WARNI NG! WARNI NG!! Po te ntial Co nflic ts o f Inte r e st I - - PowerPoint PPT Presentation

Paul G. Ambr

• se , Phar

m.D.

Cha ir, USCAST E xe c utive Co mmitte e Pre side nt, I nstitute fo r Clinic a l Pha rma c o dyna mic s

β-L

ACT AMASE I NHI BI T ORS

T he Phar mac o lo gic al Basis o f T he r ape utic s

• I

CPD ha s o ng o ing re se a rc h c o lla b o ra tio ns invo lving

β-la c ta m-β-la c ta ma se inhib ito r c o mb ina tio ns with a

numb e r o f pha rma c e utic a l c o mpa nie s

• AiCuris,
• Cub ist Pha rma c e utic a ls/ Me rc k,
• F

e do ra / Me iji/ Ro c he ,

• Gla xo SmithK

line ,

• T

he Me dic ine s Co mpa ny/ Re mpe x, a nd

• Ve na to Rx
• I

n a dditio n, I CPD is c urre ntly c o nduc ting studie s in suppo rt o f Na tio na l He a lth Se rvic e o b je c tive s fo r ma rke te d β-la c ta ma se inhib ito rs

2

WARNI NG! WARNI NG!!

Po te ntial Co nflic ts o f Inte r e st

• Wha t is the PK
• PD de te rmina nt o f β-la c ta ma se inhib ito r

e ffic a c y in the c o nte xt o f a typic a l β-la c ta m e xpo sure ?

• Wha t is the impa c t o f β-la c ta ma se g e ne tra nsc riptio n

le ve l o n the ma g nitude o f the PK

• PD me a sure

a sso c ia te d with β-la c ta ma se inhib ito r e ffic a c y?

• Ca n we ide ntify a tra nsla tio na l re la tio nship a llo wing fo r

the inte g ra tio n o f β-la c ta ma se inhib ito r e xpo sure - re spo nse re la tio nships a c ro ss iso la te s?

• I

s the tra nsla tio na l re la tio nship the sa me a c ro ss

β‐la c ta ms pa ire d with the sa me β-la c ta ma se inhib ito r?

3

OUR MI SSI ON

T

• Bo ldly Go Whe r

e No One Has Go ne Be fo r e

• Wha t is the impa c t o f the pa rtne r β-la c ta m o n the

PK‐PD de te rmina nt o f β-la c ta ma se inhib ito r e ffic a c y in the c o nte xt o f a typic a l β-la c ta m e xpo sure ?

• I

s the PK

• PD de te rmina nt o f β-la c ta ma se inhib ito r

e ffic a c y the sa me a c ro ss β-la c ta ma se inhib ito rs?

• I

s the re a b a sis fo r the de ve lo pme nt o f a sta nd-a lo ne

β-la c ta ma se inhib ito r?

• Wha t is the re la tio nship b e twe e n β-la c ta m-β-

la c ta ma se inhib ito r e xpo sure a nd re sista nc e a mplific a tio n?

• Ho w c a n we utilize pre -c linic a l mo de l info rma tio n to

suppo rt susc e ptib ility b re a kpo ints?

4

OUR MI SSI ON

T

• Bo ldly Go Whe r

e No One Has Go ne Be fo r e

OUR T OOL BOX

One -Co mpar tme nt Infe c tio n Mo de l

• A 24 ho ur c he mo sta t mo de l wa s use d to me a sure the

impa c t o f a fr

ac tionate d β- lac tamase inhibitor e xposur e o n b a c te ria l de nsity in the c o nte xt o f a fixe d

β- lac tam e xposur

e

• Huma n fre e -drug c o nc e ntra tio ns we re simula te d fo r e a c h

individua l a g e nt a nd me a sure d b y L C/ MS/ MS

• Sta rting ino c ulum wa s 106 CF

U/ mL

• Sa mple s c o lle c te d a t

0, 2, 4, 8, 12, a nd 24 ho urs a nd pla te d o n drug -fre e pla te s fo r de te rmina tio n

5

Va nSc o y B, Me nde s RE , Nic a sio AM, Ca sta nhe ira M, Bulik CC, Okusa nya OO, Bha vnani SM, F

• rre st A, Jo ne s RN, F

rie dric h L V, Ste e nb e rg e n JN, Amb ro se PG. Pha rma c o kine tic s-pha rmac o dynamic s o f ta zo b a c tam in c o mb inatio n with c e fto lo za ne in a n in vitro infe c tio n mo de l. Antimic ro b Ag e nts Che mo the r 2013;57:2809-2814.

OUR T OOL BOX

Ho llo w-F ibe r Infe c tio n Mo de l

• A ho llo w-fib e r mo de l wa s use d ide ntify the β- lac tam-

β- lac tamase inhibitor e xpo sure ne c e ssa ry to pre ve nt

re sista nc e a mplific a tio n (Drusa no / L

• uie )

6

• Huma n fre e -drug c o nc e ntra tio ns we re simula te d

fo r e a c h individua l a g e nt a nd me a sure d b y L C/ MS/ MS

• Sta rting ino c ulum wa s 108 CF

U/ mL

• Sa mple s we re c o lle c te d da ily
• ve r 10-14 da ys a nd pla te d o n

drug -fre e a nd –c o nta ining pla te s fo r CF U de te rmina tio n

• Sa mple s we re c o lle c te d o ve r the

first 48 ho urs fo r drug a ssa y

Va nSc o y B, Me nde s RE , Ca sta nhe rira M, Mc Caule y J, Bha vnani SM, F

• rre st A, Okusa nya OO, Jo ne s RN, F

rie dric h L V, Ste e nb e rg e n JN, Amb ro se PG. Re la tio nship b e twe e n c e fto lo za ne / ta zo b ac tam e xpo sure a nd drug -re sista nc e a mplific a tio n in a ho llo w-fib e r infe c tio n mo de l. Antimic ro b Ag e nts Che mo the r 2013;57:4134-4138.

7

What is the PK-PD de te r minant o f β-lac tamase inhibito r e ffic ac y in the c o nte xt o f a typic al β-lac tam e xpo sur e ?

DOSE F RACT I ONAT I ON ST UDI E S

Str ains and Susc e ptibility T e sting

• T

hre e iso g e nic CT X-M-15-e la b o ra ting E . c o li we re utilize d in the se studie s

• Ge ne tic a lly e ng ine e re d b la CT

X-M-15-c a rrying ve c to rs c o nta ining

va rying upstre a m pro mo te r re g io ns tha t pro vide d diffe re nt le ve ls o f mRNA tra nsc riptio n we re c re a te d

• Re c o mb ina nt ve c to rs we re the n tra nsfo rme d into a wild-type

susc e ptib le E . c o li stra in

8

Va nSc o y B, Me nde s RE , Nic a sio AM, Ca sta nhe ira M, Bulik CC, Okusa nya OO, Bha vnani SM, F

• rre st A, Jo ne s RN, F

rie dric h L V, Ste e nb e rg e n JN, Amb ro se PG. Pha rma c o kine tic s-pha rmac o dynamic s o f ta zo b a c tam in c o mb inatio n with c e fto lo za ne in a n in vitro infe c tio n mo de l. Antimic ro b Ag e nts Che mo the r 2013;57:2809-2814.

DOSE F RACT I ONAT I ON ST UDI E S

PK-PD Mo de ling

9

• Da ta fro m the e ffic a c y studie s we re mo de le d using

a Hill-type mo de l a nd no n-line a r le a st sq ua re s re g re ssio n

• T

he da ta we re we ig hte d using the inve rse o f the e stima te d me a sure me nt va ria nc e

• T

he re la tio nship b e twe e n lo g 10 CF U a t 24 ho urs a nd C ma x, AUC 0-24, a nd % T ime >thre sho ld wa s e va lua te d

• T

he % T ime >thre sho ld wa s ide ntifie d thro ug h a n ite ra tive pro c e ss

• Ca ndida te thre sho ld c o nc e ntra tio ns o f 0.01, 0.05, 0.1, 0.25,

0.5, 1, a nd 2 mg / L we re e va lua te d

• T

hre sho ld va lue disc rimina tio n wa s b a se d upo n re so lutio n a lo ng the e xpo sure a xis a nd r

2 o ptimiza tio n

Va nSc o y B, Me nde s RE , Nic a sio AM, Ca sta nhe ira M, Bulik CC, Okusa nya OO, Bha vnani SM, F

• rre st A, Jo ne s RN, F

rie dric h L V, Ste e nb e rg e n JN, Amb ro se PG. Pha rma c o kine tic s-pha rmac o dynamic s o f ta zo b a c tam in c o mb inatio n with c e fto lo za ne in a n in vitro infe c tio n mo de l. Antimic ro b Ag e nts Che mo the r 2013;57:2809-2814.

DOSE F RACT I ONAT I ON ST UDI E S

T azo bac tam E xpo sur e -Re spo nse In Vitr

• 10

1: T he thre sho ld ta zo b a c ta m c o nc e ntra tio n fo r the lo w- a nd mo de ra te -β-la c ta ma se g e ne tic c o nstruc ts wa s 0.05 mg / L a nd wa s 0.25 mg / L fo r the hig h-β-la c ta ma se g e ne tic c o nstruc t

Ce ftolozane - T azobac tam

Va nSc o y B, Me nde s RE , Nic a sio AM, Ca sta nhe ira M, Bulik CC, Okusa nya OO, Bha vnani SM, F

• rre st A, Jo ne s RN, F

rie dric h L V, Ste e nb e rg e n JN, Amb ro se PG. Pha rma c o kine tic s-pha rmac o dynamic s o f ta zo b a c tam in c o mb inatio n with c e fto lo za ne in a n in vitro infe c tio n mo de l. Antimic ro b Ag e nts Che mo the r 2013;57:2809-2814.

F

• r ta zo b a c ta m in c o mb ina tio n with c e fto lo za ne , % T

ime > T hre sho ld is the PK

• PD de te rmina nt o f β-la c ta ma se inhib ito r e ffic a c y

11

What is the impact of β-lac tamase ge ne tr

ansc r iptio n le ve l o n the magnitude o f the PK-PD me asur e asso c iate d with β-lac tamase inhibito r e ffic ac y?

GE NE T RANSCRI PT I ON I MPACT

T azo bac tam E xpo sur e -Re spo nse In Vitr

• 12

Ce ftolozane - T azobac tam

Va nSc o y B, Me nde s RE , Nic a sio AM, Ca sta nhe ira M, Bulik CC, Okusa nya OO, Bha vnani SM, F

• rre st A, Jo ne s RN, F

rie dric h L V, Ste e nb e rg e n JN, Amb ro se PG. Pha rma c o kine tic s-pha rmac o dynamic s o f ta zo b a c tam in c o mb inatio n with c e fto lo za ne in a n in vitro infe c tio n mo de l. Antimic ro b. Ag e nts Che mo the r 2013;57:2809-2814.

As g e ne tra nsc riptio n le ve l inc re a se s, so to o do e s the β-la c ta ma se inhib ito r ta rg e t thre sho ld

13

Can we ide ntify a tr anslatio nal r e latio nship allo wing fo r the inte gr atio n o f β-lac tamase inhibito r e xpo sur e - r e spo nse r e latio nships ac r

• ss iso late s?

DOSE RANGE ST UDI E S

Str ains and Susc e ptibility T e sting

14

15

DOSE

• RANGE

ST UDI E S

T azo bac tam E xpo sur e -Re spo nse In Vitr

• Va nSc o y B, Me nde s RE

, Mc Ca ule y J, Bha vnani SM, Bulik CC, Okusa nya OO, F

• rre st A, Jo ne s RN, F

rie dric h L V, Ste e nb e rg e n JN, Amb ro se PG. Pha rma c o lo g ic al b a sis o f β-la c ta mase the ra pe utic s: ta zo b a c tam in c o mbinatio n with c e fto lo za ne . Antimic ro b Ag e nts Che mo the r 2013;57:5924-5930.

Ce ftolozane - T azobac tam

16

T RANSL AT I ONAL RE L AT I ONSHI P

T azo bac tam E xpo sur e -Re spo nse In Vitr

• Va nSc o y B, Me nde s RE

, Mc Ca ule y J, Bha vna ni SM, Bulik CC, Okusa nya OO, F

• rre st A, Jo ne s RN, F

rie dric h L V, Ste e nb e rg e n JN, Amb ro se PG. Pha rma c o lo g ic a l b a sis o f β-la c ta ma se the ra pe utic s: ta zo b a c ta m in c o mb ina tio n with c e fto lo za ne . Antimic ro b Ag e nts Che mo the r 2013; 57:5924-5930.

Ce ftolozane - T azobac tam

17

T RANSL AT I ONAL RE L AT I ONSHI P

T azo bac tam E xpo sur e -Re spo nse In Vitr

• Va nSc o y B, Me nde s RE

, Mc Ca ule y J, Bha vnani SM, Bulik CC, Okusa nya OO, F

• rre st A, Jo ne s RN, F

rie dric h L V, Ste e nb e rg e n JN, Amb ro se PG. Pha rma c o lo g ic al b a sis o f β-la c ta mase the ra pe utic s: ta zo b a c tam in c o mbinatio n with c e fto lo za ne . Antimic ro b Ag e nts Che mo the r 2013;57:5924-5930.

Ce ftolozane - T azobac tam F

• r c e fto lo za ne -ta zo b a c ta m, a

tra nsla tio na l re la tio nship wa s ide ntifie d a nd a llo we d fo r the inte g ra tio n o f β-la c ta ma se inhib ito r e xpo sure -re spo nse re la tio nships a c ro ss iso la te s

18

Is the tr anslatio nal r e latio nship the same ac r

• ss

β‐lac tams pair

e d with the same β-lac tamase inhibito r ?

T RANSL AT I ONAL RE L AT I ONSHI P

T azo bac tam E xpo sur e -Re spo nse In Vitr

• Va nSc o y BD, Me nde s RE

, Mc Ca ule y J, Bha vna ni SM, Bulik CC, Okusa nya OO, F

• rre st A, Jo ne s RN, F

rie dric h L V, Ste e nb e rg e n JN, Amb ro se PG. Pha rma c o lo g ic a l b a sis o f β-la c ta ma se the ra pe utic s: ta zo b a c ta m in c o mb ina tio n with c e fto lo za ne . Antimic ro b Ag e nts Che mo the r 2013;57:5924-5930.

Ce ftolozane - T azobac tam Ce fe pime - T azobac tam

Va nSc o y BD, T e ne ro D, T urne r S, L ive rmo re DM, Mc Ca ule y J, Co nde H, Me nde s R, Bha vna ni SM, Rub ino CR, Amb ro se PG. Pha rma c o kine tic s-pha rma c o dyna mic s o f ta zo b a c ta m in c o mb ina tio n with c e fe pime in a n in vitro infe c tio n mo de l.. Po ste r A-499, 2015 I CAAC.

T he tra nsla tio na l re la tio nship is no t the sa me a c ro ss β-la c ta m pa rtne rs

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What is the impac t o f the par tne r β-lac tam o n the PK‐PD de te r minant o f β-lac tamase inhibito r e ffic ac y in the c o nte xt o f a typic al β-lac tam e xpo sur e ?

DOSE F RACT I ONAT I ON ST UDI E S

T azo bac tam E xpo sur e -Re spo nse In Vitr

• 1: T

he thre sho ld ta zo b a c ta m c o nc e ntra tio n fo r the lo w-, mo de ra te -, a nd hig h-β-la c ta ma se g e ne tic c o nstruc ts we re 0.25, 0.5, a nd 2 mg / L , re spe c tive ly.

PK

• PD de te rmina nt o f β-la c ta ma se inhib ito r e ffic a c y do e s no t c ha ng e with

the β-la c ta m pa rtne r Pipe r ac illin- T azobac tam

21

22

Is the PK-PD de te r minant o f β-lac tamase inhibito r e ffic ac y the same ac r

• ss β-lac tamase inhibito r

s?

PK

• PD E

F F I CACY DE T E RMI NANT S

Var io us β-L ac tamase Inhibito r s with Me r

• pe ne m

23

CB- 618 Me rope ne m

Va nSc o y BD, Rub ino CM, Mc Ca ule y J, Co nde H, Bha vna ni SM, F rie dric h L

• V. Ale xa nde r DC, Amb ro se
• PG. Pha rma c o kine tic s-pha rma c o dyna mic s o f

CB‐618, a no ve l β-la c ta ma se inhib ito r, in c o mb ina tio n with me ro pe ne m in a n in vitro infe c tio n mo de l. Po ste r A-044, 2015 I CAAC.

Dia za bic yc looc ta ne Me rope ne m

No , the PK

• PD de te rmina nt o f

β‐la c ta ma se inhib ito r e ffic a c y is no t

the sa me a c ro ss β-la c ta ma se inhib ito rs

24

Is the r e a basis fo r the de ve lo pme nt o f a stand-alo ne

β-lac tamase inhibito r

?

BASI S F OR A ST AND AL ONE I NHI BI T OR?

Po te ntial to Re sc ue Multiple Age nts and Re gime ns

25

Va nSc o y BD, Rub ino CM, Mc Ca ule y J, Co nde H, Bha vna ni SM, F rie dric h L

• V. Ale xa nde r DC, Amb ro se PG.

Pha rmac o kine tic s-pharmac o dynamic s o f CB-618 in c o mbinatio n with multiple β-la c tam a g e nts. Po ste r A-501, 2015 ICAAC.

F ro m a PK

• PD pe rspe c tive , it is po ssib le to ide ntify o ne β-la c ta ma se inhib ito r

e xpo sure to re sc ue multiple β-la c ta ms a nd do sing re g ime ns

26

What is the r e latio nship be twe e n β-lac tam-

β-lac tamase inhibito r

e xpo sur e and r e sistanc e amplific atio n?

27

CE F T OL OZANE

• T

AZOBACT AM

On-T he r apy Re sistanc e Amplific atio n

No te : Ave ra g e d d a ta with e rro r b a rs re pre se nting the ra ng e o f d a ta o ve r two se pa ra te stud ie s.

28

Va nSc o y B, Me nde s RE , Ca sta nhe rira M, Mc Caule y J, Bha vnani SM, F

• rre st A, Okusa nya OO, Jo ne s RN, F

rie dric h L V, Ste e nb e rg e n JN, Amb ro se PG. Re la tio nship b e twe e n c e fto lo za ne / ta zo b ac tam e xpo sure a nd drug -re sista nc e a mplific a tio n in a ho llo w-fib e r infe c tio n mo de l. Antimic ro b Ag e nts Che mo the r 2013;57:4134-4138.

CE F T OL OZANE

• T

AZOBACT AM

On-T he r apy Re sistanc e Amplific atio n

T he re la tio nship b e twe e n c e fto lo za ne -ta zo b a c ta m e xpo sure a nd re sista nc e a mplific a tio n is tha t o f a n inve rte d U

29

Ho w c an we utilize pr e -c linic al mo de l info r matio n to suppo r t susc e ptibility br e akpo ints?

ME T HODS

Mo nte Car lo Simulatio n

Rub ino CM, Bha vna ni SM, Ste e nb e rg e n JN, K rishna G. Amb ro se PG. Pha rma c o kine tic -pharmac o dynamic ta rg e t a tta inme nt a na lysis suppo rting the se le c tio n o f in vitro susc e ptib ility te st inte rpre tive c rite ria fo r c e fto lo za ne / ta zo b ac tam a g a inst E nte ro b a c te riac e ae . Po ste r A-1347. ICAAC 2014.

31

CE F T OL OZANE

• T

AZOBACT AM

Pr

• bability o f T

ar ge t Attainme nt

• K

no w the PK

• PD de te rmina te o f the β-la c ta ma se

inhib ito r

• T

he y a re no t a ll the sa me !

• K

no w the β-la c ta ma se inhib ito r e xpo sure ma g nitude ne e de d fo r e ffic a c y in c o mb o with the β-la c ta m do se re g ime n yo u will study c linic a lly

• L
• o k fo r unifying tra nsla tio na l re la tio nships a c ro ss iso la te s to

inc re a se c e rta inty a ro und do se re g ime n de c isio ns

• Do se justific a tio n a nd b re a kpo int e va lua tio ns re q uire

c o nside ra tio n o f b o th β-la c ta m a nd β-la c ta ma se inhib ito r e xpo sure s

• Pre ssure te st c linic a l re g ime ns in ho llo w-fib e r infe c tio n

mo de ls prio r to c linic a l tria ls

32

SUMMARY

Do se Se le c tio n o f β-L ac tamase Inhibito r s