ANI MAL I NF E CT I ON MODE L S Ide ntifying the Phar mac - PowerPoint PPT Presentation

ANI MAL I NF E CT I ON MODE L S Ide ntifying the Phar mac o lo gic De te r minants o f E ffic ac y Sujata M. Bhavnani, Phar m.D., M.S. E xe c utive Vic e -Pre side nt, I nstitute fo r Clinic a l Pha rma c o dyna mic s

L I NK I NG DRUG E XPOSURE T O E F F E CT Why Do It? — T o Make and Co nfir m Pr e dic tio ns 2

ANI MAL I NF E CT I ON MODE L S Pr inc iple s Dr . Cr aig T aught Us • Do se fra c tio na tio n • T he impa c t o f diffe re nt va ria b le s o n e xpo sure re q uire me nts fo r e ffic a c y o Pro te in b inding o I nfe c ting b a c te ria l pa tho g e n o Re sista nc e de te rmina nts 3

DOSE F RACT I ONAT I ON A T o o l that L e d to Appr o pr iate Do sing Re gime ns • Do se -fra c tio na tio n studie s lite r e vo lutio nize d o ur ally r unde rsta nding o f a ntib a c te ria l pha rma c o lo g y Cra ig WA. I nte rre la tio nship b e twe e n pha rma c o kine tic s a nd pha rma c o dyna mic s in de te rmining do sing re g ime ns fo r b ro a d spe c trum 4 c e pha lo spo rins. Dia g n Mic ro I nfe c t Dis 1995;22:89-96.

DOSE F RACT I ONAT I ON Do e s It Wo r k? • Ye s! We ll, the ma jo rity o f time , a nywa y • Do se fra c tio na tio n is a n e le g a nt de sig n whic h de c o uple s the a uto c o rre la tio n b e twe e n e xpo sure me a sure s se e n in a simple do se -ra ng ing study • I t is c ritic a l to unde rsta nd tha t the do se -fr ac tio natio n study de sig n pro vide s info rma tio n o n mainte nanc e r e gime n pe r fo r manc e • I t do e s no t pro vide info rma tio n o n: o T he impa c t o f lo ading do se s, o T he o ptimal le ngth o f the r apy, o r o Re sistanc e e me r ge nc e 5

DOSE F RACT I ONAT I ON Ho w Do We Kno w It Do e sn’t Always Wo r k? • F o r a zithro myc in, AUC:MIC r atio is the PK -PD me a sure mo st a sso c ia te d with b a c te ria l killing in vivo • Ye t the same AUC de live re d thr e nt ways de mo nstra te d e e diffe r e nt b a c te ria l killing dr astic ally diffe r Okusa nya OO e t a l. Pha rma c o kine tic s a nd pha rma c o dyna mic s o f a zithro myc in in g e rb ils with Hae mo philus influe nzae middle e a r infe c tio n. Pre se nte d a t 106th Ame ric a n So c ie ty fo r Clinic a l Pha rma c o lo g y a nd T he ra pe utic s, 2005. 6

ORI T AVANCI N PK-PD Basis o f Single -Do se T he r apy • F o r o rita va nc in, fro nt lo a ding the e xpo sure a llo ws e ffe c tive e xposur e s to b e a c hie ve d o n Da y 1 Bo x plo ts re pre se nt the me dia n a nd inte rq ua rtile ra ng e fo r da ily a ve ra g e to ta l-drug AUC:MIC ra tio s b a se d o n simula tio ns o f 2,000 pa tie nts. T he a sso c ia te d whiske rs re pre se nt the 5 th a nd 95 th pe rc e ntile fo r the da ily a ve ra g e to ta l-drug AUC:MIC ra tio s. T he ho rizo nta l so lid a nd da she d line s re pre se nt the a ve ra g e to ta l-drug AUC:MIC ta rg e ts o f 1078 a nd 1204 a sso c ia te d with ne t b a c te ria l sta sis a nd a 1 lo g 10 CF U de c line , re spe c tive ly, b a se d o n da ta fro m a murine thig h-infe c tio n mo de l fo r S. aure us 7 a fte r 48 hrs o f study [Okusa nya OO, e t a l., ICAAC 2009. Ab stra c t A1-1287]. Da ta o n F ile , T he Me dic ine s Co mpa ny.

ORI T AVANCI N PK-PD-Base d Dr ug De ve lo pme nt De c isio ns Asse ssme nt of simulate d mur ine and human or itavanc in E L F c onc e ntr ation- time pr ofile s ove r 120 h for S. aur e us pne umonia • E ffic a c io us e xpo sure s b a se d o n a S. aure us ne utro pe nic lung infe c tio n mo de l we re a c hie ve d in mic e a nd huma ns a t 24 a nd 96 ho urs, re spe c tive ly • T o o ve rc o me diffe re nc e s in ra te c o nsta nts to a nd fro m E L F a nd pla sma c o mpa rtme nts b e twe e n huma ns a nd mic e , a fro nt-lo a de d do sing re g ime n in huma ns wo uld b e ne e de d Ho we ve r, a ve ry la rg e lo a ding do se wo uld b e o ne e de d in pa tie nts with pne umo nia to ma tc h the e a rly a nd e ffe c tive e xpo sure s a c hie ve d in a nima ls • T he se da ta we re c ritic a l to ha lting the pro g ra m fo r o rita va nc in tre a tme nt o f S. aure us pne umo nia Bha vna ni SM e t a l. Use o f PK -PD princ iple s to g uide c linic a l drug de ve lo pme nt fo r o rita va nc in. I n: Pro g ra m a nd a b stra c ts o f the 48th I nte rsc ie nc e Co nfe re nc e o n Antimic ro b ia l Ag e nts a nd Che mo the ra py (Wa shing to n, DC). 2008. Ab stra c t A-51. Amb ro se PG e t al . Pha rma c o kine tic -pha rma c o dyna mic c o nside ra tio ns in the de sig n o f ho spita l-a c q uire d o r ve ntila to r- 8 a sso c ia te d b a c te ria l pne umo nia studie s: L o o k b e fo re yo u le a p! Antimic ro b Ag e nts Che mo the r 2010; 51:S103-S110.

DOSE F RACT I ONAT I ON Whe n Do We Ne e d to Kno w Mo r e ? • T he q ue stio n fo r the drug de ve lo pme nt sc ie ntist is: Whe n do we ne e d to kno w mo re than a do se - frac tio natio n study de sig n pro vide s? o Whe n the drug is fro m a c la ss fo r whic h the re a re no we ll-c ha ra c te rize d prio rs o Whe n a drug displa ys ma rke d a c c umula tio n in huma ns  Ma y b e e spe c ia lly impo rta nt fo r a drug with a c o nc e ntra tio n-de pe nde nt pa tte rn o f b a c te ric ida l a c tivity o ve r a wide -ra ng e o f c o nc e ntra tio ns 9

PROT E I N BI NDI NG Do e s It Alte r the E xpo sur e Ne e de d fo r E ffic ac y? No , if the PK-PD inde x is e xpr e sse d in the fr e e -do main. A fe w e xc e ptio ns do o c c ur . Ande s DR a nd Cra ig WA. 40th a nd 41st I CAAC, 2000 a nd 2001.

PROT E I N BI NDI NG Do e s It Alte r the E xpo sur e Ne e de d fo r E ffic ac y? No , if the PK-PD inde x is e xpr e sse d in the fr e e -do main. A fe w e xc e ptio ns do o c c ur . Cra ig WA. Ba sic pha rma c o dyna mic s o f a ntib a c te ria ls with c linic a l a pplic a tio ns to the use o f β -la c ta ms, g lyc o pe ptide s a nd line zo lid. I nfe c t Dis Clin N Am 2003;17:479-502.

PK -PD T ARGE T Do e s It Var y by Patho ge n? Ye s, ge ne r ally Gr am-ne gative bac illi r e quir e gr e ate r e xpo sur e c o mpar e d with Gr am-po sitive o r ganisms Class Or ganism % T ime >MIC Stasis Maximum Kill Pe nic illins Gra m-ne g a tive 30-40 60-70 Pne umo c o c c i 25-35 35-50 Sta phylo c o c c i 20-30 40-50 Ce pha lo spo rins Gra m-ne g a tive 40-50 70-80 Pne umo c o c c i 35-40 40-50 Sta phylo c o c c i 20-30 40-50 Ca rb a pe ne ms Gra m-ne g a tive 20-30 40-50 Pne umo c o c c i 15-25 30-45 Sta phylo c o c c i 10-20 25-40 12 Da ta c o urte sy o f Dr. Willia m A. Cra ig .

RE SI ST ANCE Do e s It Alte r the E xpo sur e Ne e de d fo r E ffic ac y? No . It is no t the pr e se nc e o r abse nc e o f par tic ular r e sistanc e de te r minants that pr e dic t o utc o me but r athe r , the dr ug e xpo sur e inde xe d to MIC 13 Cra ig WA a nd Ande s DR. T re a tme nt o f infe c tio ns with E SBL -pro duc ing o rg a nisms: pha rma c o kine tic -pha rma c o dyna mic c o nside ra tio ns. Clin Mic ro b io l I nfe c t 2005;11:10-17.

MAK I NG AND CONF RI MI NG PRE DI CT I ONS Sho w Me the Mo ne y! 14

PK -PD I N MAN Analyse s o f Clinic al Data T he numbe r of dr ug c lasse s and indic ations studie d to date c ontinue s to gr ow, pr oviding the oppor tunity to impr ove our knowle dge about tr anslating fr om animal infe c tion mode ls Amino g lyc o side Ba c te re mia β -L a c ta ms Co mmunity-Ac q uire d Re spira to ry T ra c t Infe c tio ns F luo ro q uino lo ne s Glyc o pe ptide s E ndo c a rditis K e to lide s Intra -Ab do mina l Infe c tio ns L ipo g lyc o pe ptide s No so c o mia l Pne umo nia L ipo pe ptide s Skin a nd Skin Struc ture Infe c tio n Ma c ro lide s T B Me ning itis Oxa zo lidino ne s T ypho id F e ve r Ple uro mutilins Urina ry T ra c t Infe c tio ns T e tra c yc line s 15

E XPOSURE -RE SPONSE I N VI VO T ige c yc line Against E nte r o bac te r iac e ae Data for 3 E nte r obac te r iac e ae isolate s studie d in a ne utr ope nic ine - thigh infe c tion mode l a mur AUC:MIC r atio tar ge ts 3 R2=86% Ba c te ria l e ffic ac y for Change in Log 10 CFU/Thigh 2 re duc tion e ndpoint 1 re e - drug b T ota l- drug F 0 Ne t b a c te ria l 20.2 2.63 -1 sta sis -2 1-lo g 10 CF U 43.9 5.71 re duc tio n -3 2-lo g 10 CF U -4 626 81.4 2 5 10 20 50 100 200 500 1000 2000 re duc tio n 24 Hr AUC/MIC a . va n Og tro p ML e t al . I n vivo pha rma c o dyna mic a c tivitie s o f two g lyc ylc yc line s (GAR-936 a nd WAY 152,288) a g a inst va rio us Gra m- po sitive a nd Gra m-ne g a tive b a c te ria . Antimic ro b Ag e nts Che mo the r 2000; 44:943-949. b . Cra ndo n JL e t al . Pha rma c o dyna mic s o f tig e c yc line a g a inst phe no typic a lly dive rse Staphylo c o c c us aure us iso la te s in a murine 16 thig h mo de l. Antimic ro b Ag e nts Che mo the r 2009; 53:1165-1169.