Anti-Tuberculosis Activity of Pyrazinamide Varies by Lesion Type in ...
Transcript of Anti-Tuberculosis Activity of Pyrazinamide Varies by Lesion Type in ...
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