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
SMART_READER_LITE
LIVE PREVIEW

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

Oct 30, 2022 12 likes •174 views

PK -PD T ARGE T SE L E CT I ON Its 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

slide-1
SLIDE 1

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

PK

  • PD T

ARGE T SE L E CT I ON

It’s All Abo ut the Go al

slide-2
SLIDE 2

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

  • 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

  • Suppo rt a hig h a nd a ppro pria te susc e ptib ility b re a kpo int
  • Pre ve nt re sista nc e a mplific a tio n
  • 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

slide-3
SLIDE 3

HOW MUCH I S E NOUGH?

Se le c t the PK-PD T ar ge t with the Go al in Mind

L

  • we r

Mar gin

  • I

nta c t immune syste m

  • L
  • w ino c ulum infe c tio n
  • Hig h no -tre a tme nt re spo nse ra te
  • Surg ic a l inte rve ntio n

Uppe r

Mar gin

  • Ne utro pe nic pa tie nt
  • Hig h ino c ulum infe c tio n
  • L
  • w no -tre a tme nt re spo nse ra te

But b e fo re yo u just sa y, “I want ≥ 2 log10 CF

U r e duc tio n!” Stasis 1 L

  • g 10 Kill

2 L

  • g 10 Kill

E

Ma x

Optimize d time -to -re spo nse re sista nc e pre ve ntio n Clinic a l e ffic a c y, uppe r ma rg in Clinic a l e ffic a c y, lo we r ma rg in Re a so na b le in so me situa tio ns?

3

slide-4
SLIDE 4

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 1998;26:1-10.

4

slide-5
SLIDE 5

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

  • F

a ilure s a re no t in the inte re st o f pa tie nts, drug de ve lo pe rs,

  • r re g ula to rs
  • 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

  • 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

slide-6
SLIDE 6

CASE

  • I

N-POI NT

L e t’s L

  • o k at L

e vo flo xac in

Pre sto n SL , Drusa no GL , Be rma n AL , F

  • 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: A ne w pa ra dig m fo r e a rly c linic a l tria ls. JAMA 1998;279:125-129.

6

slide-7
SLIDE 7

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…
  • A g o o d unde rsta nding o f ta rg e t pa tie nt po pula tio n PK
  • 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

  • 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

slide-8
SLIDE 8

CASE

  • I

N-POI NT

L e t’s L

  • o k at T

ige c yc line

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 Che mo the r 2000;44: 943-949.

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)

8

slide-9
SLIDE 9

PK

  • PD T

ARGE T T HRE SHOL D SE L E CT I ON

We Can Also L

  • o k Ac r
  • 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 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

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

  • 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
  • r c o mmunity-a c q uire d a nd ho spita l-a c q uire d pne umo nia .

A‐295. 53rd 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.

9

slide-10
SLIDE 10

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

  • 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. 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.

10

slide-11
SLIDE 11

11

T a m VH, L

  • 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 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

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

slide-12
SLIDE 12

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

Bha vna ni SM. Da pto myc in e xpo sure a nd the pro b a b ility o f c re a tine pho spho kina se e le va tio ns. [Ab stra c t 1862]. 52nd 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. Sa n F ra nc isc o , CA. Se pt. 9-12, 2012. P = 0.013 Sa fda r N, Ande s D, Cra ig WA. I n vivo pha rma c o dyna mic a c tivity o f da pto myc in. Antimic ro b Ag e nts Che mo the r 2004;48:63-68.

T he AUC:MI C ra tio ne c e ssa ry 2 lo g 10 CF U re duc tio n in a nima ls is simila r to tha t suppre ssing re sista nc e a mplific a tio n in pa tie nts

AUC:MIC ra tio % proba bility of inc re a se d MIC a t 30 da ysa .b Numbe r of inc re a se d MIC e ve nts T

  • ta l

<1480 21 ≥1480 - <1970 27.8 5 18 ≥1970 8.1 6 62 T

  • ta l

11 101

L

  • g ra nk p = 0.013

a . K a pla n-Me ie r e stima te d. b . Increased MIC was defined as a ≥4 fold increase in MIC re la tive to b a se line . T he o b se rva tio n pe rio d e nde d a t Da y 42.

12

slide-13
SLIDE 13

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. 45th Interscience Conference

  • n Antimicrobial Agents and Chemotherapy. Washington, DC, 2005.

Amb ro se PG, F

  • 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 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.

PK

  • PD T

ARGE T T HRE SHOL D SE L E CT I ON

Whe n Be ne fit Outwe ighs Any Risk

13

slide-14
SLIDE 14

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!
  • 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

  • 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
  • f c linic a l c irc umsta nc e s

14

slide-15
SLIDE 15

F I NAL T HOUGHT S

A Pr e sc r iptive Opinio n

  • We a re in a n e ra o f unme t me dic a l ne e d so g re a t

tha t we ha ve re a c he d a po int o f ma king tra de o ffs

  • Wha t is the e xplic it tra de o ff?
  • T

he c e rta inty a sso c ia te d with 2 la rg e c linic a l tria ls fo r…

  • T

he c e rta inty o f sma ll c linic a l da ta se ts unde rpinne d b y ro b ust PK

  • PD da ta
  • I

, fo r o ne , think this a ppro a c h is se nsib le

  • Ho we ve r, I

b e lie ve E MA a nd US F DA sho uld b e pre sc riptive (a lb e it, minima lly)

  • Co mpa nie s risk time a nd mo ne y; pa tie nts risk the ir live s

15

slide-16
SLIDE 16