Anti-Tuberculosis Activity of Pyrazinamide Varies by Lesion Type in ...
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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
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Introduction
• Humans develop a wide variety of lesion types when infected with M. tuberculosis.
• Commonly used mouse models develop only intracellular lesions.
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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
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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
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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?
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• 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
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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
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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
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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
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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
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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
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POA activity in C3HeB/FeJ mice
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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
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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
* *
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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
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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
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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