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

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

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

L I NK I NG DRUG E XPOSURE T O E F F E CT

Why Do It? — T

• 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

• Pro te in b inding
• I

nfe c ting b a c te ria l pa tho g e n

• Re sista nc e de te rmina nts

3

DOSE F RACT I ONAT I ON

A T

• o l that L

e d to Appr

• pr

iate Do sing Re gime ns

• Do se -fra c tio na tio n studie s lite r

ally r e vo lutio nize d o ur

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 c e pha lo spo rins. Dia g n Mic ro I nfe c t Dis 1995;22:89-96.

4

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:

• T

he impa c t o f lo ading do se s,

• T

he o ptimal le ngth o f the r

apy, o r

• 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?

Okusa nya OO e t al. 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.

• F
• 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 e diffe r e nt ways de mo nstra te d dr astic ally diffe r e nt b a c te ria l killing

6

7

ORI T AVANCI N

PK-PD Basis o f Single -Do se T he r apy

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 5th a nd 95th 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 a fte r 48 hrs o f study [Okusa nya OO, e t al., ICAAC 2009. Ab stra c t A1-1287]. Da ta o n F ile , T he Me dic ine s Co mpa ny.

• F
• 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

8

ORI T AVANCI N

PK-PD-Base d Dr ug De ve lo pme nt De c isio ns

Bha vna ni SM e t al. 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- a sso c ia te d b a c te ria l pne umo nia studie s: L

• 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.

Asse ssme nt of simulate d mur ine and human or itavanc in E L F c onc e ntr ation- time pr

• file 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 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

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

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?

• 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

• 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

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.

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 .

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?

Da ta c o urte sy o f Dr. Willia m A. Cra ig .

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

PK

• PD T

ARGE T

Do e s It Var y by Patho ge n?

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

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?

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.

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

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

• f dr

ug c lasse s and indic ations studie d to date c ontinue s to gr

• w, pr
• viding the oppor

tunity to impr

• ve our

knowle dge about tr anslating fr

• m 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

• bac te r

iac e ae

24 Hr AUC/MIC

2 5 10 20 50 100 200 500 1000 2000

Change in Log10 CFU/Thigh

• 4
• 3
• 2
• 1

1 2 3

R2=86% Ba c te ria l re duc tion e ndpoint

AUC:MIC r atio tar ge ts for e ffic ac y

T

• ta l- drug

F re e - drug b

Ne t b a c te ria l sta sis 20.2 2.63 1-lo g 10 CF U re duc tio n 43.9 5.71 2-lo g 10 CF U re duc tio n 626 81.4

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 thig h mo de l. Antimic ro b Ag e nts Che mo the r 2009; 53:1165-1169.

Data for 3 E nte r

• bac te r

iac e ae isolate s studie d in a ne utr

• pe nic

mur ine - thigh infe c tion mode la

16

CL I NI CAL E XPOSURE

• RE

SPONSE

T ige c yc line -T r e ate d Patie nts with c IAI

Bha vna ni SM e t al. I mpa c t o f diffe re nt fa c to rs o n the pro b a b ility o f c linic a l re spo nse in tig e c yc line -tre a te d pa tie nts with intra -a b do mina l infe c tio ns. Antimic ro b Ag e nts Che mo the r 2010; 54:1207-1212.

Pe rc e nta g e s of Suc c e ssful Clinic a l Re sponse in T ig e c yc line - T re a te d Pa tie nts with c IAI by T

• ta l- Drug AUC:MIC Ra tio T

hre shold

10 20 30 40 50 60 70 80 90 100 <3.1 ≥3.1 50.0 88.9 AUC:MI C ra tio Pe rc e nt c linic a l suc c e ss 10 20 30 40 50 60 70 80 90 100 <13 ≥13 75.0 92.3 AUC:MI C ra tio Pe rc e nt c linic a l suc c e ss

All e valuable patie nts (n=123) Patie nts with E nte robac te ria c e a e at base line (n=97)

17

CL I NI CAL AND NON-CL I NI CAL DAT A

T r anslating fr

• m Mic e to Me n

Compar ison of T ige c yc line AUC:MIC r atio T ar ge ts for E nte r

• bac te r

iac e ae E ffic ac y

Ba c te ria l re duc tion e ndpoint Non- c linic a l da ta from a murine - thig h infe c tion mode la Clinic a l da ta from pa tie nts with c IAI a nd E nte roba c te ria c e a e a t ba se line b T

• ta l- drug

F re e - drug c T

• ta l- drug

F re e - drug d

Ne t b a c te ria l sta sis 20.2 2.63 13 2.6 1-lo g 10 CF U re duc tio n 43.9 5.71 2-lo g 10 CF U re duc tio n 626 81.4

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 . Bha vna ni SM e t al. I mpa c t o f diffe re nt fa c to rs o n the pro b a b ility o f c linic a l re spo nse in tig e c yc line -tre a te d pa tie nts with intra - a b do mina l infe c tio ns. Antimic ro b Ag e nts Che mo the r 2010; 54:1207-1212. c . 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 thig h mo de l. Antimic ro b Ag e nts Che mo the r 2009;53:1165-1169. d. T yg a c il pa c ka g e inse rt. Wye th Pha rma c e utic a ls, I nc . Phila de lphia , PA. De c e mb e r 2014.

18

CL I NI CAL E XPOSURE

• RE

SPONSE

T ige c yc line -T r e ate d Patie nts with c IAI

Bha vna ni SM e t al. I mpa c t o f diffe re nt fa c to rs o n the pro b a b ility o f c linic a l re spo nse in tig e c yc line -tre a te d pa tie nts with intra - a b do mina l infe c tio ns. Antimic ro b Ag e nts Che mo the r 2010; 54:1207-1212.

F ina l Multiva ria ble L

• g istic Re g re ssion Mode l for F

a c tors Pre dic tive of Clinic a l Suc c e ss

Inde pe nde nt var iable E stimate Odds r atio (95% CI) P- value

I nte rc e pt

• 9.831

< 0.001 We ig ht <94 kg a 1.849 6.35 (1.25, 32.4) 0.026 Ab se nc e o f P. ae rug ino sa in b a se line c ulture sb 2.317 10.1 (1.43, 72.0) 0.021 APACHE I I sc o re <13c 2.390 10.9 (1.28, 93.3) 0.029 Ra c e = no n-Hispa nic d 2.503 12.2 (2.12, 70.6) 0.005 Dia g no sis = c o mplic a te d a ppe ndic itis o r c ho le c ystitise 2.545 12.7 (2.27, 71.5) 0.004 AUC:MI C ra tio ≥3.1f 3.497 33.0 (3.27, 333) 0.003

a . Reference group included patients weighing ≥94 kg (n=19). b . Re fe re nc e g ro up inc lude d pa tie nts with P. ae rug ino sa in b a se line c ulture s (n=10). c . Reference group included patients with APACHE II scores ≥13 (n=6). d. Re fe re nc e g ro up inc lude d pa tie nts who a re o f Hispa nic ra c e (n=25). e . Re fe re nc e g ro up inc lude d dia g no se s o f pe rito nitis due to pe rfo ra tio n o f sma ll/ la rg e inte stine , intra -a b do mina l he pa tic , o r sple nic a b sc e ss,

• r o the r (n=37).

f. Re fe re nc e g ro up inc lude d pa tie nts with AUC:MI C ra tio <3.1 (n=6).

19

CL I NI CAL E XPOSURE

• RE

SPONSE

T ige c yc line -T r e ate d Patie nts with c IAI

Bha vna ni SM e t al. I mpa c t o f diffe re nt fa c to rs o n the pro b a b ility o f c linic a l re spo nse in tig e c yc line -tre a te d pa tie nts with intra -a b do mina l infe c tio ns. Antimic ro b Ag e nts Che mo the r 2010; 54:1207-1212.

Proba bility of Clinic a l Suc c e ss in the Pre se nc e of One Unfa vora ble F a c tor

F a c tor

a

Pr

• ba bility

We ig ht ≥94 kg 0.968 Pre se nc e o f P. ae rug ino sa in b a se line c ulture s 0.950 APACHE I I sc o re ≥13 0.947 Ra c e = Hispa nic 0.941 Dia g no sis = a b sc e ss, pe rito nitis d ue to pe rfo ra tio n o r o the r 0.938 AUC:MIC ra tio <3.1 0.855

a . Re ma ining fa c to rs we re se t to the c o nditio n fa vo ring c linic a l re spo nse . T he fo llo wing c o nditio ns re pre se nte d the mo st fa vo ra b le fo r o ptimizing c linic a l re spo nse : we ig ht <94 kg , a b se nc e o f P. ae rug ino sa in b a se line c ulture s, APACHE I I sc o re <13, ra c e = no n- Hispa nic , dia g no sis = c o mplic a te d a ppe ndic itis o r c ho le c ystitis, a nd AUC:MI C ra tio ≥3.1.

20

CL I NI CAL E XPOSURE

• RE

SPONSE

T ige c yc line -T r e ate d Patie nts with c IAI

Bha vna ni SM e t al. I mpa c t o f diffe re nt fa c to rs o n the pro b a b ility o f c linic a l re spo nse in tig e c yc line -tre a te d pa tie nts with intra -a b do mina l infe c tio ns. Antimic ro b Ag e nts Che mo the r 2010; 54:1207-1212.

Proba bility of Clinic a l Suc c e ss in the Pre se nc e of T wo Unfa vora ble F a c torsa

F ac tor

• ne

F ac tor two b Pr

• bability

We ig ht ≥94 kg Pre se nc e o f P. ae rug ino sa in b a se line c ulture s 0.751 APACHE I I score ≥13 0.737 Ra c e = Hispa nic 0.714 Dia g no sis = pe rfo ra tio n 0.706 AUC:MI C ra tio <3.1 0.481 Pre se nc e o f P. ae rug ino sa in b a se line c ulture s APACHE I I score ≥13 0.637 Ra c e = Hispa nic 0.610 Dia g no sis = pe rfo ra tio n 0.600 AUC:MI C ra tio <3.1 0.367 APACHE I I score ≥13 Ra c e = Hispa nic 0.593 Dia g no sis = pe rfo ra tio n 0.583 AUC:MI C ra tio <3.1 0.350 Ra c e = Hispa nic Dia g no sis = pe rfo ra tio n 0.555 AUC:MI C ra tio <3.1 0.324 Dia g no sis = a b sc e ss o r pe rito nitis due to pe rfo ra tio n AUC:MI C ra tio <3.1 0.316

a . E a c h pa ir o f unfa vo ra b le fa c to rs is sho wn o nly o nc e . b . Re ma ining fa c to rs we re se t to the c o nditio n fa vo ring c linic a l re spo nse . T he fo llo wing c o nditio ns re pre se nte d the mo st fa vo ra b le fo r

• ptimizing c linic a l re spo nse : we ig ht <94 kg , a b se nc e o f P. ae rug ino sa in b a se line c ulture s, APACHE

I I sc o re <13, ra c e = no n-Hispa nic , dia g no sis = c o mplic a te d a ppe ndic itis o r c ho le c ystitis, a nd AUC:MI C ra tio ≥3.1.

21

NE W DE VE L OPME NT PAT HWAYS

Inc r e asing We ight o f PK-PD Data

• PK
• PD b a se d no n-c linic a l da ta he lps de -risk drug

de ve lo pme nt a nd stre ng the ns NDA sub missio ns

• Gre a te r we ig ht is put o n suc h da ta fo r drug s fo r

unme t me dic a l ne e d a nd fo r whic h re c ruitme nt o f la rg e numb e rs o f pa tie nts is c ha lle ng ing

• Give n the impo rta nc e o f suc h da ta , it is c ritic a l to
• ptimize study de sig n a nd a na lysis o f da ta fro m

a nima l infe c tio n mo de ls

22

DE SI GN AND ANAL YSI S CONSI DE RAT I ONS

So me Co mmo n Pr

• ble ms
• Misma tc h b e twe e n a nima l infe c tio n mo de l use d

a nd indic a tio n o f inte re st

• Po o rly c ha ra c te rize d a nima l PK

a nd limite d ra ng e o f studie d do se s

• L

a c k o f e ffe c t site PK

• I

na de q ua te g ro wth c o ntro l

• Size o f b a se line ino c ulum
• Misspe c ific a tio n o f o utlie rs

23

DE SI GN AND ANAL YSI S CONSI DE RAT I ONS

Po o r ly Char ac te r ize d Phar mac o kine tic s

• GSK

2140944 do se s o f 1.56 to 400 mg / kg q 6h we re e va lua te d

Wo nhe e S e t al. Antimic ro b Ag e nts Che mo the r 2015; 59:4956-4961.

Phar mac okine tic Studie s In vivo e ffic ac y in a ne utr

• pe nic

lung infe c tion mode l

• Sing le GSK

2140944 do se o f 6.25 to 200 mg / kg we re studie d

• 8 b lo o d sa mple s we re c o lle c te d
• ve r 4-6 ho urs; 3 BAL

sa mple s we re c o lle c te d o ve r 3-4 ho urs

24

DE SI GN AND ANAL YSI S CONSI DE RAT I ONS

Po o r ly Char ac te r ize d Phar mac o kine tic s

Wo nhe e S e t al. Antimic ro b Ag e nts Che mo the r 2015; 59:4956-4961.

Phar mac okine tic Studie s

• PK

pro file s a fte r 3 ho urs sug g e st the pre se nc e o f a 2nd c o mpa rtme nt

• Ne e de d lo ng e r PK

sa mpling pe rio d fo r the hig he r do se s to c o nfirm

• Hig he st do se studie d fo r e ffic a c y

wa s 400 mg / kg q 6h; PK wa s o nly studie d up to 200 mg / kg

• By a ssuming line a rity b e yo nd the do se

ra ng e studie d, the re is a risk o f c a lc ula ting b o th %T ime >MI C a nd AUC with e rro r

• I

f pla sma PK a re po o rly e stima te d, this a ffe c ts E L F PK a nd pla sma a nd E L F PK

• PD
• Ca n this b e fixe d with mo de ling ?

Study De sign Implic ations

25

DE SI GN AND ANAL YSI S CONSI DE RAT I ONS

Optimizing De sign and Analysis

L

• uie A e t al. Co mb ina tio n tre a tme nt with me ro pe ne m plus le vo flo xa c in is syne rg istic a g a inst Pse udo mo no as ae rug ino sa infe c tio n in a murine

mo de l o f pne umo nia . J I nfe c t Dis 2015; 211: 1326-33.

Phar mac okine tic Studie s

• Me ro pe ne m do se ra ng e : 50 to 400

mg / kg

• Pla sma a nd E

L F da ta we re o b ta ine d a t the sa me time po ints o ve r 6 ho urs

• PK

da ta we re c o -mo de le d

• A line a r thre e -c o mpa rtme nta l mo de l

b e st de sc rib e d the murine PK da ta

In Vivo E ffic ac y Studie s

• Hig he st me ro pe ne m do se studie d fo r

e ffic a c y in a ne utro pe nic murine Pse udo mo na s pne umo nia mo de l wa s 50 mg / kg q 4h

26

DE SI GN AND ANAL YSI S CONSI DE RAT I ONS

Diagno sing Une xpe c te d F indings

Ma c Va ne SH e t al. Antimic ro b Ag e nts Che mo the r 2014;58:6913-6919.

• I

nve rte d U sha pe func tio n b e twe e n MI C a nd c ha ng e in lo g 10 CF U

• Que stio n: Wha t do e s the b y-

iso la te g ro wth c o ntro l da ta sho w?

• A la c k o f g ro wth in the 2- a nd 24-

ho ur g ro wth c o ntro ls c a n le a d to

• ve re stima tio n o f the e ffic a c y o f

the drug

• Do e s this e xpla in why c e fta zidime

sho we d e ffic a c y a t MI C = 64 µg / mL (%T ime >MI C = 0)?

• Are ve ry hig h do se s o f a vib a c ta m

PK c o ntrib uting une xpe c te d kill?

• PK

no t a va ila b le b ut unlike ly

Study F indings

27

DE SI GN AND ANAL YSI S CONSI DE RAT I ONS

Diagno sing Une xpe c te d F indings

Cra ig WA. Pha rma c o dyna mic s o f a ntimic ro b ia ls: Ge ne ra l c o nc e pts a nd a pplic a tio ns. I n: Antimic ro b ia l Pha rma c o dyna mic s in T he o ry a nd Clinic a l Pra c tic e . C.H. Nig hting a le , T . Mura ka wa , P.G. Amb ro se E

• ds. Ma rc e l De kke r, I

nc . NY, NY.

• T

his is the re la tio nship b e twe e n c e fta zidime %T >MI C a nd c ha ng e in lo g 10CF U tha t Dr. Cra ig sho we d us ma ny ye a rs a g o

• I

f we ha ve studie d a g ive n

β-la c ta ma se inhib ito r

pro pe rly, this re la tio nship sho uld b e re plic a te d using a β-la c ta ma se -pro duc ing iso la te

Ce fta zidime % T ime >MI C L

• g 10 CF

U/ T hig h a t 24 Hrs

28

DE SI GN AND ANAL YSI S CONSI DE RAT I ONS

Diagno sing Une xpe c te d F indings

• 3.5
• 3
• 2.5
• 2
• 1.5
• 1
• 0.5

0.5 20 40 60 80 100

Change in L

• g 10 CF

U/ mL fr

• m 0 hour

Contr

• ls

F r e e - Dr ug % T >Ce ftazidime - Avibac tam MIC

Sta sis

Cra ig WA. Pha rma c o dyna mic s o f a ntimic ro b ia ls: Ge ne ra l c o nc e pts a nd a pplic a tio ns. I n: Antimic ro b ia l Pha rma c o dyna mic s in T he o ry a nd Clinic a l Pra c tic e . C.H. Nig hting a le , T . Mura ka wa , P.G. Amb ro se E

• ds. Ma rc e l De kke r, I

nc . NY, NY. Ma c Va ne SH e t al., Antimic ro b Ag e nts Che mo the r 2014;58:6913-6919.

• A re la tio nship b e twe e n

c e fta zidime / a vib a c ta m %T >MI C a nd c ha ng e in lo g 10CF U is diffic ult to se e ; tre nd lo o ks c o unte rintuitive

29

Ce fta zidime % T ime >MI C L

• g 10 CF

U/ T hig h a t 24 Hrs

DE SI GN AND ANAL YSI S CONSI DE RAT I ONS

Misspe c ific atio n o f Outlie r s

• Be wa re o f a na lyse s in whic h la rg e a mo unts o f da ta

we re e xc lude d witho ut a va lid de finitio n fo r o utlie rs

• Outlie rs must b e ide ntifie d sta tistic a lly a nd e xc lude d to

a llo w a va lid a na lysis o f the da ta

• I

t is no t a c c e pta b le to e mpiric a lly e xc lude la rg e a mo unts

• f da ta
• A me tho d fo r a sse ssing po te ntia l o utlie rs sho uld b e

pa rt o f the a na lysis pla n

• One e xa mple : I

f the diffe re nc e b e twe e n the fitte d a nd

• b se rve d va lue s is ≥3 sta nda rd e rro rs a nd if e xc lusio n o f the

da ta po int sig nific a ntly impro ve s the fit to the o the r

• b se rva tio ns, the da ta po int c a n b e c o nside re d a n o utlie r

a nd e xc lude d fro m the a na lysis

30

NON-CL I NI CAL I NF E CT I ON MODE L S

Pr

• spe c tus
• Optima l use o f e xisting no n-c linic a l mo de ls
• Use o f in vitro a nd in vivo syste ms to study do se

fra c tio na tio n a nd ide ntify PK

• PD inde x a sso c ia te d with

e ffic a c y

• Use o f in vivo syste ms to study do se ra ng e a nd ide ntify the

ma g nitude o f PK

• PD inde x re q uire d fo r diffe re nt le ve ls o f

e ffic a c y

• Use o f in vitro syste ms to study inte re sting do sing re g ime ns

a nd the impa c t o f dura tio n o f the ra py o n re sista nc e

• Co ntinue de ve lo pme nt o f a nima l infe c tio n mo de ls
• I

n vivo mo de ls tha t b e tte r re fle c t spe c ific dise a se sta te s

• I

nc re a sing dura tio n o f tre a tme nt

31

32

Lasting Contributions to the Field of Antimicrobial Pharmacokinetics and Pharmacodynamics Scientist, Ambassador, Mentor William A Craig