A PHARMACOME T RI C-BASE D APPROACH T O F ACI L I T AT E - - PowerPoint PPT Presentation

▶
a pharmacome t ri c base d approach t o f aci l i t at e
SMART_READER_LITE
LIVE PREVIEW

A PHARMACOME T RI C-BASE D APPROACH T O F ACI L I T AT E - - PowerPoint PPT Presentation

Nov 12, 2023 15 likes •207 views

A PHARMACOME T RI C-BASE D APPROACH T O F ACI L I T AT E CRI T I CAL L Y NE E DE D NE W ANT I BI OT I C DE VE L OPME NT Paul G. Ambr ose , Phar m.D., F IDSA I nstitute fo r Clinic a l Pha rma c o dyna mic s L

slide-1
SLIDE 1

A PHARMACOME T RI C-BASE D APPROACH T O F ACI L I T AT E CRI T I CAL L Y NE E DE D NE W ANT I BI OT I C DE VE L OPME NT

Paul G. Ambr

  • se , Phar

m.D., F IDSA I nstitute fo r Clinic a l Pha rma c o dyna mic s L a tha m, Ne w Yo rk Ho no ra ry Re se a rc h F e llo w, I nfe c tio us Dise a se s Nuffie ld De pa rtme nt o f Me dic ine Unive rsity o f Oxfo rd Oxfo rd, E ng la nd, Unite d K ing do m

slide-2
SLIDE 2

T HE PROBL E M

Re gulato r y Unc e r tainty

  • Antimic ro b ia l drug de ve lo pme nt ha s g re a tly

diminishe d due to the impa c t o f re g ula to ry unc e rta inty re g a rding

  • T

he magnitude o f dr

ug e ffe c t a nd

  • T

he a b ility o f c o nte mpo ra ry c linic al tr

ial e ndpo ints to c aptur e dr ug be ne fit

  • T

he se e le me nts a re c ritic a l to sta tistic a lly po we r no n- infe rio rity studie s

  • T

he la c k o f this info rma tio n unde rmine s the via b ility o f c o nte mpo ra ry c linic a l tria l de sig ns

slide-3
SLIDE 3

HI ST ORI CAL DAT A E XAMI NAT I ON

One So lutio n

  • One a ppro a c h to g a in kno wle dg e a b o ut the

ma g nitude o f tre a tme nt e ffe c t is thro ug h the e xa mina tio n o f histo ric a l da ta

  • Ho we ve r, the re a re o bvio us limitatio ns to histo ric a l

da ta tha t c a n intro duc e po te ntia l b ia s

  • No pla c e b o c o ntro l,
  • L

a c k o f b linding a nd ra ndo miza tio n,

  • Use o f me dic a lly dub io us inte rve ntio ns, a nd
  • I

na b ility to a uthe ntic a te the so urc e da ta

  • So urc e da ta ve rific a tio n is a n e sse ntia l c o mpo ne nt in

Go o d Clinic a l Pra c tic e g uide line s

slide-4
SLIDE 4

HI ST ORI CAL DAT A E XAMI NAT I ON

One So lutio n

  • Using histo ric a l da ta , the US F

DA a nd o the rs ha ve prima rily e mplo ye d a sing le sta tistic a l a ppro a c h

  • F

re q ue ntist infe re nc e

  • Alte rna tive sta tistic a l a ppro a c he s ha ve no t b e e n fully

(a nic e wa y o f sa ying “no t a t a ll”) c o nside re d b y the US F DA o r o the rs

  • F

re q ue ntist infe re nc e c o mb ine d with pha rma c o me tric me tho ds

  • Ba ye sia n infe re nc e c o mb ine d with pha rma c o me tric me tho ds
slide-5
SLIDE 5

BAYE SI AN VE RSUS F RE QUE NT I ST S

T he Ke y Diffe r e nc e s

  • F

re q ue ntist a na lyse s do no t inc o rpo ra te prio r info rma tio n o r b e lie fs

  • I

n a fre q ue ntist a na lysis, me a n is c o nside re d to b e a re a l va lue a nd o nly the study da ta de te rmine s nume ric a l re sults

  • I

n a Ba ye sia n a na lysis, b o th prio r info rma tio n a nd the study da ta influe nc e the re sults a nd c o nc lusio n

  • Sinc e the po pula tio n me a n is no t c o nside re d fixe d in a

Ba ye sia n a na lyse s, prio r info rma tio n c o nc e rning the like liho o d o f the me a n to fa ll within spe c ifie d inte rva ls c a n b e q ua ntifie d a nd inc o rpo ra te d

slide-6
SLIDE 6

A BAYE SI AN APPROACH

T hr e e Re aso ns this is Ratio nal

  • F

irst, tig e c yc line ha s de mo nstra te d in vitro a c tivity a g a inst b a c te ria o f c linic a l inte re st

  • Se c o nd, tig e c yc line wa s

e va lua te d in a nima l infe c tio n mo de ls, whe re it wa s e ffe c tive in b a c te ria l killing

  • T

ig e c yc line e xpo sure , a s me a sure d b y the AUC 0-24:MI C ra tio , a nd

  • utc o me we re we ll-de sc rib e d b y

e xpo sure -re spo nse mo de ls

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 a g a inst 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.

slide-7
SLIDE 7
  • T

hird, tig e c yc line wa s studie d in pa tie nts fo r who m e ffic a c y wa s de mo nstra te d a nd re la te d to AUC 0-24:MI C ra tio using e xpo sure -re spo nse mo de ls

  • I

n o the r wo rds, antimic r

  • bial age nts tha t e nte r la te -

sta g e c linic a l de ve lo pme nt ha ve b e e n e ffe c tive ly

pr e -sc r e e ne d fo r e ffic ac y

  • As suc h, it is hig hly like ly tha t suc h a g e nts wo uld b e

e ffic a c io us if a ppro pria te do se re g ime ns a re se le c te d fo r c linic a l study

A BAYE SI AN APPROACH

T hr e e Re aso ns this is Ratio nal

slide-8
SLIDE 8

OBJE CT I VE S

A Ne w Appr

  • ac h
  • Our o b je c tive wa s to de mo nstra te the utility o f

fre q ue ntist- a nd Ba ye sia n-pha rma c o me tric -b a se d lo g istic re g re ssio n a na lyse s

  • De te rmine the ma g nitude o f tre a tme nt e ffe c t
  • De te rmine the a b ility o f c linic a l tria l e ndpo ints to c a pture

drug b e ne fit

  • A HAP/ VAP c linic a l tria l da ta se t wa s se le c te d fo r

a na lysis

  • Co nte mpo ra ry Pha se 3 tria l invo lving tig e c yc line
  • L

a b e ling indic a tio ns ha ve g e ne ra te d c o nside ra b le disc ussio ns a t US F DA a nd I DSA c o -spo nso re d wo rksho ps a nd in Guida nc e Do c ume nts

slide-9
SLIDE 9
  • L
  • g istic re g re ssio n mo de ls
  • T

he de pe nde nt va ria b le s we re mic ro b io lo g ic a l a nd c linic a l suc c e ss

  • T

he inde pe nde nt va ria b le in e a c h a na lysis wa s the lo g 10 tra nsfo rm o f the AUC 0-24:MI C ra tio

  • F

re q ue ntisit lo g istic re g re ssio n a na lyse s we re c a rrie d

  • ut in the sta nda rd fa shio n b a se d o n ma ximum

like liho o d e stima tio n

ME T HODS

Statistic s

slide-10
SLIDE 10
  • Ba ye sia n lo g istic re g re ssio n a na lyse s we re pe rfo rme d

e mplo ying a no n-info rma tive unifo rm prio r distrib utio n fo r the inte rc e pt pa ra me te r

  • Ba ye sia n lo g istic re g re ssio n a na lyse s we re pe rfo rme d

e mplo ying a no rma l prio r distrib utio n fo r the slo pe pa ra me te r c o rre spo nding to drug e xpo sure

  • No rma l prio r e stima te s fo r the Ba ye sia n a na lyse s we re

se le c te d to re fle c t a 99% prio r like liho o d o f tre a tme nt e ffe c t within a n inte rva l o f -0.25 to 0.75

 F

a vo rs a po sitive tre a tme nt e ffe c t (drug he lps pa tie nts)

 Allo ws the po ssib ility o f a ne g a tive tre a tme nt e ffe c t (drug hurts

pa tie nts)

ME T HODS

Statistic s

slide-11
SLIDE 11
  • T

re a tme nt e ffe c t wa s de fine d a s the diffe re nc e in like liho o d o f suc c e ss a t lo w a nd hig h ma g nitude s o f drug e xpo sure

  • L
  • w a nd hig h e xpo sure s we re

fixe d a t fre e -drug AUC 0-24:MI C ra tio s o f 0.01 a nd 25, re spe c tive ly

  • 95% lo we r b o unds fo r tre a tme nt

e ffe c t we re o b ta ine d using 1,000 b o o tstra p sa mple s a nd the b ia s-c o rre c ting a c c e le ra tio n me tho d

ME T HODS

Statistic s

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 a g a inst 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.

slide-12
SLIDE 12
  • 61 pa tie nts who we re b o th c linic a lly e va lua b le a nd

mic ro b io lo g ic a lly e va lua b le a nd ha d suffic ie nt PK da ta we re inc lude d in the se a na lyse s

  • Clinic a l a nd mic ro b io lo g ic a l re spo nse we re hig hly

c o nc o rda nt (95%, 58/ 61)

  • 42 pa tie nts we re c a te g o rize d b o th a s c linic a l a nd

mic ro b io lo g ic a l suc c e sse s

  • 16 pa tie nts we re c a te g o rize d b o th a s c linic a l a nd

mic ro b io lo g ic a l fa ilure s

  • 2 pa tie nts we re c a te g o rize d mic ro b io lo g ic a l b ut no t c linic a l

suc c e sse s

  • 1 pa tie nt wa s c a te g o rize d a s a c linic a l b ut no t mic ro b io lo g ic a l

suc c e ss

RE SUL T S

Analysis Po pulatio n

Bha vna ni SM, Rub ino CM, Ha mme l JP, F

  • rre st A, Da rto is N, Co o pe r A, K
  • rth-Bra dle y J, Amb ro se PG. Pha rma c o lo g ic a l

a nd Pa tie nt-Spe c ific Re spo nse De te rmina nts in Pa tie nts with Ho spita l-Ac q uire d Pne umo nia T re a te d with T ig e c yc line .

Antimic ro b Age nts Che mo the r. Awa iting Dispo sitio n.

slide-13
SLIDE 13

Amb ro se PG, Ha mme l JP, Bha vna ni SM, Rub ino CM, E llis-Gro sse E J, Drusa no GL . A Ba ye sia n Pha rma c o me tric -Ba se d Appro a c h to F a c ilita te Critic a lly Ne e de d Ne w Antib io tic De ve lo pme nt: Ove rc o ming L ie s, Da mn L ie s a nd Sta tistic s.

Antimic ro b Age nts Che mo the r. Awa iting Dispo sitio n.

RE SUL T S

F r e que ntist L

  • gistic Re gr

e ssio n, Clinic al Endpo int

0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0 0.01 0.1 1 10 25

Relative Frequency Probability of Clinical Success Free-Drug AUC024:MIC Ratio

slide-14
SLIDE 14

Amb ro se PG, Ha mme l JP, Bha vna ni SM, Rub ino CM, E llis-Gro sse E J, Drusa no GL . A Ba ye sia n Pha rma c o me tric -Ba se d Appro a c h to F a c ilita te Critic a lly Ne e de d Ne w Antib io tic De ve lo pme nt: Ove rc o ming L ie s, Da mn L ie s a nd Sta tistic s.

Antimic ro b Age nts Che mo the r. Awa iting Dispo sitio n.

RE SUL T S

Baye sian L

  • gistic Re gr

e ssio n, Clinic al Endpo int

0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0 0.01 0.1 1 10 25

Relative Frequency Probability of Clinical Success Free-Drug AUC024:MIC Ratio

slide-15
SLIDE 15

0.0 0.2 0.4 0.6 0.8 1.0 0.0 0.2 0.4 0.6 0.8 1.0 0.01 0.1 1 10 25

Relative Frequency Probability of Clinical Success Free-Drug AUC024:MIC Ratio

Best Estimate

RE SUL T S

Be st Estimate s o f T r e atme nt e ffe c t

M1 Estimate

Amb ro se PG, Ha mme l JP, Bha vna ni SM, Rub ino CM, E llis-Gro sse E J, Drusa no GL . A Ba ye sia n Pha rma c o me tric -Ba se d Appro a c h to F a c ilita te Critic a lly Ne e de d Ne w Antib io tic De ve lo pme nt: Ove rc o ming L ie s, Da mn L ie s a nd Sta tistic s.

Antimic ro b Age nts Che mo the r. Awa iting Dispo sitio n.

slide-16
SLIDE 16

Amb ro se PG, Ha mme l JP, Bha vna ni SM, Rub ino CM, E llis-Gro sse E J, Drusa no GL . A Ba ye sia n Pha rma c o me tric -Ba se d Appro a c h to F a c ilita te Critic a lly Ne e de d Ne w Antib io tic De ve lo pme nt: Ove rc o ming L ie s, Da mn L ie s a nd Sta tistic s.

Antimic ro b Age nts Che mo the r. Awa iting Dispo sitio n.

RE SUL T S

Estimate s o f T r e atme nt Effe c t

Me thod E ndpoint E stimate s of E ffe c t

Be st M1 I CPD M1* F re q ue ntist Mic ro b io lo g ic a l 0.655 0.004 0.166 Clinic a l 0.672 0.043 0.211 Ba ye sia n Mic ro b io lo g ic a l 0.468 0.074 0.301 Clinic a l 0.405 0.085 0.314

* 95% lo we r b o und o f tre a tme nt e ffe c t b a se d upo n 1000 b o o tstra p a na lysis

slide-17
SLIDE 17

E XPOSURE

  • RE

SPONSE ANAL YSE S

Implic atio ns

  • T

he re la tio nships the mse lve s indic a te tha t c o nte mpo r

ar y c linic al e ndpo ints (e .g . suc c e ss o r fa ilure a t the T

OC),

c aptur e a me asur e o f dr ug e ffe c t

  • T

his o b se rva tio n ne g a te s the first o f two re a so ns unde rpinning the use o f histo ric a l da ta to de te rmine the ma g nitude o f tre a tme nt e ffe c t

  • T

he pe rc e ptio n tha t da ta a re no t a va ila b le suppo rting the a b ility o f c o nte mpo ra ry e ndpo ints to c a pture drug e ffe c t

  • T

he b e st e stima te o f the ma g nitude o f the tre a tme nt e ffe c t (c linic a l re spo nse ) is la rg e fo r HAP/ VAP

  • 0.405 fo r Ba ye sia n
  • 0.672 fo r fre q ue ntist
slide-18
SLIDE 18

E XPOSURE

  • RE

SPONSE ANAL YSE S

Implic atio ns

  • F

re q ue ntist a nd Ba ye sia n lo g istic r

e gr e ssio n mo de ls pr

  • vide d e stimate s o f the re spo nse ra te s a s drug

e xpo sure a ppro a c he s ze ro , supplying a n e stima te o f the no -tr

e atme nt r e spo nse

  • T

his o b se rva tio n ne g a te s the se c o nd re a so n unde rpinning the use o f histo ric a l da ta

  • T

he pe rc e ptio n tha t da ta a re no t a va ila b le to pro vide a n e stima te o f the pla c e b o re spo nse ra te .

  • I

t is impo rta nt to no te the ma g nitude s o f tre a tme nt e ffe c t de sc rib e d a b o ve a re b a se d upo n the diffe re nc e in drug e ffe c t a t hig h a nd lo w e xpo sure (ra the r tha n pla c e b o ).

 T

he se ma g nitude s o f the tre a tme nt e ffe c t a re b ia se d lo w

slide-19
SLIDE 19

CONCL USI ONS

A Phar mac o me tr ic -Base d Appr

  • ac h
  • We de mo nstra te d the utility o f Ba ye sia n

pha rma c o me tric -b a se d a na lyse s fo r the de te rmina tio n

  • f tre a tme nt e ffe c t a nd c a lc ula tio n o f NI

ma rg ins

  • I

nc o rpo ra tio n o f b o o tstra pping to o b ta in lo we r b o unds fo r tre a tme nt e ffe c t impro ve d upo n a n o ve rly impre c ise a nd a rb itra ry pra c tic e o f ta king a diffe re nc e b e twe e n inte rva l e stima te s

  • We fe e l tha t this me tho d inte g ra te s c o nte mpo ra ry da ta

with pha rma c o me tric -b a se d a ppro a c he s pro vide s a b ridg e fo rwa rd fo r drug de ve lo pme nt tha t is a nc ho re d

  • n so unde r sc ie ntific fo o ting s