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Penetration of rifampin and rifapentine
into diseased lung in the rabbit cavity
pulmonary disease model of TB
Dalin Rifat, Ph.D.
9-17-2015
D I V I S I O N O F
CLINICAL
PHARMACOLOGY
• Rifampin (RIF) and rifapentine (RPT) are potent sterilizing drugs
• In mouse models daily RPT can cure TB in 3 months
• In clinical trials, substitution of 10 mg/kg of daily RIF with 10 mg/kg of
daily RPT is not more efficacious; higher doses of RPT seem to
improve microbiologic outcomes
• There is little information about the penetration of rifamycins into
infected areas in humans
• The rabbit cavitary pulmonary TB model has human-like TB pathology
(necrotic granulomas and cavities) and may provide some insights
into drug distribution of anti-TB drugs in humans.
Background
Rabbit cavitary model
105 -106 CFU/ml of Mtb H37Rv
Cavitary
lesion
Aerosol infection
Bronchoscope infection
Injection of Mtb:H37Rv
1-0.3ml
105 -107 CFU/ml
Experimental design
Drug delivery:IV infusion
Plasma
70%methanol
Homogenate
LC/MS
MALDI-MSI
Uninvolved lung tissue (UI)
Tissue surrounding lesion (SL)
Cellular lesion (LE)
Cavitary lesion wall (CAW)
caseum (CAC)
RIF: 5mg/ml
RPT: 10mg/ml
In vehicle solution
RIF : 10mg/kg
RPT: 30mg/kg (single dose)
20mg/kg 9multiple-dose)
Optimizing experimental conditions: healthy rabbits
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0 100 200 300 400 500
Co
nc.
of
RIF
(n
g/g
)
Conc. of lung tissue (mg/ml)
RIF in lung tissue
0
1000
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6000
0 100 200 300 400 500
Co
nc.
of
RP
T (
ng
/g)
Conc. of lung tissue (mg/ml)
RPT in lung tissue
0
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15000
20000
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30000
0 1 2 3 4 5 6 7 8 9 10111213141516
Co
nc.
of
RP
T(n
g/m
l o
r n
g/g
)
post IV-injection (hour)
plasma (ng/ml)
lung tissue(ng/g)
PK of RPT (30mg/kg)
in plasma and lung tissueCmax : 27µg/ml (0.5h)
AUC 0-15 : 100 µg*h/ml
T ½: 4.5h
In human plasma PK of single dose of RPT
(20mg/kg, oral administration)
Cmax : 25µg/ml (5h)
AUC 0-12 : 403µg*h/ml
T ½: 25.9 h
Clin Pharmacol Ther. 2012 May ; 91(5): . doi:10.1038/clpt.2011.323
Penetration of single dose of RIF (10mg/kg) by LC/MS : rabbits with TB disease
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0 1 2 3 4 5 6 7
Co
nc.
of
RIF
(n
g/m
l o
r n
g/g
)
Post IV-injection (hour)
PK of RIF in plasma anddiseased lung
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12000
14000
2 3 6
Co
nc.
of
RIF
(n
g/g
)
Post IV-injection (hour)
Penetration of RIF in diseased lung
** • P<0.02
** p<0.01
*
*
C max : 17µg/ml
AUC 0-6 : 40 µg*h/ml
T ½: : 2h
UI : uninvolved lung tissue
SL : tissue surrounding lesion
LE: cellular lesion
CAC: caseum from necrotic lesion
In human plasma PK of single dose
(10mg/kg, oral administration)
C max : 10.5µg/ml
AUC 0-12 : 57.5 µg*h/ml
T ½: : 3h
Clin Pharmacol Ther. 2012 May ; 91(5): . doi:10.1038/clpt.2011.323
2h 3h 6h
MALDI-MSI and H&E staining of lung tissue: single dose of RIF
Necrotic lesion Cellular lesion Necrotic lesion
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50000
60000
0 1 2 3 4 5 6 7
Co
nc.
of
RP
T (
ng
/ml
or
ng
/g)
Post IV-injection (hour)
PK of RPT in plasma anddiseased lung
Penetration of single dose of RPT (30mg/kg) by LC/MS :
rabbits with TB disease
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20000
30000
40000
50000
60000
70000
80000
2 3 6
Co
nc.
of
RP
T (
ng
/g)
Post IV-injection (hour)
Penetration of RPT in
diseased lung
*p <0.01
UI: uninvolved lung tissue
LE: cellular lesion
CAW: cavitary lesion (wall)
CAC: cavitary lesion (caseum)
SL: tissue surrounding lesion
**
C max : 50µg/ml
AUC 0-6 : 175µg*h/ml
T ½: : 4.5h
2h 3h 6h
MALDI-MSI and H&E Staining of lung tissue : single dose of RPT
cellular lesion cavitary lesion cavitary lesion
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35000
40000
0 30min 5h 30min 4h 30min 2h
First dose Second dose Third dose
Co
nc.
of
RIF
(n
g/m
l)
PK of RIF in plasma (M2h)
05000
100001500020000250003000035000400004500050000
0
30
min 4h
30
min 4h
30
min 4h
30
min
12
h
First dose Seconddose
Third doseForth dose
Co
nc.
of
RIF
(n
g/m
l)
PK of RIF in plasma (M12h)
0
5000
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15000
20000
25000
30000
M2h M12h
Co
nc.
of
RIF
(n
g/g
)
Penetration of RIF in different compartments of TB disease
UI: uninvolved lung tissue
LE: cellular lesion
CAW: cavitary lesion (wall)CAC: cavitary lesion (caseum)
SL: tissue surrounding lesion
AUC 0-12.5:241µg*h/ml AUC 0-26:431µg*h/ml
In human plasma PK of multiple-dose
(10mg/kg, oral administration, 14 days)
Cmax : 7.5µg/ml (5h)
AUC 0-12 : 45.2µg*h/ml
T ½: 2.4 h
Clin Pharmacol Ther. 2012 May ; 91(5): .
doi:10.1038/clpt.2011.323
Penetration of multiple-dose of RIF (10mg/kg) by LC/MS :
rabbits with TB disease
M2h
M12h
Uninvolved lung Cavitary lesion (1) Cavitary lesion (2)
Uninvolved lung Necrotic lesionCellular lesion
MALDI-MSI and H&E staining of lung tissue : multiple-dose of RIF
0
10000
20000
30000
40000
50000
60000
70000
80000
0 30min 3h 30min 3h 30min 3h 30min 2h
First dose Second dose Third dose Forth dose
Co
nc.
of
RP
T (
ng
/ml)
PK of RPT in plasma (M2h)
0
10000
20000
30000
40000
50000
60000
70000
0 30min 3h 30min 3h 30min 3h 30min 12h
First dose Second dose Third dose Forth dose
Co
nc.
of
RP
T (
ng
/ml)
PK of RPT in plasma (M12h)
UI: uninvolved lung tissue
SL: tissue surrounding lesion
LE: cellular lesion
CAW: cavitary lesion (wall)
CAC: cavitary lesion (caseum)0
10000
20000
30000
40000
50000
60000
70000
80000
M2h M12h
Co
nc
. o
f R
PT
(n
g/g
)
Penetration of RPT in different compartments of TB disease
Penetration of multiple-dose of RPT (20mg/kg) by LC/MS :
rabbits with TB disease
AUC 0-13: 494µg*h/ml AUC 0-23: 833µg*h/ml
In human plasma PK of multiple-dose
(20mg/kg, oral administration, 14 days)
Cmax : 34.1µg/ml (5h)
AUC 0-12 : 483 µg*h/ml
T ½: 16h
Clin Pharmacol Ther. 2012 May ; 91(5): .
doi:10.1038/clpt.2011.323
M2h
M12h
Uninvolved lung
Cavitary lesion (1) Cavitary lesion (2)Uninvolved lung
Cellular lesion
Necrotic lesion
MALDI-MSI and H&E staining of lung tissue: multiple-dose of RPT
Conclusions
• We have established the PK of IV RIF and IV RPT in rabbits; half-life of RPT
is much shorter in rabbits than humans. Data can be used to determine
human-equivalent dosing for subsequent single and multiple dose
experiments.
• Penetration into granulomatous lesions was excellent for both RIF and RPT
and drugs remained in this type of lesions longer than in healthy lung tissue.
• Penetration of RIF into caseum in necrotic or cavitary lesions was poor, but
accumulation of RIF in caseum can be achieved by giving multiple- dose of
RIF with longer exposure time, which is consistent with that in human
necrotic caseum.
• RPT penetrated into caseum even poorer than RIF in comparison to their
uninvolved lung tissue; multiple dosing with longer exposure time seemed
not to improve penetration of RPT into caseum during the observation time,
which remains to be confirmed in humans.
Brendan Prideaux1,et al. Nature medicine online 7 September 2015; doi:10.1038/nm.3937
JHU- Divisions of Clinical Pharmacology and
Infectious Diseases
Dr. Kelly Dooley
JHU- Bishai laboratory (rabbit model)
Mike Urbanowski
Robyn Becker
Haidan Guo
Laurene Cheung
Brian Luna
Bill Bishai
JHU-Clinical Pharmacology Analytical Laboratory (tissue/plasma PK)
Teresa Parsons
Thuy Hoang
Mark Marzinke
JHU-Jain laboratory (PET imaging)
Mariah Klunk
Peter DeMarco
Alvaro Ordonez
Sanjay Jain
Rutgers (MALDI)
Brendan Prideaux
Veronique Dartois
UCSF (mathematical modeling)
Rada Savic, pharmacometrician
NIH/DAIDS
ACTG Novel Formulations Award
Acknowledgements
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