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

Aug 20, 2022 •356 likes •697 views

-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 Paul G. Ambr ose , 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 WARNI

  1. 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 Paul G. Ambr ose , 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

  2. WARNI NG! WARNI NG!! Po te ntial Co nflic ts o f Inte r e st • 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 o AiCuris, o Cub ist Pha rma c e utic a ls/ Me rc k, o F e do ra / Me iji/ Ro c he , o Gla xo SmithK line , o T he Me dic ine s Co mpa ny/ Re mpe x, a nd o 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

  3. OUR MI SSI ON T o Bo ldly Go Whe r e No One Has Go ne Be fo r e -PD de te rmina nt o f β -la c ta ma se inhib ito r • Wha t is the PK 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

  4. OUR MI SSI ON T o 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 ? -PD de te rmina nt o f β -la c ta ma se inhib ito r • I s the PK 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 4 suppo rt susc e ptib ility b re a kpo ints?

  5. 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 ac tionate d β - lac tamase inhibitor impa c t o f a fr e o n b a c te ria l de nsity in the c o nte xt o f a fixe d e xposur β - lac tam e xposur e o 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 o Sta rting ino c ulum wa s 10 6 CF U/ mL o 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 , Nic a sio AM, Ca sta nhe ira M, Bulik CC, Okusa nya OO, Bha vnani SM, F o rre st A, Jo ne s RN, F Va nSc o y B, Me nde s RE rie dric h L V, 5 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 .

  6. 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 o uie ) o 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 o Sta rting ino c ulum wa s 10 8 CF U/ mL o Sa mple s we re c o lle c te d da ily o 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 o 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 , Ca sta nhe rira M, Mc Caule y J, Bha vnani SM, F o rre st A, Okusa nya OO, Jo ne s RN, F Va nSc o y B, Me nde s RE rie dric h L V, 6 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. minant o f β -lac tamase inhibito r What is the PK-PD de te r e ffic ac y in the c o nte xt o f a typic al β -lac tam e xpo sur e ? 7

  8. 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 o 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 o 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 , Nic a sio AM, Ca sta nhe ira M, Bulik CC, Okusa nya OO, Bha vnani SM, F o rre st A, Jo ne s RN, F Va nSc o y B, Me nde s RE rie dric h L V, 8 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 .

  9. DOSE F RACT I ONAT I ON ST UDI E S PK-PD Mo de ling • 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 o 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 o 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 o 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 o T hre sho ld va lue disc rimina tio n wa s b a se d upo n re so lutio n 2 o ptimiza tio n a lo ng the e xpo sure a xis a nd r , Nic a sio AM, Ca sta nhe ira M, Bulik CC, Okusa nya OO, Bha vnani SM, F o rre st A, Jo ne s RN, F Va nSc o y B, Me nde s RE rie dric h L V, 9 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 .

  10. DOSE F RACT I ONAT I ON ST UDI E S T azo bac tam E xpo sur e -Re spo nse In Vitr o Ce ftolozane - T azobac tam 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 1: T fo r the hig h- β -la c ta ma se g e ne tic c o nstruc t 0.05 mg / L a nd wa s 0.25 mg / L F o 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 -PD de te rmina nt o f β -la c ta ma se inhib ito r e ffic a c y PK , Nic a sio AM, Ca sta nhe ira M, Bulik CC, Okusa nya OO, Bha vnani SM, F o rre st A, Jo ne s RN, F Va nSc o y B, Me nde s RE rie dric h L V, 10 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 .

  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? 11

  12. GE NE T RANSCRI PT I ON I MPACT T azo bac tam E xpo sur e -Re spo nse In Vitr o Ce ftolozane - T azobac tam 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 , Nic a sio AM, Ca sta nhe ira M, Bulik CC, Okusa nya OO, Bha vnani SM, F o rre st A, Jo ne s RN, F Va nSc o y B, Me nde s RE rie dric h L V, 12 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 .

  13. Can we ide ntify a tr anslatio nal r e latio nship allo wing fo r atio n o f β -lac tamase inhibito r the inte gr e xpo sur e - r e spo nse r e latio nships ac r o ss iso late s? 13

  14. 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 o Ce ftolozane - T azobac tam , Mc Ca ule y J, Bha vnani SM, Bulik CC, Okusa nya OO, F o rre st A, Jo ne s RN, F Va nSc o y B, Me nde s RE rie dric h L V, Ste e nb e rg e n 15 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.

  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 o Ce ftolozane - T azobac tam Va nSc o y B, Me nde s RE , Mc Ca ule y J, Bha vna ni SM, Bulik CC, Okusa nya OO, F o rre st A, Jo ne s RN, F rie dric h L V, Ste e nb e rg e n JN, 16 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.

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