Pharmacokinetics and pharmacodynamics of pyrazinoic acid

in murine models of tuberculosis

8th International workshop on Clinical Pharmacology of TB Drugs17 September 2015, San Diego, CA

Jean-Philippe Lanoix, M.D.

Center for TB Research

Johns Hopkins University

Introduction

• Humans develop a wide variety of lesion types when infected with M. tuberculosis.

• Commonly used mouse models develop only intracellular lesions.

Introduction

• Humans develop a wide variety of lesion types when infected with M. tuberculosis.

• Commonly used mouse models develop only intracellular lesions.

• Like humans, C3HeB/FeJmice develop necrotic granulomas, caseous pneumonia and, occasionally, cavities.

Davis et al, 2009

Pyrazinoic acid (POA)

• POA is the active metabolite of PZA, produced through the action of the bacterial pyrazinamidase, PncA

• POA is also produced during metabolism of PZA by humans and other mammals

• A past study attributed poor in vivo activity in acute mouse infection to poor oral bioavailability

Via et al, ACS ID 2015Zhang et al, IJTLD 2003

Konno et al, AJRCCM 1967

Pyrazinoic acid (POA)

• Would systemic administration of POA be useful to treat TB caused by pncA mutants?

• Could POA concentrations produced by humans contribute to activity against pncAmutants?

• Is POA orally bioavailable?

• Objectives:

– Describe the PK of POA in plasma, epithelial lining fluid (ELF) and lung lesions of C3HeB/FeJ mice after PZA administration (POA metabolite)

– Describe the PK of POA in plasma and ELF after oral administration of POA (POA dosed)

– Describe the activity of POA after oral administration

POA MIC against H37Rv

7H9 pH 6.8

POA concentrations µg/ml

0 30 45 60 90 120 180 240 360 480 720 960

H37Rv +++ ++ ++ ++ + - - - - - - -

• 16-32µg/ml in 7H10 media at pH 5.8,• 62-496 µg/ml at pH 6.5 in 7H9 or 7H11

Speirs et al, AAC 1995Via et al, ACS ID 2015

Dose-proportional PK in plasmaafter administration of PZA

AUC [0-t]= 1511 h.µg.ml-1

Cmax = 253.3 µg/ml

AUC [0-t]= 221 h.µg.ml-1

Cmax = 52.6 µg/ml

AUC [0-t]= 179 h.µg.ml-1

Cmax = 111.5 µg/ml

AUC [0-t]= 1965 h.µg.ml-1

Cmax = 904.3 µg/ml

0 5 1 0

0 .1

1

1 0

1 0 0

1 0 0 0

1 0 0 0 0

In fe c te d C 3 H e B /F e J

1 5 0 m g /k g

In fe c te d B A L B /c

1 5 0 m g /k g

U n in fe c te d B A L B /c

1 5 0 m g /k g

In fe c te d C 3 H e B /F e J

4 5 0 B ID m g /k g

A

T im e (h o u rs )

PO

A c

on

ce

ntr

ati

on

s (

µg

/ml)

LO Q

Dose-proportional PK in plasmaafter administration of POA

Dose-proportional PK in lesionsafter administration of PZA

0 2 4 6 81

10

100

1000

A

150 mg/kg

450 mg/kg BID

Time (hours)

PO

A c

on

cen

trati

on

s (

µg

/ml)

LOQ

Open symbols are intralesional concentrationsSolid and dotted lines are duplicates

0 5 1 0 1 5

0 .1

1

1 0

1 0 0

1 0 0 0

1 0 0 0 0

B

T im e (h o u rs )

PO

A c

on

ce

ntra

tio

ns

(µ

g/m

l)

ELF PK of POA

No dose-proportional PK in ELF

POA activity in C3HeB/FeJ mice

POA activity in C3HeB/FeJ mice

Un

t

PZ

A 7

5b

id

PZ

A 1

50q

d

PZ

A 4

50b

id

PO

A 7

5b

id

PO

A 1

50q

d

PO

A 4

50b

id

0

2

4

6

8

CF

U c

ou

nt

(lo

g1

0/l

un

g)

A

POA activity in BALB/c mice

Un

t

PZ

A 1

50q

d

PO

A 3

7.5

PO

A 7

5q

d

PO

A 7

5b

id

PO

A 1

50q

d

PO

A 4

50q

d

PO

A 4

50b

id

2

4

6

8

CF

U c

ou

nt

(lo

g1

0/l

un

g)

B

* *

Conclusion

• POA has good bioavailability, good dose proportional exposures in plasma, comparable to those produced by PZA administration

• Possibly a saturable secretion in ELF

• No dose proportional activity

Conclusion

• Future direction to improve POA efficacy:

– more efficient delivery of POA into (or near to) bacilli at the site of infection

– through new pro-drugs metabolized by M. tuberculosis,

– novel vehicles to deliver a POA payload to infected macrophages,

– intrapulmonary administration

AcknowledgementsNuermberger LABEric Nuermberger

Aimee OrmondFabrice Betoudji

Si-Yang LiJin Lee

Rokeya TasneenSandeep TyagiPaul Converse

Rutgers UniversityVéronique Dartois

Matthew Zimmerman

FundingNIH-NIAID (supplement to P30 AI-094189), NIH (1R01AI106398-01), Bill & Melinda Gates Foundation (OPP1037174 and OPP1066499),

Collège des Universitaires des Maladies Infectieuses et Tropicales (CMIT)

Center for TB Research

Colorado State UniversityAnne Lenaerts