PK -PD T ARGE T SE L E CT I ON Its All Abo ut the Go al - PowerPoint PPT Presentation

PK -PD T ARGE T SE L E CT I ON It’s All Abo ut the Go al 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

PK -PD T ARGE T T HRE SHOL D SE L E CT I ON It’s All Abo ut the Go al T he c ho ic e o f a ra tio na l PK -PD ta rg e t thre sho ld is • de pe nde nt upo n wha t it is tha t yo u wish to a c hie ve o Se le c t a do se tha t will re sult in c linic a l re spo nse ra te s c o nsiste nt with re g ula to ry a ppro va l o Suppo rt a hig h a nd a ppro pria te susc e ptib ility b re a kpo int o Pre ve nt re sista nc e a mplific a tio n o Optimize spe e d o f re spo nse T he disa g re e me nts fo lks ha ve in re g a rd to PK -PD • se le c tio n o fte n ste ms fro m a misma tc h in g o a ls 2

HOW MUCH I S E NOUGH? Se le c t the PK-PD T ar ge t with the Go al in Mind Uppe r L owe r Mar gin Mar gin I nta c t immune syste m Ne utro pe nic pa tie nt o o L o w ino c ulum infe c tio n Hig h ino c ulum infe c tio n o o Hig h no -tre a tme nt re spo nse ra te L o w no -tre a tme nt re spo nse ra te o o Surg ic a l inte rve ntio n o E Stasis 1 L og 10 Kill Ma x 2 L og 10 Kill Clinic a l e ffic a c y, Optimize d time -to -re spo nse lo we r ma rg in re sista nc e pre ve ntio n Re a so na b le in so me Clinic a l e ffic a c y, situa tio ns? uppe r ma rg in But b e fo re yo u just sa y, “I want ≥ 2 log 10 CF U r e duc tio n!” 3

PK -PD T ARGE T T HRE SHOL D SE L E CT I ON Cho o se Wise ly! …re me mb e r tha t no t e ve ry a ntib io tic c a n a tta in a 2 lo g 10 re duc tio n in CF U Cra ig WA. Pha rma c o kine tic / pha rma c o dyna mic pa ra me te rs: ra tio na le fo r a ntib a c te ria l do sing o f mic e a nd me n. Clin I nfe c t Dis 4 1998;26:1-10.

PK -PD T ARGE T T HRE SHOL D SE L E CT I ON What We All Agr e e Upo n A ro b ust a na lysis o f c linic a l tria l da ta se ts c o nsisting o f • ple nty o f suc c e sse s a nd fa ilure s wo uld b e o ptima l o F a ilure s a re no t in the inte re st o f pa tie nts, drug de ve lo pe rs, o r re g ula to rs o Sho uld no t b e a fre q ue nt o c c urre nc e g ive n the pre dic tive po we r o f o ur pre -c linic a l infe c tio n mo de ls T hus, we a re o fte n le ft with ro b ust a na lyse s o f c linic a l • da ta se ts with fe w fa ilure s o I nste a d o f c o ntinuo us e xpo sure -re spo nse re la tio nships with tig ht c o nfide nc e b o unds, fa r mo re o fte n tha n no t, we o nly ha ve da ta se ts tha t c a n suppo rt a CART -de rive d b re a kpo int 5

CASE -I N-POI NT L e t’s L o o k at L e vo flo xac in Pre sto n SL , Drusa no GL , Be rma n AL , F o wle r CL , Cho w AT , Do rne e if B, Re ic hi V, Na ta ra ja n J, Co rra do M. Pha rma c o dyna mic s o f le vo flo xa c in: 6 A ne w pa ra dig m fo r e a rly c linic a l tria ls. JAMA 1998;279:125-129.

PK -PD T ARGE T T HRE SHOL D SE L E CT I ON What We All Agr e e Upo n We e nd up with… • o A g o o d unde rsta nding o f ta rg e t pa tie nt po pula tio n PK o L e ss info rma tive PK -PD e ffic a c y re la tio nships T he c linic a l PK -PD re la tio nships e nd up b e ing • c o nfirma to ry ra the r tha n disc rimina to ry T hus, we re ly upo n vie wing the c linic a l da ta in the • c o nte xt o f re sults fro m a nima l infe c tio n mo de ls o T he tra nsla tio na l linka g e s b e twe e n pre -c linic a l a nd c linic a l da ta b e c o me c ritic a l 7

CASE -I N-POI NT L e t’s L o o k at T ige c yc line T he AUC:MI C ra tio ne c e ssa ry fo r a hig h c linic a l re spo nse ra te (>17.9) is simila r to tha t ne e de d fo r ne t b a c te ria l sta sis in a nima ls (15-20) Me a g he r A, Pa ssa re ll J, Cirinc io ne B, Va n Wa rt S, L io lio s K , Ba b inc ha k T , E llis-Gro sse E J, Amb ro se PG. E xpo sure -re spo nse a na lysis o f the e ffic a c y o f tig e c yc line in pa tie nts with c o mplic a te d skin a nd skin struc ture infe c tio ns. Antimic ro b Ag e nts Che mo the r 2007;51:1939-1945. va n Og tro p ML , Ande s D, Sta msta d T J, Co nklin B, We iss WJ, Cra ig WA, a nd Ve sg a O. 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 8 Che mo the r 2000;44: 943-949.

PK -PD T ARGE T T HRE SHOL D SE L E CT I ON We Can Also L o o k Ac r o ss NDAs • Re la tio nship b e twe e n the re g ula to ry a ppro va l a nd the pro b a b ility o f pre -c linic a l PK -PD ta rg e t a tta inme nt (1996-2011) 1 PK -PD ta rg e t: 1-2 lo g 10 CF U o de c re a se fro m ne t sta sis • I ndic a tio ns inc lude d c o mmunity- a nd ho spita l- a c q uire d pne umo nia 17 a ntib io tic s in to ta l with 14 o re g ula to ry a ppro va ls a nd 6 fa ilure s Bulik CC, Bha vna ni SM, Ha mme l JP, F o rre st A, Dudle y MN, E llis-Gro sse E J, Drusa no GL , Amb ro se PG. E va lua tio n o f the pro b a b ility o f re g ula to ry a ppro va l b a se d o n pre -c linic a l PK -PD ta rg e t a tta inme nt F o r c o mmunity-a c q uire d a nd ho spita l-a c q uire d pne umo nia . 9 A ‐ 295. 53 rd 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. De nve r, CO. Se pte mb e r 10-13, 2013.

PK -PD T ARGE T T HRE SHOL D SE L E CT I ON T ime to Re spo nse AUC:MI C ra tio s o f 75-150 a nd >150 ha d the sa me re spo nse ra te b y Da y 11 b ut la rg e r e xpo sure s sho rte ne d the time to e ve nt T he AUC:MI C ra tio ne c e ssa ry fo r a 2-lo g 10 CF U re duc tio n in a nima ls is simila r to tha t re sulting in the mo st ra pid re spo nse F o rre st A, Nix SE , Ba llo w CH, Sc he nta g , JJ. Pha rma c o dyna mic s o f intra ve no us c ipro flo xa c in in se rio usly ill pa tie nts. Antimic ro b Ag e nts Che mo the r 1993;37:1073–1081. 10 USCAST F luo ro q uino lo ne Bre a kpo int Re po rt (2015), http :/ / www.usc a st.o rg / ne ws/ q uino lo ne -in-vitro -susc e ptib ility-te st-inte rpre tive - c rite ria -e va lua tio ns-re po rt.

PK -PD T ARGE T T HRE SHOL D SE L E CT I ON Pr e ve nting Re sistanc e Amplific atio n T he re la tio nship b e twe e n drug e xpo sure a nd re sista nc e a mplific a tio n ta ke s the fo rm o f a n inve rte d-U T he lo ng e r o ne tre a ts, the g re a te r the drug e xpo sure ne e ds to b e to suppre ss re sista nc e a mplific a tio n T a m VH, L o uie A, De zie l MR, We ig uo L , L e a ry R, Drusa no GL . Ba c te ria l-po pula tio n re spo nse s to drug -se le c tive pre ssure : e xa mina tio n o f 11 g a re no xa c in's e ffe c t o n Pse udo mo nas ae rug ino sa . J I nfe c t Dis 2005;192:420-428.

PK -PD T ARGE T T HRE SHOL D SE L E CT I ON Pr e ve nting Re sistanc e Amplific atio n P = 0.013 T he AUC:MI C ra tio ne c e ssa ry % proba bility of Numbe r of AUC:MIC ra tio inc re a se d MIC inc re a se d MIC T ota l 2 lo g 10 CF U re duc tio n in a nima ls is a t 30 da ys a .b e ve nts <1480 0 0 21 simila r to tha t suppre ssing ≥1480 - <1970 27.8 5 18 ≥1970 re sista nc e a mplific a tio n in pa tie nts 8.1 6 62 T o ta l 11 101 L o g ra nk p = 0.013 a . K a pla n-Me ie r e stima te d. Increased MIC was defined as a ≥4 fold increase in MIC re la tive b . to b a se line . T he o b se rva tio n pe rio d e nde d a t Da y 42. Bha vna ni SM. Da pto myc in e xpo sure a nd the pro b a b ility o f Sa fda r N, Ande s D, Cra ig WA. I n vivo pha rma c o dyna mic c re a tine pho spho kina se e le va tio ns. [Ab stra c t 1862]. 52 nd a c tivity o f da pto myc in. Antimic ro b Ag e nts Che mo the r I nte rsc ie nc e Co nfe re nc e o n Antimic ro b ia l Ag e nts a nd 2004;48:63-68. 12 Che mo the ra py. Sa n F ra nc isc o , CA. Se pt. 9-12, 2012.

PK -PD T ARGE T T HRE SHOL D SE L E CT I ON Whe n Be ne fit Outwe ighs Any Risk P.G. Ambrose, A. Forrest, W. A. Craig, C. M. Rubino, S. M. Bhavnani, G.L. Drusano, H.S. Heine. PK-PD of Gatifloxacin in a Lethal Murine- Bacillus anthracis Inhalation Model and PK-PD Target Attainment Analyses to Support Adult and Pediatric Dosing Regimens. 45 th Interscience Conference Amb ro se PG, F o rre st A, Cra ig WA, Rub ino CM, Bha vna ni SM, Drusa no GL , He ine HS. Pha rma c o kine tic s-pha rma c o dyna mic s o f g a tiflo xa c in 13 in a le tha l murine - Bac illus anthrac is inha la tio n infe c tio n mo de l. Antimic ro b Ag e nts Che mo the r 2007;51:4351-4355. on Antimicrobial Agents and Chemotherapy. Washington, DC, 2005.

SUSCE PT I BI L I T Y BRE AK POI NT S Our Vie w o f the F utur e A wo rld witho ut susc e ptib ility b re a kpo ints! • o A MI C b re a kpo int ma ke s a b o ut a s muc h se nse a s a n AUC b re a kpo int I t’ s re a lly a b o ut the pro b a b ility o f a tta ining e ffe c tive • e xpo sure s in a g ive n pa tie nt a nd infe c tio n site o A sing le susc e ptib ly b re a kpo int do e s no t c o ve r the ma jo rity o f c linic a l c irc umsta nc e s 14