Page 1
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`RB Ex. 2024
`BDSI v. RB PHARMACEUTICALS LTD
`IPR2014-00325
`
`

`
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`ISBN ‘J78-I}-7817-:')f)1’}9-7
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`
`Page 2
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`CCS1209
`
`Page 2
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`

`
`CHAPTER
`
`Therapeutic Relevance
`
`CLINICAL SETTING
`
`'l‘|'1t):se pzttienls who stiller ['t‘t)m ehrtmit: ailments stteh as (lii1l)(’L(‘5'(lll(l e]Jile])st}-' 11121}-' have
`lo take (lrttgs tavezy (lay lot‘ the rest 01' their live:-2. Al the. ntltert.-xtt'e.111e are tlmsae who tttke
`at single dose nf';t tltwtg to relieve an <.)t'e;tsit)1t;tl l‘I{'EltlElt.‘l'I(.'. The tlurtttitm ulitlrttg tl1et‘;tpy
`is ttstutlly hetwetzn these exttetttes. The mnnttet‘ in whieh ':1(ll'tlg is taken is ('2lllt.'(l zt dosage
`regimen. Both the (lllI"cH_it)I] n['t.lt‘ttg l|t<-'1‘;tp}-' and the <l<as;tgt- t‘egimett tlepetttl ()1! the ther-
`El]J(.'UIl(‘ t.Jh_]e(:1ive, whitth nut}-' he tlte ettre. the I1ti1ig:tt'itatt, tn‘ the [)l'(‘.\’['illIl()ll t}['tli.~;e.:t:at* or
`etmclitimt.~t su['I'e1‘e(l by ])t11ient.~t.
`l5(‘.(‘E1tIH(? all (lrttg‘.<t exhihit smne ll|l(l(‘Hl]‘1ll)lt'3 t.'llt‘{.‘l.‘-%, h‘tlt.‘lI
`213-; clruwsi11e:~ts, (ll‘)J'lIt'.?:s'5 of the tttmtlh, }_§:t.~'.1mintestitt;1I it‘t‘it2tIim1, t1ttLtse2t.;tt't<l |typ<)ten.~timt,
`attttteestsfttl tirttg tltt-.t';1p)* is 2t(:|1ieve(i I:-y ttptitttztlly l):1lmtt'ittg the (lt'Hit'2t|)|t.- ‘dl'tLl the '.llI(l('..H'll‘—
`able efl'ee1<;. Tu :1(‘.i1l{':\’t‘." uptitnal tlterttpy. the ll])].)]'()pl‘ii1I{? "(I1'1t;_=_' of eltoiet--" must lirst he
`stelttctt-.-(1. 'I:his (l(f(‘.l!s‘l()l1 implies ill] 2tt:t‘ttt':1te ciiztgttusir-; ulitlte (li.~te;1.~'e or ('(}ll(lllit)n, 11 knowl-
`etlgre of the ttlittieul state ttlithe pdllt-‘I'1t,'¢1I‘t(l ;1.~;t)ttn(l 1tt1<let'5tett1dittg' -:)|' the ])i'l21I‘l‘ll1l(‘t)li1{‘I'—
`apet1t.i(‘ I1'1;11t:tg_r_'ert1ettt of the (ll:-%C2lSt:.'. Then the qttestimtrt til", Itow t1tut'h? lt0\-\-' olten? and
`how inttg‘? must he ;1I]SW('I‘()(l.
`'I‘i1eqt1t:stit>n, him much? [‘t;‘.('{}gI‘tlY.tLZ.\‘- that the t1t;tg_=_'t'tittttie.~t n|' the ther:tpeI.tti(' ;tn(l;1<i—
`\’t’l‘St;E I‘{?S[J0ll.*§{:S are ftttttitintts of the size ttlklttst: given. 'l'n |)2tt';tpht‘;tse the ]tith—t'ettlttt)-'
`physicitttt Pztrttcel.-ttt.a, "nil drttgs ;1:‘t--
`])(li.‘«3{JI1S.
`it isjttst :1 mullet‘ of tltaste." hut‘ example.
`23') mg tJi';1spi1‘it1 (_l0e.~: little to ztlievittte 21 Iteadztttltez :1 (lo.-te Cl{l.*i{‘l‘ to .‘-ltltl in ($00 tug is
`Iteetletl. with ]it.t.le ill e['|‘eet.
`|I(>we.ve.t‘, 10 3; taken all at ()I1(‘.('.
`(2211) he ilttttl,
`ttscpt-'('i‘.tlh-' in
`ymmg t‘.hiit,lt'eI1.’l'l1e t]lI(?Hll{)l1, how often? t‘et:ttgtti?.es Ilte lII1I}()I‘lill‘1(‘.t.‘ of time. in that t.I1e
`|1l:lgllll.U(lt'.: n['the effet‘t eventttztlly tleelitttts with titne Ittllntvittg 11 single (inst-‘ t>I'tlI'ttg. 'l'|te
`([1l(3.‘x'llfJl'l,l'1t)Wl(}I]g?l‘C(Tt}}_{I)lZtEH that statue t‘.0t1tlitinn.~t are til" limited tlttrutiutt, t-\'|ti1e;1t‘0.~:t
`(in t_et'ms 0[':~'i(le e.['l"et‘ts. l.()Klt'll)', eemmn1it'..~s) is int‘t1t'reti with (.‘(}1‘Illltll()'|.IH (lt'tI§.;' El(lI]lliliH—
`1:';11i()|1. In [)l‘}ltIllt.'t:_ tltcse qttestlitatts etttttmt he t'<m1pIete|y tlivttttetl limtn one 2ll1tJlll(‘l'.
`I,-0]. (_xm“P]{.3, 1|-,1; (‘t}tl\’()lllt.:ltt‘.(: ttlgix-'ittg t1 l;1t'gt‘t'
`(lt).‘.«'t;'. less lteqttetttly may he llttll‘-1‘ than
`()l'iSet hy an lIl(ZI‘{?El5t‘.(l ineitlenee tJ[' t0xieit.,\-'.
`iI.~' tttatttttet‘ tttttl l't'eq1te:t('y nI' 2l(.l—
`Wllill detertnitter-t the tlterapettlit‘ (lose old thug 2'£l't(l
`ministratintt, as‘. well as the evettts‘. expet'iet'1eet.i {)\’t;'.!' time by [)1\[lt'l].l_*§t‘.-II taking the t‘t-et>m-
`l‘l‘I(El'l[lt.E(l (.lt>s:tgt: regitttett:-1. (:un:»'titttIe.s the both.-' nfthis hunk. It aims to tlenmttstrztte that
`there are t1ot1t'e]')t.~;emttttmtt to all tl1‘1tgs and that, equippt.-ti with these t'nt1t‘epts. not null)!
`cm: litany of the nthetwise ('nt1[it.~;in;_=_' events liuiluwing rirttg :l(l|lliI1l.‘iIl'}1llt>H he t':1tim1nl-
`ized, httt ethao the key qtttrrttitattt-t sut‘rnttt1tlittg' the \'CI'}’
`ltztsis of tln.~;;tg't'
`t'eg‘ittte.t1.~' mu he
`llI1(lC]'.‘iLf)0(l. The intetttleri result is 21 hetter and snlet‘ use 0]" (ltttgs [hr the treattmettt U1‘
`:lI1l(i'll()l'£11it)ll
`t>[‘tlise.;1ses tn‘ etmtlititms .~;tt|l'et'etl hy pzttietttet.
`l’;e:tt' in mind, for example,
`that still tntltty, SOIII-1‘ :"t"n 0|Wp21tie.ttts attlmittetl illlt}l1().*ipllEll are there het';mst-- of the inap-
`p]'()P]‘i}11(f use 0I'(lt‘ttg:-2. tntltth 0| whirh is 2l\-'t>l(iE1l}it‘.
`
`Thisrnaterialwascupied
`at the NLM and may he
`5ub'et:t U5 Co
`Fli'|i.l.i\'\r5
`
`Page 3
`
`

`
`n SECTIUNl
`
`I Basic Considerations
`
`FIGURE 1-1. An empirical approach to the design of a
`dosage regimen. The effects, both desired and adverse, are
`monitored after the administration of a dosage regimen of a
`drug and used to further refine and optimize the regimen
`through feedback {dashedline}.
`
`is pt:s.~ai|)le, &1I1(i itttleetlilu':t~i;1t'tm1mrm }):1.~'I pt':teIit'e. in {'.‘«'lElilii.‘-«'11 |i'i(’[1(J.*iil§_{t‘I'(':_:'i-
`It
`men nftt (lt‘ti_<_;' l|tmti;_=,'lt trial atnrl error i)j.' :t(ljttsIit1_g'
`.~<t1('}t
`f':tt't<3r.-; as the (i(J.‘«‘(' :tn(l iutet'\':1|
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`I—l,
`.-\ t'e:1.~i<m;t|)le
`regitnett I‘Ili§_{i1l('\’(‘llHlEl”}'i)(-(-*-i{11i}iiSi1('(ii)1lI nut Wltiltlltl<(JIi1{'|)£lli('IH‘< e.\‘perien(‘itt§_{ ex-
`('(_“i.‘i1\"I‘.’ :tcl\'e1'se efl'et'Is LIIHI ()li'l('1'.'i ii1ef‘l‘et'ti\'e tltei';ip}'. (i('I‘I:li1li_\'. this wm the pm(‘etltt|'e
`I't>|lmx'etl to est;tI)lislt
`that tliguxin neetletl In he giver: :1!
`tlu.~'e.~+ i1(’E\\'('(‘I]
`I'll...-"J mg and
`0.2:") 1tt;_>_'tm|}'tmee :1 (lay it)!‘ |i1{' treutntenl uf' t‘t>i1_u;e»'ti\'e t':u'(|i:u'
`l:1iltu'e. \\'heI'e:t~i mot‘-
`pltittesttlfitte iteetlerl to lit‘iI(in1iIlifil('l'('(i :1I
`tlu.-;e~< lit-tween ll] ittgiitttl :'3l}1n_t_{ttp I'0l'rtitne.~'
`21 clay In :uleqtt'.1Iel_\-‘ relieve the t'ln't>|tit.' h'I‘.'\'{'|'(' pain exlat--rit-m'etl by |);l|i(‘]i1\' stIl'f'eI'ing.;'
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`son liar this rlil'l'e1‘enee in the !'t’}_{illl(.'.1l.‘~'l)I'(ilg't)!(iI1éIlIfi Il1tJ1']Jil1Il(‘i)LIl:llH(Jt'(>IIll‘1i)l1I(’Sii1-
`tle. il';1n}-'tI'ting, t<m';u'(l e-'t:t|JIi.s|tin§_{ the ]}I‘1H{‘1[)i('"i
`t1n(lerl_\'ing_{ el'let'ti\'e (1{}‘-{2Ig'("
`rt-_9_'irnen.~4
`ta[‘c1t}t<-t'cii‘tigs. 'l'l1:tt is,r:tti'l>;1.~:ietmtlei'sI:ttt(1i1tg;'ul'rla'ng~<lmsrmt In-en iIl{'!‘(‘}l.‘~;('-ii.
`
`l'NPUT—RESPONSE PHASES
`
`i’I'r>g‘t‘<-.-s.~i 11:15 mil}-' i}(.‘('H fhr'tht‘titni:tg_{ by re:tli7.i1ig' Iltztt L‘mt(‘eItt:';IIimt.s :1! 2i(‘Il\'(" sites. I‘ii||It‘l'
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`it
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`Wilhitl the imd}-'.
`'l\‘iIl('il
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`is ‘.1ltei't-(1)
`is (Iivitletl inln IWO p;11‘I.s'.
`:1 pharmacokinetic phase anti :1 phzmltacodynalrlic
`plmse hull! with rraots (i('l‘i\'('(i limit the (ire:-l< tmrrl If)J"h|’.|'.i'l'.*rl(."r‘I’:.l.l. Ill('2lHii1;{ :1 (lrttg, or inter-
`e.~stittgl}'.
`:1 poismt. The pl::tmt:tt'nkit1eti(‘ |}il}l.*§L'
`('<l\'(‘I'.‘i
`lite t't.'l:1tim1.slIi|)
`i)(‘[\\’(‘{‘l1 (i|'1I}_‘{
`iI1})l1I.\\'iI1('il(‘{}I‘H})I'iS{'S HIl(‘iIEltiillrillihit‘i'§l(‘ItJl'S&1*l(if)S-‘.‘.(i()52I§3,'('ii.’}I‘III.11't‘(]l1{'I1I;'}';lil(1I't)IIl(‘
`t1|‘:t(lmiI1istI‘:tIitm.and the (‘(Ji]t“('1'lll'21l1()lI :tt'l'tie\'e(l ruff)’: rim». Tilt‘ pl1:u‘m;1t‘t><|}'t::tn:i(‘ pltatse
`
`Pharmacokinetics
`
`Pharmacodynamics
`
`A rational approach to
`FIGURE 1-2.
`the design of a dosage regimen. The
`pharmacokinetics and pharmacody-
`namics of the drug are first defined.
`Then, responses to the drug, coupled
`with phartnacolcirtetic information, are
`used as a feedback {dashed lines} to
`modify the dosage regimen to achieve
`optimal therapy. For some drugs, active
`metabolites formed in the body may
`also need to be taken into account.
`—
`
`Dosage
`Regime"
`
`E
`::Jpg::ge
`within
`Body
`
`--.
`Thisrnaterialwascopied
`at the NLM and may be
`Sub‘-ECTUS Co riht Laws
`
`.-o
`
`Page 4
`
`

`
`CHAPTER1 I Therapeutic Relevance E
`
`cm-‘t.-rs tht: 1't'i‘.tti(msitip i)t'l\\"t‘('I1 (‘r>11r‘t~1ttI‘:1timt Elllfi hnth the titrsi1't-ti anti 21(i\'(‘t'>i(' vi'l'{‘t'ts
`protittttctl trrrfli.
`tfi-rm’. ht sitttpirc tc1'Itt.s, plmnn:tc0kineliI:s In:t\_-‘ hr \-'it‘\\'t‘ti us imw the both-'
`i'I:l]!(iit;'.S the (i1'u;;', and pharmacodynamics :15 imw the time" ;1i'['t'u:‘ts the body. Scum.-tiim-.s.
`the 11tct21|m1itt'.~' ui'(it‘tI§_{s iin'mttr.i within the i:-ml}-' h;t\-'t‘ ;t-:'ti\'it}-' Llttti also mtt-ti in he t:1kt‘n
`into El(‘.(‘.L)liIl1 when rciatting (irttg :tth11inistr2tIimt to l‘{‘H|)(‘.-Ii!-EC.
`S(3\‘v.1‘;1l r)ti1cri):1.~;i(' irit-as ii:-Wt‘ i]t'.i])(‘(i it!]Jiitt‘('(i1'1l§_{iltiitliliif-illlliitlll rm :1 mutt‘ |'z1ti<m;ti
`i'imtin§_;'. Tilt‘ lirst, anti p;11'ti;tii}-'atiiutlt-cl to ;1i>:.>\-1', is that the i|1tt'|1sityn:'iii~;ciihtmri<>i't*i'l't-ct
`ii){‘I'{-‘Elf-itffi with iIlC1‘t':1Si!1g (‘X|J().‘il1I‘l‘i()1i1{‘ {i1'll_q', hut UIli)'lt}*+{)lIIt'iilllilitig,t)l'Iii2iXi.m1l111
`\"ziil1(.‘. ;ti)rwc. which the I'('Sp{ll1.H't_' cant go no ltigitcr, t‘t*§_{:1I'rlit'.ss n['|1t>\\-' high the cr.\'pn.sltI't--.
`St.-ttmtri, (i1‘11g.s act rm (lil'ii'|‘<:nt parts til" the hmiy, and the Itmxitntmt L--l'ii‘ct ])l't}(ilt(‘{‘{i by
`(III-1‘ rirttg nmyi)c\=(*1}+riii'|et't'1t1 iirmn that ni';mntiu':'. ('\'I;'.I‘1 ti1<1t1;_{h the Il]t‘:1!x'tlI'('.(i1‘t’S})(JII>i(2
`is the .~;;1mc. Fm‘ c:<:m1pit-.. lmth t1.~spi1'in and n'm1'phint'
`l'L'iitF\'(‘ pain, hut \\'|ttt1‘tr;1saspirin
`1m1_y1'ciit'\-'t' miitl pain, ii.t‘:lll11.(!l i‘L?ii(?\-"(‘ the .~rt:\-'r:1't.- pain t-xpc1'it'11t‘t-cl by putit-nts with H(’.\"(‘l'(’.
`l1‘L1tIll1':1 or ttatturr‘ ex-‘mt
`\\-'il(‘I] g'i\'(‘n in lI‘|'.t.‘-iHi\’t? rinses. ii('I't‘, i110t‘])iliIlt', U1‘ ‘.umt|urt' npirriri
`;1Imigttsi(', is the rl1‘1tg of citt;-ice. 'l‘hirtl, whirit iiriluws in part iimn the st-crrttti i(i(';l, is the
`l‘t‘E1ii'!El1i(>li that (iI'lIf.{'H |)I'(lt_ill('{‘ 21 11tt|it'iplirtiIy oi‘ tri'i't:t'ts. scrim‘ riesirt-.r.i and utltmzs l1I1{i.(‘.-
`sirtrtl, whiclt when t'Ul1|)it:'(i with the iirst idea, h:t.~a the ihilmt-1113.-1' implimlimt. T00 imv zut
`<'xpnst1t‘t' 1'trsttit's in an imttlt-qtt:1ttr [i(?SiI‘(‘t’i 1't-spmisr--. witt'I'c:t.~; too high :11}
`t;-x])ust|1‘t-
`in-
`(I1'{?Elh'('?S the iikciiimmi and intensit'\_-' oi" }l(i\'t‘t‘$it‘. ('.iit?t'lS.
`l'}x})1't&sst'tl riil'i'c1't‘i1tiy, tht'I'c exists
`an nptimzil |‘et1ig'(' oi" t-xpn.s1Irc.s i){‘l\\"t.‘('|1 these (‘XT.l'("1I1t‘h‘. the therapeutic window, simwn
`.~;L:heI1t;1ti(".1li}-' in I*‘ig. I-3. Fm‘ St}111t‘ clrttgs, the ii1t‘l‘}l])I;'.1lli(‘\\"il1IZi{J\—\' is I1;1I‘l'{)\\’. an-:1 lil(11‘[ri(Jl'(‘
`the 1n;tr§_{iI1 ui's21['t‘ty is small. For nth:-r.-4,
`it
`is \\-'i(i('..
`.-\itl1<J1t;_=_'h the 2'.]J])l'(JpI‘i&1l'.(' r:<:tt(‘.mttt".t—
`li(J]‘I slmuiri he that at the site 01' E1{'ii(Z-1']. rm‘:-It-' it is 21t't:t~.«_sii)|tr; ittstczui, the ('m1ttt'i1t|'attimt is
`gtttttmtii}-' rm-".1.s1|rcri 211 an Eli.it."l‘1'I}lii\'{‘ Elliti Ill()l‘{? ;tt:rtt-5.sii)lt- site. thv plztsmn.
`r"\l‘1t1t.'(i with titestr sinrpie i(lt';ts, it
`is now pr,~ssii)|t- tn t-xpiuin the rmsmt for the (iil'ilti‘—
`{?li('(? in the tinsiitg |'1't'qtit'n('y in"--I\\-‘ct-.|1 (iigrsxin zmti mm'pl:inc. Bnth (i1'1tg'sl1:1\'<".t H-:I21ti\'('|}'
`
`FIGURE 1-3. At higher concentra-
`tions or higher rates of administration
`on chronic dosing, the probability of
`achieving a therapeutic response in-
`creases {from gray to white}, but so
`does the probability of adverse ef~
`tects {toward increasing redness}. A
`window of opportunity, called the
`"therapeutic window,“ exists, how-
`ever, within which the therapeutic re-
`sponse can be attained without an
`undue incidence of adverse effects.
`
`Page 5
`
`Therapeutic Window
`
`9:I
`U)
`-:-<
`Lu
`:5:
`:E
`D
`
`DC
`
`Theraheutic
`Response
`
`Page 5
`
`

`
`n SECTIONI I Basic Considerations
`
`FIGURE 1-4. When a drug is given in a
`fixed dose and at fixed time intervals ide-
`noted by the arrows},
`it accumulates
`within the body until a plateau is reached.
`With regimen A, therapeutic success is
`achieved aithcugh not
`initially. With
`regimen B, the therapeutic objective is
`achieved more quickly. but the drug ccn—
`centration is ultimately too high, resulting
`in excessive adverse effects.
`
`
`
`PlasmaDrugConcentration
`
`Outcome:
`
`Excessive
`Adverse
`Effects
`
`Therapeutic
`Window
`
`lfleffeciive
`Th‘-‘=TaPV
`
`Regimen B
`
`Regimen A
`
`Time
`
`i'tai'1't:w |i]t.'1'i1})I;?11Ii{' witttlnw, hut \-vht'.rtras IIt()l'})i1lIl(? is t.-liIni11at.t:t.i very rapidly Iitmt ll1(‘
`lmtl}-'_. so that it must l)(’ 3.-,'i\-'t-n Ii‘:-qtit.-nil}-' tn ntaintain an E1(l(!t‘.1tlEl!(‘t'tJI1(‘t:t]lt'i1ll()]1 to t'.nstt1‘tr
`rtrlit-l" of pain without (.‘X(.‘t'.‘S_H'i\'t’ 1«'L(l\-’('1'S(’.
`t-.l'l't?t‘ts, stitth as rt-.spii';tItn'y titrprtrssitm, tiigtaxin is
`i‘t.-lati\-’t--.l}-' sI.;thlt- anti so with iiltlt‘ lust t-ach (lay, t’JItt‘t'
`tlail}-‘ atlniitiistralitan sttliitx--.s. 'l‘lics(-_
`pi'int‘iplcs also help to explain an :l(l(lt‘(l lt‘;11tn‘t.- t)l‘tiig>;m<iti. ('}i\-'tén daily, tligtntiii was t-rithtrr
`int-t'i't.-tztit-‘tr d(‘tI1t_Ti)’ or trvttntttally |)t‘t>(ll1(2(ftl ltIlil('(‘t'|Jl;li)lt.? toxicity when a tltising‘ rate sI.tl'ii-
`t‘it.-ittly high to l'JL.' L.-l'i't-t'ti\'tr acttltrly was inaiittaint-.-ti. B(?C21lI3-it‘ it is trlitttinatctl slowly with lit-
`tle lust
`(.'1I('lt
`(lay.
`it attttiitttlattrs a|JpI'ttt:ial)l}-' with I‘t_'[)CE1I("(l
`tiaily atltninistratitnt. as
`tlt1pit'It.-tl H(‘.l}t‘I1I2lli(.iilll)-' in l"ig.
`I--'1. At low daily tinst.-s, the initial (I(Jl'1(‘(‘.Illt‘Elll(J]1 is tun low to
`ht? ttf'['ct‘Iivt_- hut t?\*'t.?lI|lIEl]l)-', it rises In within thtr tht-.-i'apt't1I_it' wintltiw. Int'1't.':tsing tilt.‘ daily
`tlr>st;.- lirings Illt‘ t:m1t'c11traIitm witltin thtr thc1'aptr1ttit' wintltaw t.‘1tl'ii(.'I‘, hut with lllt‘ (‘.t)I]('{‘Il—
`n‘2ttit:n stiil
`I‘isii1g.
`t'vt.-Iitttally thtr t_‘.tntt‘.t:nt1‘atitm htrtttnntts [00 l'1ig‘lt, anti tt]l2'i(IC(?I)i:ll)l(‘
`l().*(i(‘it}' t-nsutrs.
`lltiwt.-\-'t-r. what was l1(.'t'.(i(‘(l was rapid E1(‘.i‘li(?\-'{?Iltt'I‘t[ anti Slll).'-ltZ([1lt.?t'Il main-
`tvltantttr t>l'
`'¢1{l{:f(]lIE1I(‘ tligtixiit (‘(}vI](‘{.‘.l’ttl“¢t[i(ll't_‘-L Willi-{Jill tlntlttc atlvtr1‘str t-vllcttts. Tht: atiswtu‘
`was In t_>_'ivt.-
`.\'('.\-'t‘I‘ili sniall t|tist:s within the Iirsl (lay, t‘.tnmntit'1Iy known rtilltttttivtrly as at (digi-
`rttiiziiig rfmr’, In I':1])l{li)-'E1(‘l1i(‘\'{‘ t|1tt1'a].)trt:t.it' t‘tmt't-.i1ti'aIitms ltwilnwt-ti liy small tlaily tltistrs to
`maintain lll(‘ t'(>Il(‘{'Iill‘&1|l():I't within tht: llI(‘I'Elp(.'.llli('Wll1(ltJw.'I.l1(?lL!.*§S0lI to ht-r i{‘}1l‘I’t{:'(l l'm1n
`lllt’ t'ast- 0l'tlig'tixin anti intltrtrtl inns! tlrttgs is that nnly tl1t‘tntglI an Illicit-rI‘staritli:1gt>l'Iht-
`tmnpmal t-\-'t-nts that ()(‘.(‘.llI' ztlit-r the tli'ug's tttliiiiiiistratitm can i11caititig'l'ttl tltrcisitans he
`math‘ i't-g'at'tli1ig its nplinial nstn
`'[‘ht* iss1tt‘t)l'timt.- tlttlays htttwtrt-.i1 (ling atltttitiistralititt anti Itésptittst-. is |1{Jl tttinlint-.(l to
`i)il£lI'Ill£I(‘tJkill-1’il('S hut t-xttrntls to plIamtactitlyitittttitis Int). Part tJl'sut:l1 tlttlays is a :'t'stIlI til"
`Ihv Iimr rt.-qttirtrtl i'n1'tlI't1_t;' tutlistI‘il)tItt.' [t)iit{T IaI'gt:tsi1't%. whitth is ni'tt:n in a cell within a
`tissuetu'tn‘t{;tit,sIIt'l1ast|1tri)I'ain.'i'iiisis t‘t:rtainlytl1tt cast: with tligt)xi1i,wi1t--.i‘tr tht-r ptralt t:l"—
`l't-t:I tut thtr il{'.:l]‘|
`tJt'(‘1II's s(¥\'t?I‘£ll lmius altttr t)l)S{?IVltlg' the [wait t-txptastinr in plasina. Part is
`also a rtrsttll oi" (lt'lil}’S within lltt‘ afl't‘t'tt-ti systt-‘iii within the htitly, as I'(?2t(lil)’ sot-it with the
`urai &tilllt“t‘)}1§3;lli£lTll t\-'ari'arin. ll.‘i(?{i as a pi‘tap|ivl2Ixis in the pI'L‘V(?Illl()I'| t)t"rlt-cp vein thmini:ta—
`sis and nth:-I‘ tIimi'nl)nt'Inhnlit‘ t‘tmi]Jlit‘atitms.
`l".vt*.n Ihtntglt the (lt't1gis 1'apit.llyztllstirlitttl,
`)'i('i(iiI]t{llig‘]1,(?2l1'l}'('()l]t'(‘IlII'£1Ilt‘}it!-tIltrtillglltlill lilt‘ l‘JU(i}-'. as seen in Fig. [-5,t.litrpt:a1k t=.i'l't-tit,
`in It.-rms t.~l' p1‘t>lt)11;_§atitm tJi_Il1{‘ clotting tinttr, nt‘t'.ttrs appttixiittaltéiy 2 (lays afttrr 21 (Inst: of‘
`\\-'at'l'aI‘iI1. (llt-;tI'ly.
`it
`is iinptirtaltt In I:1I<t' this lag in It-.sptntstt into El{'.(‘{)lllll wht.-n (it-rttitliitg
`how IntIt'h In tttljttst tl()St‘ In at‘hit‘\-‘t‘ anti mailttaiit a g'i\'t-.i1 tl1ct‘apctttic rttsptittstt. Failing in
`do so and :tIt<_tnipti1t;_>_' to atljtist (l()_*i£I}_’_'(’ |iast'(l, liar t-,\':11nplt%, on il't{'? I‘{-?S])()l'|!-it‘ S-I‘{"l1 al'ttn'
`] titty,
`i)t.‘itJI‘(’ the hill t.-l'f't'.t.'I tit-t-'t'|t>ps, llt(‘l't'2t.‘s'{‘s tht: tl:t1I_t;‘t'i‘ til't>\!tri‘ti<:siIIg the patient, with _st-rritatis
`])()i(‘Illi2i.l ('(J]l.‘it'q1l{FIiI.’.‘t'.‘i. s1It'li as inlttrnal lttrII1m'1'l1agt‘, with this low Itt;tt‘;_§itt-tillsttltrty th'ttg'.
`Page 6
`
`Page 6
`
`

`
`_L I\3
`
`
`
`PlasmaWarfarrn
`
`
`
`Concentration(mgfL)
`
`CHAPTER I
`
`I Therapeutic Relevance n
`100
`
`W(3
`
`
`NI-lbO}DOD Percent
`
`DecreaseinNormalProthrombin
`
`Activity
`
`2 D
`
`ays
`
`FIGURE 1-5. The sluggish response in the plasma prothroinbin complex activity {colored line}.
`which determines the degree of coagulability of blood, is clearly evident following administration of
`the oral anticoagulant warfarin. Although the absorption of this drug into the body is rapid, with a
`peak concentration seen within the first few hours, for the first 2 days after giving a single oral
`1.5 mgikg dose of sodium wartarin, response {defined as the percent decrease in the normal complex
`activity} steadily increases reaching a peak after 2 days. Thereafter, the response declines slowly as
`absorbed drug is eliminated from the body. The data points are the averages of five male volunteers.
`iFr0m: Nagashirna R. U’Rei|ly RA, Levy 6. Kinetics of pharmacologic effects in man: The anticoagu-
`lant action of warfarin. Clin Pharmacol Ther l969;10:22—35.l
`e_.
`
`Am.Jtl1c1' ttxalttpltr of El timrc (It;-.I21y in plizu'z1iz1t‘0(Iyti;tiiiitts <:t>nt‘trnts an ettlx-'t.-rsc cfll-.(‘t, £1
`snlttty issue, .‘itf(?l1 in Fig. 1-0 tiller :1 siiigle iiitmvcitititis (lose 01' th:-.
`'.mtit".tnct't‘ (hug incli-
`tatxt-el. A (.‘.{}tI1tt‘t(.JJt and ciinittztlly sigitilittzttit l{)Xit'i1}" oi" l‘I1i1]l}’ 2llI1iC:l]]('[?I‘ tlrttgs is lct1kt1|1c—
`Mid, 1111 ;il)n01‘tt1;tl fill] in tht-. 1ttttt1i)t‘t't)f|t:ttk0t:yltrs in i)]{)t)(i. l.t‘t1knt‘}-'tcs are in1pm‘t;1nt. in
`li‘t(‘ iI]'llIllll10i(Jgi{‘}li (.lt:ic1tst‘ oi‘ the body and ii‘ the lt'i:k(it:ytt- cminls I11]! I00 flu‘,
`il plarit-s
`the pal'it:11t at st:vt:rt: risk. Most (iiiltiflli i'm:us tlitti'cl'm‘c is on the lowest lt-ttkut:yt.t- t‘.m.tnt
`ni't.(-tr C]](:T1]](Jli1{‘?l“¢‘t}}y t'rc:1ttt1tr11l., httl the time cnttt'st* til" the iitll
`in ('.t)ltttl and rt-.ttu'n to
`hasclitttr is also i1ll])(‘J]‘l}l]1l.
`lltzspitc |):l(‘]il1lx('i
`|)eii1g_v_‘ eli:11iI1'.1tvtl
`l":'mt1 the hotly within
`
`
`
`SurvivingFraction
`
`0
`
`100
`
`300
`200
`Hours
`
`400
`
`500
`
`FIGURE 1-6. The fraction of leukocytes in blood [relative to baseline} with time in a patient receiv-
`ing a single intravenous dose of paciitaxel. Notice the sluggish return of the leukocyte count to the
`baseline value. The continuous line is the best line fit of a model of the production and destruction of
`leukocytes to the data, with paclitaxel inhibiting mature cell production. (From: Nlinaini H, Sasaki Y,
`Saijo N. et al. |ndirect—response model for the time course of leukopenia with anticancer drugs. Clin
`Pharmacol Ther 1998;64:5ll~52t.l
`
`This rrlateriaiwas copied
`
`Page 7
`
`Page 7
`
`

`
`u SECTION] I Basic Considerations
`
`l(ElIl(tJt?)"l(¥H in l)lt)t)(l is L'xll't‘]]l('l_\' slltggislt, tttkiiig
`2 (lE1)".‘i. lllt‘ <'lt;ttigct~' in the lrttctititi n|'
`()\-’('I' G \$-'L't_‘l»’. tn l'{.'ElI‘.'lI
`lllt‘ l<)wc.st ['<)UI1l and mil}-' rctu1't1i1I;.{ to the lJEl.‘-3["lil1L' V;-tlttc 3 W('.t'l<..*i
`illlcl‘(ling;1(lmini.~;I1'z1Iitm.
`l.ctIknc_\-'tcss in blood 1‘t:ilL-(‘I thv l):ll£l]1(‘.(‘ l)(.'l\\'(‘t'l] |)!'(){lllClll}Il
`tutti{It-strtttrtimi.'l"l1t-tlirt-('I inhibitor}-'trllkrtrt<)l'|J:1clit2tx(>li5ttpst'r<*:1IIim1 |)I'fJ§_{t‘I1ilt'.lI'tii{.fllS
`within the l)(JI!{.' trittrmw tlu.-i'cI)j.'
`rt-(ltt<‘.i|ig_»_' thu pl‘tJLlll('l.l-f'JI'1 til‘ ]'I}&llll1‘(’
`|t'ttk(:(‘yltr.~;.
`l*"c\«-'61‘
`lIIE1l1lI'(‘
`It-ttk0t‘_\'tu_~e I'<~.-ml into llit‘ V-'11St'1ll21I' pool so that ll1(F}')(){_)l3-3lZ{‘(lt?Clll1('H. hut a lung
`tint-1' i_~;iicv(lt-.-tl to [)]‘t)(l1l(‘t‘ 21stIl'ii('it'nt l1i.l]]Il)(‘I‘ t.~l'nI;tI.Ii1‘c lt'tIkt:-rylt--5 to ugttiit t'mIt>1‘v the
`ilt‘.-]'I]12ll hlnml ]Jt}{Jl.
`tl1t:_v Cxliihil (lil'itri‘trI1l cl-
`As I1l('l]1it’)IlL‘(l. an ia1I<ri‘(rsti1'1gl'k‘;1I.iIr(?<al'I11;1t1y(lt'tt§_;'sistlmt
`limqts with plttsiiitt C{J[1tI(?IIlI‘1I[l()lI. An ttiittslutl hut tclliltgt-xt1nIpl{* is St.'(-Ell with clniiiclinc.
`()1‘ig_=,'imi|l},- (lt.‘\'L‘ln]Ju‘.?{l as ;t
`I1£l5}\l tltrtttaltgtrstitiit. Wllt-Fl!
`t.'\.-'i1lII:1|t?(l [hr this iI‘i(ll(':lIl{lII.
`.~amm~
`s'tIl)_jcct.s' l)L.-(';11m' Iitint, l){.'('}lllH(?t)l'1l then ti1i(r.\’ptr(‘tt-‘(I lI}’l)(Jl{‘IlHl\’(‘ t.-ll":-.rt. 'I‘u(lz1y, the ther-
`:tp(-.-utic user 01' this tiring is H5‘ an tuttiltyp{'I‘teIisi\-*t‘.
`l'lt)W(‘\’{'l', f'tu'IlIci'
`lII\"{3Sl.ij_{21[it>II sltnwul
`that
`it wuss pm.-s.~'il)lc
`to [)I't){lllI‘..'t.‘ not only it
`|I_v|J(JIt*I1si\-'0 ttllctit
`l)lll also ll)-'])(.‘l‘It'I].*il{Jl].
`tlcptsntliiig on llltt plzvalmt cmt(.'t.-nlrtltitnt. (Iltmitlimt acts on two ('lilH.'il;.'.\i ul‘1't‘(‘tr])tm'. one
`t‘;u1.~:ii'tg‘:t lnwt.-riltg<>|'I)|t)0(l [)I'{.'hi_‘a'l1I'(‘ and the t)[l‘1t.'I‘ tut t.?l(‘\’Elll{Jll in Iilnml pI‘{-'.*iHll!‘L'. At low
`(‘()]It"L2l}II'Elll()lI.‘i 2l(.‘l'll('.\"(.‘lIl with IlIt?l'2l]J(TlIl'l(.‘ tlustrx,
`I'll-i.’ lowering c['['t'(‘t on l)lt)(){l p1'csas1ti't‘
`|JI't.'(lU]‘|1lll:lI()S. but at ltigh (.‘()I1(‘.(3IIll‘1l|ltnlfi,1lSIlIlg'l1[W('ll hr: zttrliit.-vutl (lltring't11i 0v(r1‘tlu.~st.'.
`the li}’pt:I‘tctisi\-'L: ellcct ]JI'I‘.P(lt)IIIl]Hll(.'.S, ztltlmtiglt this L-['l'c('t will .‘illl).*il(l{' and the ltypt}tcn—
`-‘Sh-’-1‘ t‘l'li%ttt will ttgttiit lilrtlcailiiitattt: as the systcttiit‘ (_TX}){}.‘§lll'C litlls. Fm‘ .‘1'()}l]|'.' olltcr cl:‘IIg.*a,
`sucli as W'21l'l}tl'lI‘I, the tmrtilizlllisiit oi" Eltilltlll is thv 9-ielllltf I'm" pmrlttttiiig‘ (lt..':~ill‘t:(l and '.1<.l\-'<.-|'_s'c
`t:l'l1'r_:I.s'. WztI'[':lt'it'1'.~' illlilflfit sitigttlztl‘ ;1(‘tim'1 is inttitrnngttltttimi, )»'r:1
`thi.~s c-rI'i'c(:t
`is tlvfinctl as
`IllI;.'I‘11]Jl..'llll(‘Wlltfll Il1{)(?()ll(i(FI'Ill'Elll{)!‘] is .~;iI(‘li as to llllllillli‘/_t‘ the risk nl‘<lc\'L:l<>pim:1it ol';m
`(’II1llt}liR]‘J'I and as 1l(l\-'(-'I‘.‘it' at ltighcr c0I'1t'(-:ntrzuiuits at which thv risk til‘ ll'Il["i'll2ll
`l]('I‘I‘1()[‘—
`rltztgo l;-r..-(mitt.-.~s high,
`‘cl:-4.‘it.)(‘.lEl|{;.'(l with excc-essivc ‘.1111l(?0Zlj_‘{lll&1[l()l1.
`'l‘]u--
`l('ES.‘i{llI
`is (‘l(_-:11‘,
`l_.l]'l(lt‘.I'_*iI2Hl(llllg Il]t.' .~sp{'t'iiic cmnrt.-i11mtit'm—t't::sp0i1st- time I‘t'l}lllUIISlll]J.*i ltclps in the man-
`ttgt-trlcitt and captimul tum: n|”{lt'ttg.~;_
`
`VARIABHJ TY IN DRUG RESPONSE
`
`Ilwtr Wt'i‘{F all alike, tlicrv wuultl only l)-': mu: (lost? stmitgtli ancl 1't;'.g‘itt1v1i Ulél(ll'l1gI]t.'(P(l(:(l
`I'm‘ the {'llIiI‘{.' pntit-mt [)lJ[)ul‘.t.[lt)]l. But w F art‘ not ztlikc: iI1(.lt:(:tl, we often t.?.\’lIll)ll g_=;1'c:It in-
`t(:t'imli\-'i(ltt;il
`'2lI'i2tl}llll}-' in r<:spun.s'(r In Llrttgs. This is gt-tit-1':-ill)-' not so importtmt fut’ (lt'1tg‘s
`with \\-'l(l(’ Il]I‘..'I‘}l]Jt2HIi(‘ witttlows, l}(‘{‘.ill.l.‘il.‘ pnlicitts (inn [tJl(:l‘Ell.{T 21 \\-'l(lt.‘ raulgv t1l‘('x]')t>stI1‘c.~»'
`li.'.>rsi111il:tt'(ltrgi'(rt'snl‘|)t't'1L'lit.,]'):u'ti(rul211‘l)-'when thtr dose t-'tt1pl()yt'(l (.‘I3h'1ll‘(?.*i that tlw m;Ix~
`imilm lJ(‘ll(?li('ldl L-ilt-(‘I
`is trxpt.-|'ic.-n(‘c(l by trsstttltiztlly all pattitrllts, in whith tt‘;:.~.-ct El
`.~eit1glt=.
`(lnsv ol'cli't|g, Illt.‘ "cutc—(lnst-—lii:'-till" l(l(.'£i.
`.~;ui'li('tr.~:. i'\|tlm1tg|1 soiitv patit-ms inn)-‘ still not
`Ivspntttl In tltwttp}-' l)('(‘}lllSL' they l;1r_‘.l< the pttttllivc1't:t‘(*ptuI'0t1 Wlll(.'ll [l1{T(lI'Ilg'cl(‘|.‘i. :1 I‘1lI‘t?
`in(li\-'itluul I}l2l‘\_-' (r.\'pt'I‘it.-Ian‘ :1 ll}-‘pt.-i‘.~scii.~;itivil}-' t‘t:;tct'i<_m, sttclt as an acttt r }illt..'l"E_l"l{' t'|.)i:m(lc.
`(Ilv;n'|_\*. the (l1'tt;.>; is (‘UHlt':ll]l(li(EllL'(l in the last. two tylies til" patient. 'l‘ht- pmhlcnt nl'\-'zu'i—
`nhilil}-'
`l‘.-{'(‘tJII1{.'.‘4 1Jm‘Iit'ttl;1:'l}= 21{'l£I.(: I'm‘ (lt'tIg5 with an llIl{FI‘l‘t1{?(ll'rll{' or n:1I'I‘m.\-' {llt'l';1])(.’tlll{.‘
`\\'ilI(,lt>\\', nl'wlIit'|i !ll('l't'£1l‘(‘IlI}'tIl}-’, l11(‘ll1(llI]j_§ thc iII1nilIIlt)Sll[)p]‘()SSl\"{? ;tg'L'riI L‘)-'(‘lcJspt;I'iI1t',
`l1.\'t‘(l
`In })l'(‘\'{-‘Ill
`(Ji‘g‘;ti1 ngjtrtttinit
`l'tJl|0i\-'iiig_{ II‘21]I.*ipli1]‘I[Elliot], and the niititrpilcptic‘ drug,
`pl!(’II}"[()l]I (Fig. I-7), in 11(l(llllt)I] In the trxuinplcs til" inurphinc a11t(l(lig(:xiI1 rm-ntimn-(1
`|Ji'L-\'it)tIs'ly. Fm‘ [llt.'S('
`t|I‘ttg.~;, the stiltttimi is the 1l\"i1ll2.ll}illl.)' 01' tin ;11'i".ty (Jl rlcmr .~att't.-.ti;_=,'Ilis,
`with Iitrttlinn ul'v;t(‘l: I}dll(,’i]I tn the l‘Cql1iI'(.‘fl rlusttgtr.
`\-";t|'i;thiliI}-' in tht- |'{'Hl}i‘]11St.‘ ttrizciitg [')21ll('.[]l'.'-; In pltmiytoin and tnztng.-' ntlwr (l1'ttgs is pri-
`mtn'i|}-' ]Jli;1rn1;1t‘oki1i(tIic in tirigin. In <itl1c1't'.a.~;L-.5, pli;ti'tt121t:raLl}-'1mIItics is tht: lIIitj(Jl' c;11t.~;t-
`r1l'\'2t:'i;1l)ility in I'('.*i]Jt)Ii_*x'-1?. as shown, li1:‘L'..\';1Iii])lt.', in I’ig. 1-8 by the with.‘ nutgo in pl:1sm2I
`cr.~1tccntrzttimi.w nltltc oral éttitittciztgttlttttt \\-':lI‘l}lI‘iI1 l1{3t'::(l{‘(l to IllEllI‘tl.dlI1 :1silllil21I'(lL‘gl'{‘t?()l'
`EIll[l(‘()i1glll£IlitJl1 in p:1Iit'I1t.~.'.
`l‘('..*ip()ll.‘i(? are mtuliloltl and in(‘|u(lt: tho pz1titr11t'.~i tlgtr,
`'l'llt.- ('1tllS(‘:~i ul'\-'2li'i;1hiliIy in (l0.*;<'
`\\"(?lf_{l1l, (l('§_{I'{T[' til" t)l)('.‘ill}’,
`t,\_-‘pr zlllfl r|c;_;'1‘t't- oi":-it-.\-'cI‘ity ul'(li.~itrtt!sc, tJIll(?l‘(ll‘llg'S(1t)ll{?llI'|'{‘]lIl}v'
`;ttlIIIi1Ii.~tI(:1't.'tl.gtntl{'1t\-'imI1mcIIl;tl llt('tt:t's. .'-\n0Il1(?t' im]mt'I;uIt and p(:n';i_-;i\-'L- ¢JlIt'.'.‘ is }.;'{?1It:ti(‘.s'.
`This materialwascuied
`Page 8
`
`Page 8
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`

`
`CHAPTER} I Therapeutic Relevance E
`
`average
`FIGURE 1-?. Although the
`plasma concentration of phenvtoin on
`chronic dosing tends to increase with
`the dosing rate, there is large variation in
`the individual values.
`lFrom: Lund, L.
`Effects of phenvtoin in patients with
`epilepsy in relation to its concentration
`in plasma. in Davies DS, Prichard BNC.
`eds. Biological Elfects
`of Drugs
`in
`Relation to Their Plasma Eioncentration.
`London and Basingstoke: Macmillan,
`1973:22?—238.i
`
`-h0
`
`
`
`PlasmaPhenytoin
`
`
`
`Concentration[mgi'L)
`
`5
`
`10
`
`Daily Dose (mglkg) an
`
`'l‘hi.s was known 1'01‘ mutt)-' yt*;trs_ in that W]I(‘ll t'\';1lu:tlt-(.1, IIICII‘ \\."{‘1'{‘ uni}-' tninm‘ tlif'l'k-:1‘t‘t1('cés
`in |i'I(‘. ]_)It:t1'Itt;1cnkiItctics and I‘cspmt.<sc to (iI't1;;‘.s i)t?l\\-’('(".ll
`i(i{‘]lli(‘.:li
`twins t-\-mt wltcn they
`|i\-'t-(1ztpat‘1';uul iudil'l'trI‘t:nt social t:u\-'iI'mtmt-nl.~‘.. cr.>|ttpm‘v(i with the when <-rxpt.-i'itrtt('c(l Wi(i(.'
`(lif'l'm't.-i1t:e.s in rt.-.~a|m:i.w within li1('. [)d1'it‘ltl [J()|)lli21li()I1. 'l‘|tt.- iIttpm'I:m¢‘c t>l'g‘mtt.-li('s \-vus also
`i(l'I()\\-‘ll limit liuttilinl .'-+l.11(ii{‘S and .‘-3llI{ii(‘S in tlilfi.-rvitt t-t|mit' 5_=,':'ut|ps. ()Il('. t.-xnutpltr, :-u'ir-;in§_{
`tl1tt‘i|tg Wm‘ltl War II, whiclt ()(I{‘.1ll'l‘(.'(i wht-.n lltc liglttittg H|}I‘t_‘2l(i to 1‘l‘U}}i{‘.E1i
`I‘c;_>_'it>m WiH.'I‘('
`m:1I;tI‘i;1 was riltr, wets the <>l)sct‘\':1tim1 t