie{l:
`- Area under the c<)nccIm'ation~time curve (AUC)
`- Peak ccmcentmticm
`-= Dumtmn of lime c<>|tcentmttom; exceed n cmical value
`
`Other:
`~ Extent of binding to proteins:
`» Exteiit oFd<:1ivery to less accessible lisme sites
`- lntmcellular p<:netraEi<m
`
`Ding Ccmcentmtion '3
`the Site (if ltifeetinn
`
`Pliai*i1iagg3_;§3f_i3g_tg1tic Parameters
`
`° Minimum iiiliibii0ry1’<:'r<lal cencentmticm
`(MlCfMl3'C}
`' Relationship between cencentaaiien and
`Qvemn Am-"n§cmb~m; ;\Cm,E£).
`‘ R9‘lUfli0‘1 ii‘ ’1“"‘l3‘35 0f lmlililéieiiic
`Chm aci-wily
`of Dmg Regimen
`m‘g:1msxm
`* Postaritibiotic effect {FAB}
`- Emergence (if resistance
`-= Freeettcefabsence of WEEKS, other host
`factors
`
`S"~C°“d“‘3‘3
`‘ Reilucmll 3“ ‘3191{>l<ll1}’5'U0113m}'
`
`I"IGURI§ 1. Relationship bclmsett pli2l[‘m2lC(}l(iI1€llU parmnetcrzs, pllurlilztcildytlaraiic pilraimttcrs, and drug eili3ClS!'0llCCOf]"t§2
`for zmtimicml>ials.
`
`the time course of amtimicrebizxl activity are the 24-h <;u1nulativearea under the COIiCCI1iI“atlOl1-
`Cl€SCI’il‘!€
`time curve (AUC), peak i30!1C£1I‘llI‘Elll()ti, and durzttim of time above 3 particular coiicenlratimi
`{T > C).
`
`AUC
`
`The AUC is a function oi’ the total daily dose of antibiotic and drug clearance. With some
`exeeptiozms (e.g,., certain beta1~l2ictams.),
`the AUC is not influenced by the length of the desing
`interval. ln ether w01'd5;, zidtninistrzuion of :1 given daily dose as 3 single dose or 21:»; smaller frmctions
`at lixecl intervals Sl'l()Lll£l yield the same 241-h AUC. The AUC best reflects exierall drug exposure.
`
`Peak
`
`The peak serum c<m»::entrz1ti<)i'i is largely determined by the magnitude (if any given individual
`close. Single administration of 21 daily dose of antibiotic; will yield the highest peak cmiceritraliim;
`dividecl doses will yield smaller peak eeiieentrations. Peak serum concentration may reflect maxi-
`mum drug effect anilfou‘ a “driving force" For extravascular drug delivery."‘
`
`'1‘ > C
`
`A third regimen~ciepcn<ilent vzwiable is the duration of time over which ceiteemrations exceed 21
`<:e1‘l21in value {T > C).
`,4.s:i‘z::r:f::g that {lie media .s'!ea:2’_3=~.s‘£(1!e ce=z2cem:'a!:'a2:
`e.t’(:ee:z’.s* the target
`c?{2::ce:2rr(:!i0::, tlividing a given daily (lose into many frt1<:li(:-ns ztdmiiiislerecl at short imetvals will
`iE\C1’CE1S{.“: T > C. The tiltimate €X.l€t}Si0l}
`of this; would be continuous ini’usi0n.“ Adminiimation el‘
`
`larger liactionss of the daily close at longer imervzils will tlierefore decrezise T > C. T > C 11121)? be
`importiim li:>s'cl1zirz1i:te1'i;::ing the lengtli of effect for phenomesia requirirtg 21 lllI‘€5;i"I()l{l C{)flC£3I![I‘£1ii(JI1
`for response.
`A sunimary of the impact 01’ tlusirtg regimen modificzttion (daily close, intewzil) on the regimerv
`dependent varialznles is shcewn in Table 1. Thcxe wwiables are usitiztlly iiiteweltitetl, An il”!CI‘C2‘zSC in
`the total (lziily close of drug without elizmging the imerxzzzl will l'E‘:{3l‘8f!S€ AUC, peak, zmel T > C,
`Iiiztkiiig it impeisssible to (l{’:i€)l'IT1li‘!€3 wliich of the three ~m1‘E21l>les is meat importam in increasing {ling
`el‘l'ei;£. B}; moclifylng, the closzitig interval as well, these variables they be ziltcmzd l1‘ltli3}}l3{1€,ifJ:E}{ly, As;
`will be ILi§S<.?11S.‘~3E2{l later‘, 1I3Z1>iiI”hiZiIig£iI'L!g 8Xf){ZI.‘§L}l”£3 ll"£l‘()Ltgl'l -zlillerent ~.*arital7les; ziiay be impiz-s'[:1m For
`
`|nnoPharma Exhibit 10270006
`
`

`

`Pftmviicicoizinattic»Pitamizzc()t:’_wzconic Msmlefiztg r:.;f’fr':‘ct2ei:tfi;ie _{)ri:g E_§‘":ec't.s‘
`
`.3’?
`
`TABLE I
`
`Impact of Dose Regimen Motllficntion
`on Fliztrinaeoltinetic Paraineters
`
`lncrcose daily (lose
`‘
`
`Same daily dose
`
`Bccrcnsc
`interval
`
`ABC: T
`Peak: -
`T>C:Tl
`
`.1-‘\UC:-
`
`Peak: J»
`‘t‘>c;l
`
`AUC‘: t
`
`l)€t.2r<iaSt2 daily dose
`
`Peak: ll»
`T>C:~ot‘T
`
`Sumo
`interval
`
`Inci‘cst<;e
`interval
`
`AUC: T
`Peak l
`T>C:l
`
`Attc: T
`?cal< Tl
`T>C:—orT
`
`AUC: —
`
`ABC: ~
`
`Peak: «
`'E‘>C:-
`
`AUC: t
`
`Peak: 1»
`'F>~C:~l»
`
`Peak: T
`T>c:l
`
`ADC: l
`
`Peak: —
`”l“>C:J,l
`
`Note:
`
`Impact of close modification of ztntibiotics {total daily dose, dose
`ititcwal) on t}l‘m|'I1‘lElC0l{lllt2{lt: ~mriables (AUG. peak, T > C): T, in-
`crease; —~, little or no change: ~11, <;lecrease. The table assumes first-order
`drug climinztticm and modest accurnulntion with multiple dosing.
`
`if tnaximixing the 24-h AUG is the single most
`tlifferertt classes of nntibioticis. For example,
`important method to enhance clticncy of 21 certain antibiotic, increasing or decreasing the dosing
`iittcwttl for it given daily dose of drug should not influence effect. if peak cottcentmtion is most
`‘nnportant, lengthening the dosing interval and atlininistering large, infleqncnt closet; would be best.
`Finally, if T > C determines drug effect, smaller (loses ndministcrecl frequently woulcl be the most
`efficient means of drug acltninistration.
`
`REGIMEN—INDEPENDENT VARIABLES
`
`Certain other pharmacokinetic properties of antiinicrobials also influence the concentration time
`course at the site of infection. However, because they cannot be appreciably altered by modifying
`the nosing regimen, they play only a minor role in pltarznacokineticfpharmacotlynetmie niotleliitg.
`
`Serum Protein Binding
`Moist ’c‘t[}lill"Ell<.)1‘0l)l€llS exhibit some degree of binding to serum pl‘()l€:it1S. This binding is icyerssible
`in nature anti primarily concerns hytlrophobit: and hydrophilic binding tnet:hanisms;.7‘ Most antimi-
`crobials bind to albumin, although some (primarily basic compounds) may bind to alphzt—l—acitl
`glycopmtein. In general, the extent of protein binding within a class of cotnpouncls increases with
`increasing moleoulztr weight and hydrophobicity. Protein binding in serum in not generally consid-
`ered to significantly affect the pbnttnacokinetic profile of at particular drug unless the amount ofdrug
`that is bound in sertnn exceeds 8(.l%.7‘
`Protein binding decreases the activity of aElliII‘IlCl'Ol3lEllS in serurn. Only the free, unbound portion
`of the drug in senun is active against bacteria.“ For example, if 21 drug were 87.5% bound to serum
`proteins, the concentration of drug in serum required to inhibit growth would be expected to be
`eightfolcl higher than that of gzrrotcin-free llnitl. This phenomenon generally holds true for most
`2‘t!’Illi1‘llC1‘(}l}lZ’zlEl. In some instances,
`the presence of other endogenous St1l)SiEtIl(:C1~] may enhance
`Zlhlllftllflfflblétl effect so that the activity in serotn is greater than expcctecl.” in general, llOW€\*t’ii‘, one
`shoulcl assume that, lot highly bound {:>80‘}§:) antiinierobials, total serum drug concentrations will
`0\ft3E‘t3SllI11£ll€ antimicrobial activity.
`Protein binding will itnpair passage ofatitiinicrobinli; into €EXlI'2WEtSC1.llé1I‘flL1i(l, which is often the site
`of hztcteriztl
`infection. Bccnuxe most capillary pores do not permit passage of serum nlbutnin into
`cxtravztsculzn sites, only the free, unbound component of drug in serum diffuses extt'avasculztt'ly.
`
`|nnoPharma Exhibit 1027.000?
`
`

`

`38
`
`Hai2a’i)oof< of I’ha;':::aco/(SiteIiC;’P?m:*:iia::o(z’}=::(zniic Cor‘:'et’cn‘:'wt
`
`the unbound serum drug con<:enti'ation appears to be £1 more COItS€1'VEt[i\’C(21t‘I(i accurate)
`C()ttS€C[L}t;‘:itli}',
`measure of the drug concentration at sites of infection that are reached by passive <iift’usion."‘-”
`
`‘I‘issttefF1niti Penetration
`
`In other cases, antimicrobial deliver}; into less accessible: sites is required. These include penetra—
`tion into the eerebrozapinal litiicl, eye, and prostate gland. In adtiition, penetration of‘ some 2mtinii~
`{:1‘0biitiS into intraeelluiar sites is important in treating pathogens that multiply within inznnmalizm
`cells. All of these sites {lentonstrate 21 lipophilic barrier which restricts passive diffusion of many
`ti1‘l!gS.'2 ’l‘iterefore, drugs that are more lipophilie are more likely to be able to enter these restricted
`sites by diffusion across this lipid i"JEtI“I'it3t'. Pamdoxiealiy, many ofthese some drugs are highly bound
`to serum albumin. Another mechanism by which drugs may enter il1[1’£l<.1&ilt1i2‘tl‘ fluid is through ion
`“ti'npttittg”.‘3 The qninolones are R good exninpie of this. At physiologic pH, the quinolones are tm~
`ionizotl and more lipid soltthle. Once hey enter the there acid iI"t[I‘2‘tCGiit1i£‘t1‘ fluid, they become
`ionized and are less able to dilluse out of cells.
`
`.t in»
`
`Serum protein binding and the extent ofdelive1'y of drugs to e;xti‘zw21sotIittr sites are importtt
`pharinacoi<inetic properties in determinhg the aetiise tsoncentration of" drug at the infecteci site. I
`U173
`get oral, these properties are (it'Ug~Sp6t3iiC, and not appreciably 211 ered by titodifyittg the dosii
`regimen. One possibie exception eoneer is thugs that may exhibit szttttrztble protein bitttiing. Admin-
`isteriitg these drttgs at lztrgei iol1‘eqt1eritcl<>ses will yield high peak eonceittrations, which may rest it
`in
`tzmsiently lower protein binding, hereby enhancing the extert nnclfot‘ rate of €Xil‘Z1\*E1SCltlft[‘
`deliw:i'y." Whether this practice in fact leads to greater drug efficiey is, however, unpioveti.
`In suiittmiry, pha1‘ntneol<inetic variabtes determine the time eon
`of concentratis:n1:: in setu 11
`tint, tiltimately, the site of infection. I igh protein binding and limited extraixaseular tleliveify oi‘
`{ittigfti niéty ntandtite that serum eoiieenttzttions greatly in excess of ti e desireci site oont:ent1‘atioit he
`act icvetl. By zidjustiiig the dosing freqtteiicy, one they ttcitieve either 21 serum concentration proti e
`with high peak concentrations and low minimum {trough} coiieentmtiotis, or one with relzttively
`(:01 stnnt eont:entr2ttions over time. Which regimen is preiietnh e will be influenced by ti o
`pharinz1c:o<:lynamit; properties of the agent to be used.
`
`PHARNIACODYNAMIC I’ARAi‘v‘IIi‘.’I‘ERS
`
`Phartnncodynamic pzirameters of" aritiinimobials re ate drug C()t1t:<3t}{t‘E1tit)I‘t and the Cit§Si1‘E“2(l effect.
`In most cases, these phnrinnco yntitnie pE‘t!‘£tI‘t1€I€1“S
`am: (i{3it)i‘l”t1inC(i in t.+:‘tro, and then extrapolated to
`the in viva situation. The i‘e2i:~;on for this is that repeated men:»;uros oi‘ the typical endpoint for
`tintioticrohizti effect, the numbei’ ol‘pz1ti1()genit; otgntistns, is (iiiiieult to oerlonit in viva (hiring
`tliempy. The :t1aj(}i‘itj; oi’ these )i\Zit’t1t21C(3tl)r'I}Z1I1 it‘ pz1i‘nInele1's may he iit to ti stzindztrd sigmoid Bum
`ntotiel. B}; Cxznoining the relationship between C0ll£ZL‘:Et{l’£tli()I‘1 and effect, one can design dosing
`mgimetts that will optitttize overall responsse M iii: usi ig the niiniiotnn 21mou1ttol’d1°tIg. This section
`will {iisouss variotis phztnnneoc yimzhit: pnmine ers, their reizttionship to eoiitzentrzttions achieved in
`t’t‘t’(), anti <lil'i‘ei‘eit<:e:; between (}iJSCt’VEtil()!tS in i2:'I:'r3 21 id in Vii-’o."‘
`
`'1”he minimum ztntimieiohia eoncetitmtion t\:’iAC), ininiinuni inhibitory con<.:entr21tion (MIC),
`and the minimum hat:te1'it;id2tl concentration {MEG} are estimates of the intrinsiir: activity of an
`antibiotic against ft j3€11’iiC1Il€3.i'{)t'g1tl}iSlt1.Ti3€$;C:
`gtnrnine eras trial)! he qtiztntified trey itnztthating 21 ktiowtt
`ittoeultim of bacteria in the 21ppt'<)p1'ietto ntetiin it with vzirionga t:ont:enti‘tttEotis; of antibiotic atltleti.
`Broth is the meditnn used most commonly or testing, atthougli agar Itlzly be nseti for MIC
`(it‘:l(3I't1‘titi21ii(‘m. A sttiieniznit: tiingrnm relating {lit geoneentrotion to the number‘oflynoterizi remaining
`in the medium at 24 it is shown in Figure
`
`MIC
`
`zero not eliztnge in the ntiinber
`Thtz MIC is the ininimoin coneentratios: that pI't3\*<.3ni5 growth,
`oforg:inisins over time. The MIC is the most commonly used t}1t3:E1Sttt”t3 of antibiotic: E1Cii‘t.’i’[}’. lt may
`
`|nnoPharma Exhibit 1027.0008
`
`

`

`P§irtz‘::trtm!<:}m?iic-P?:(t2‘2:ta*m({t=:2m2:i'c ll/Rgrielitzg {;}f‘I:‘t’cette:‘.si£2i’e Drttg tE:f}‘J:ec'!s
`
`39
`
`2
`
`0
`
`inLogCFU@24hrEx:3:.ii:
`Change
`
`Log Concentration
`
`I*‘I{§URl?: 2. Relationship betwacn zmtibiotic f.‘Q!lCCn!E'£lii0l1{l!}(.i the numltacr uforgtmisms rcmztining :il"t<:r 24 E1 of iitctnbzxticm.
`MAC, minimum tll'till1llCI‘C)i)l{)i conctsntrutitm, the mittimum t:{)llCCl]im[lUll resulting in any rctluctimt in organism growth;
`MIC. minimum inhibitor}; coucentrzttitm, the cmtcczntrzttion preventing any net gr-awth of organisms; and MBC, minimum
`bactericidal cottctzittrzition, the minimum C(}!lCCI‘t{ft‘t1i(>n resulting in ct rcductiott in the number of orgzuiisms by 99.9%.
`
`be estitmtteti by tzuunting actual numbers of organisms me!‘ time, 21:; is t;ht‘:3\’-2‘l1 in Figure 2‘ or by
`visually inspectiitg the media f(l1‘<'3i‘tt1l"tgCS in ctptical density causecl by gmwth. In g€3t‘l<Ztt'£1l,
`the lower
`lhc MIC, the g_retttc:' the susceptibility of the bacteria 01:, s;:otwei'sely, the greaatet‘ the activity of 2:
`particular antibiotic. Witch comparing MICS of various; attitibiotics against it pat‘ticular bztctarial
`strztirt, it shoultl he noted that MIC values must be assessed relative to the ztchicvable zmtibiotic
`COl‘tC€FllE‘ali()t‘t:,~'.
`in vim.
`
`Bach atttimicrobial has an established MIC “bt'cakp0int”. This breztkpoint is used to classify
`Sl.lSCIt:3pltl,‘1i6 vs. resistant iS(>i23.1{3S. Bacterial strains with an MIC in excess of the brezikpoitit are
`Ci)l‘tSi£l{:I‘€Ll
`“rt::;i:;t2mt” to the antibiotic, Wl1t;‘:1‘f:21S thostz with MICS less than the bre21l<p<:aint are
`
`“sttt:;ceptiblc”.
`is at cmttplicatcd and highly st1bje<;tivt: pt't::>t:es:~:. Hypoth<:ti~
`Detcrmiiiatioh of MIC bI‘€321i<pt)il1lS
`Cally,
`thc_breal<p0int should bf} tlctwminecl bztsexl on the clinical efficacy hf ahtimicr0l:«i21ls; for
`taxamplc,
`ill the l"tl£1_l<)1’ll}’ hi" itiibctitins clue: to ttrganisms with an MIC of £6 iitgfl or gI'()€iEfi3l‘
`to 21
`[)21l”lit:LIl£ll‘ antibiotic Fail to l‘6Sp()1‘t{l to thetapy with that drug and iitftzctions caused by ::3rgtmisn:s with
`MICS of 4 mgfl or less rezepond lhvorahly, st lirealqtciittt of 8 mg?! wotild he ttpprtipriztttz. Unt'mtu~
`nzttclyi hre2tl<p0ints are t‘£11‘£’:l ff clcttmniitetl based can cliiiicztl SHCCCSS.MOStCOI11lh(}ni}', bt‘€:akpOlt‘tES are
`cletcrmintztl l}2"t.Ԥ(2Ll on acitiavablc scrum cottcentrations in humans following .<;t2m<:lar<l closes, with
`little or no Ct)t’t’f:i21li{}i1 to et’ficat;},»*. Future izfforts will he s:Iire<:t<:d at El€?l<.’:t’!“flil1l1‘tg the breal<p0int based
`on in tu‘t=t:z el‘l’ica<:y and its COl‘l‘Gl21Ei0n to mic or more pltarmacokirietit:-phat'macodynatnic paramett::'s
`(see lttkil’ in cl1stptct').‘3
`
`MBC
`the MIC is only an estimate of growth inhihitittm, the use of this I11€t£tStII‘C to predict
`B€CE1t1S(3
`et‘l‘icai;§,s it: who I‘Cii€3S Qt‘: the host‘s itmmmt: system to £1.'~1Si:~§t in the t3t‘£t(liC£tliO1‘i cut" the pathogen. The
`MBC is the minimum 3I‘tlli)i{)liC ct:;mcentt'21ti0t1 that kills 953.9% of the original mtmbizr of httcterizt,
`i.c., the Ilutllbcl’ of lmcteria is rszduced by 3 log 10 units. This p€1t’2lI1‘t{;1l01’ wllczcts the ability of 21:1
`zmtibititic: not only to inhibit ga‘<:>wth, but substantially ftiducéi the: number of bztctmitz. MBC {lt3{Cl”-
`minzition is 21 more lather‘-intmtsive [)l‘OCCSS which 1‘t3E.]tli|'CS direct pathogen qt12tntil’icz1ti0h. It is used
`to assess antimicrobial activity in cliniczil situations wh<:t‘<: host lm11'lUt”tI:3 f2t<:t01‘:; art: less ltslpfttl in
`
`|nnoPharma Exhibit 10270009
`
`

`

`40
`
`H(i:irf£20()f< nay‘ Pizamicf-3Cokfrier£Cx’Pf'trit‘r:2ac(){.{yii(zi22ii: C0:‘2‘e!(m'0;e
`
`liclpiiig to eraciicate pathogens, such as citdocarditis, ()Sl{':(}I1"i}'Cll[lS, meningitix, and inl’ecti(m:~: in
`neiitropenic patients.
`For tmme drugs such as the beta-laetetm antibiotics, amirioglycosicles, and quiriczlones, the MBC
`is; often similar in magiiituclc to the MIC. Tltesic agents are often referred to as “liz1eterici::l2tl”
`antibiotics. As such, the MIC is frequcritly used as an cstimatc of the MBC for these drugs. Some
`bacteria may, however, be deficient in the important biochemical picceeses: required for 21 bacteri-
`cidal ellcct to occur. In these sitttttticiis, the MBC may far cxccctl the MIC. These tirgaiiisiris are
`often relcrrcd to as “t0le1‘ant", arid other treatment cptioris, such as C0i”f‘il"}lhZ1ll€)I1 antimierebizil
`tticrapy, may be required to produce 3 bactericidal effect.
`Other antimicrobial classes, sueii its the Il13CI‘OllCl6S, tetrztcyclines, and clilomiitpheiiiccl. do not
`relieibly pmrlucc 21 bztctaicirlal effect at cencenlratitins close to the MIC. These agents are termed
`“bactet'iostatic” drugs, and MBC testing is not usually done. Cottseqttcntly, these agerits; are typically
`ztvoitlccl vvhen treating infeetioxis vvliere bactericidal activity is required. An exception to this is the
`[1550 cf‘ chl0i‘2tmpl1cnic<)l
`for meningitis catlsctl by sttsceptible SfI':2;)IOC(JCc‘£t.? p:ie:ir:r(mi'ae or
`}‘i’c:eizic2;:u’::'!it.r ffifltfeitzaé, wlierc 21
`l)2lCtC’:I‘lCl(l21l ellcct is observech
`The MIC and MBC are tinic-hcerioretl measures 0t‘21i1timicrcbial activity against pathogens. How-
`ever, tliese meztsures are liiiiitcti as to the iitfbrinatien they prcvvicle. First, MIC and MBC cletermiriatiett
`imcs are made after Eh fixed iiictibzition perieti, and therel’:>re only reflect at specific time point: they
`dc} not p1’0\’i{l(3 iItlOt‘t‘nt1ll()tt or: the time c::i:i1.irse of aittiiiiicretiiztl activity. Second, MICS and lvlBCs are
`nettstircd using 21 standard incculuirt et’ bacteria, trstially 10* to ll)?‘ ergztriisms. lnlcctitius diseases.
`emmmnly involve much greater numbers of bacteria than are used in tttlsceptibility testiiig. This ltiglier
`‘nocttlum ct’ <:ergaruisms may require antiiiticr::)li:ial Ci)l1CCI1l1’21llOt\S in excess of the noiriinzil MIC to
`‘nhiliit growth. Tltircl, MIC and MBC tczstiiig are done on bacteriti in rapid, logaritltmirz: phase growth.
`it the in viva Sli|.1Z1il0f‘i, bacteria eausirtg inlectiott at certain sites; (eerebrospirial fltiicl, cardizrt: vegeta»
`ions, £1l7SCf3SSCS,
`il1lI‘t1f.3€3lll.tl£1t‘ envimnment) may be growing much more slewly, if at all, due tr) lack
`of ttutrients ziitclfcr oxygen. The betat—lact2im antibiotics exert :1 marltediy redticeti activity against
`slowly grriwing or nengicxving l3actet'ia."*-'7’ Cciiseqttciitly, muczlt
`ltiglier C{)t‘.£1€t‘tll'E1ll()IiS may be
`cquiretl to exert an il‘:l}il}llOl‘}’ er l“:£tCl€l‘lCi(lE1l effect in vim. Friurtlt, the antibiotic C(}!iCE3IllI"€tEl(}l“tS used
`vi) measure MICS and lvIBC:»; remain censtzmt tliretigliotit the iricubzttioti period. In the in vim setting,
`21! lll)lO[lC ’C{)i’1£}fi.3E}il"dll()!lE~1 often vary widely dtic to drug elirninatirm, which may result in tlitniitislicd
`effect ztitdfot‘
`r‘egi‘0wtit. Fifth, IVIIC,/MBC determinations are done using:
`tvvoftiltl
`tlrug diluticmi,
`at owing the posssibility cf as great as 8. tvmlbld error in precise estimation. Finally, MICKMBC
`tleterrnimttioris do not accmmt for the preserace of ltostt i‘acters such as white blood cells‘ complement,
`21:
`:1 antibodies. Tl1CS(3 heist factors may €3t’1l‘tEtElCC zmtimi+;:rt>bial activity in vivo.
`in StJE"1'I!'E1£1!')f, while MICS and MBCS provide useful iiiforinatieit regarding the iritriiisic activity
`01‘ £1‘t”tllmlCl’()bl£3.lS against patiiegcns, the iiiiermztticn is iiiatlequate for clcsaigraing dosiiig regimens;
`ai netl at (1 itirtiizirig rclrug effect it: vfvr).
`
`AC
`
`It is co manly 3S':itlmCd that, given the nominal MIC of an arititiir:-tic tigziinst :1 patliogen, drug
`C()nCfi3t'ilt'Ztli(}!1f:~‘ below the MIC will allow unimpctletl ergzrnisin grovvtlt. 'l‘l“ii.~; is in fact often not true.
`Tie i‘vi:'5tC '3 the smallest C()l}(3€.‘:f1l.l‘Eill*C)‘t‘t fotmd ii: vfrra to exliilvit any iitflueiice on the rate 01' growth
`til” l“i21Clt3t‘ltl when comparecl to control ctiltttres with no antibiotic. The NIAC may be many times
`ltiwer them the MK), and may be observed vvitli tiettt-lzicttiiiis, ztiitiiinglyctasitles, qtiiiiclottes, and
`other aritib'titics.“‘ Stibirihiliitciry £30E}CChll'2‘tli()l1S of aiitibiotici; will not only slew gicwtlt of (urgen-
`if-Ellis,
`limit may (l0Cl‘C€1$C 21(li]BK‘€.‘J‘it3{;
`to l‘(}r‘.)i11bI'£m(3S anti increase pliagoeytesis ef {)!‘g21ttlS!‘t].‘~1 by wliiti:
`l3l{)0{l cells.” In iulcliticrt, 2‘thlll’>lt)tiC cesicetitratitins; above the lvl;'3iC,‘ may help to tlelzty 3‘i3g1‘t)Wii1 of
`lid£:{<3t‘i£l tlt! “Eng periods in wliicli 2-;erttm Ii)()hC(’3Ell.I‘t>.{l()!1S timp below the MIC. This tiiziy leiigtlicri the
`pmatziittiiiiii it: cllect {sec halo‘-.vj.‘*‘ Tire precise role cl‘ the MAC as 21 pharmzictitlyntimicl vamible has
`not l‘tCCt1 tlcl'iiii.:<,i, but it likely ceutritiutesi to cnlizmeed <:t’{t(llt3E1tl{)t1()l.p21ll1{}g€3I1S in irimtunocempetertt
`l3OZ~‘.l.'s‘, even when serum E1hlllf}lOIlC r:ti:tt:ciiti'atitim; exceetl the MIC tkfir only brief periotls of tiitie.”
`
`|nnoPharma Exhibit 1027.001O
`
`

`

`339:5::'i2:a:cr;&i:ze£i'c~»Pf;¢'.s*i‘:2:c:mn’yi:g:i;ir£C 2l:l‘(}c§€i£;ig Qf‘I:’:'niie::s'i§)e’:e Dmg Ejflrzcfs‘
`
`41
`
`
`
`BactericidalRaie(cfuihr)
`
`Concentration
`
`Therapeutic Range
`“ Drug A “Drug 8
`
`FIGURE 3. Rclzttionsliip between l,>a<:tericidal rate (BR) of {we imlibiolics, A and B, and cmicimiralimi. The BR for each
`drug increases initizil1y,1hcn becoiiles ilxeil at liiglzcr concentrations. For {lrug A, the BR-comzcntratioii rizlzitinnsliip is linear
`Elu‘0ugl1<>ul the range of cmicciitrations ohsemzti iii vim. In (:£)llli‘{lSl. the reliitioxisliip is primarily imnlimzar {fixed} for drug
`8 because Ymlcll higher <:()l}C{:!llm{lODS are achieved in viva compared with the point of saturation.
`
`BACTERICIDAL RATE
`
`As wag slatetl previously, lllt’: MIC and MBC do not prox-‘ids infmmzitiou on the time course of
`miilinicmliial activity. F(}!'€Xi1mpl°3, we know that a net bactcricidai effe2c:t oc<;urs at {:{)nC€:I‘:lI’:1li()I1S
`at or above the MBC, but not whether the rate of such 21 l)dCE()I‘lCi(iZ1l el’fe<:l is further cnlizincecl at
`r;:(mccmr:11ions; £1l?O'v‘C the MBC. it is likely that, over :1 specific range, ll1Cl’€:'lS£3(l Cl'}!‘1CCl'lll‘£!.1i0I}':§ will
`rczsult in 21 grczater l'}3Cl€l‘i(1id2‘(l
`rate (BR). This phenomenon is; termed cancanmaria:e—depei:(!enr BR.
`As <:0nc<:nl1*ali0ns are ll1CI‘(3?IS€{l
`fiirlhci‘, the BR l3C:COIi‘l€§§
`lnaxitnal and is not infliicmsed by higher
`
`:1 drug
`con€cn.l1'z1ti<:iris. At this point cancanfirzfiniz-ii:a’e;Jcztia’eiif ER is obscwed. Clinically, wl1<:il1ci'
`exhibits conesm:'2iiion—(lep<:n»:i<:m or —indc:p<:nd::nl BR ilepends on the relationship of the c.:onc=:nlt‘a—
`li<‘>n~BR curve to C(}1”iC€:I1Il’E1llOI‘lS obs<:rvc{l in mix). Figure 3 shows; the relationship l){3lWxE‘:8l‘I BR and
`<.:0n<:<:n£1‘21li<:>n for two zmtimicrobials, A and B. Both exhibif COI}C€flil’3ll()i1-(i€p€l1(i(i1'll
`BR at low
`C()i"1CC1‘:iI'é1ii0llS and c;mi<;entmti<::n—inclep<:nd::nt BR at
`liigh rsoncentrzitions. In the clinical setting,
`E1Cl1l{‘,'~.’21l}iC C()E]f)€3llll'£1li()llS o