animal efficacy studies for antitubercular agents v. balasubramanian astrazeneca r&d bangalore,...
TRANSCRIPT
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Animal Efficacy Studies for Antitubercular Agents
V. Balasubramanian
ASTRAZENECA R&D BANGALORE, INDIA
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Do we need animal model(s) for determining
antitubercular efficacy?
Is the determination of blood levels sufficient
to predict the outcome against infection?
Some questions…...
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Drug Class In vitro mode in vivo efficacyof killing parameter
• -lactams Time dependent T > MIC
• Aminoglycosides Concentration dependent AUC/AUIC ratio
• Fluoroquinolones Concentration dependent AUC/AUIC ratio
• Macrolides Time dependent AUC [half-lives
and PAE high]
T > MIC [half lives
and PAE low]
Some generalizations…..
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Drug [mg/kg] MIC Cmax Fold T1/2 T > MIC[ug/ml] [ug/ml] [h] [h]
Isoniazid [25] 0.02 7 350 2 18
Rifampicin [25] 0.1 10 100 3.5 28
Rifabutin [25] 0.05 10 200 45 10 d
Rifapentine [25] 0.02 15 750 13.2 5 d
Pyrazinamide [100] 6 30 5 10 36
Ethambutol [100] 2 4 2 3 6
Pharmocokinetic Properties of Anti-mycobacterial Drugs
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Drug [mg/kg] MIC Cmax Fold T1/2 T > MIC[ug/ml] [ug/ml] [h] [h]
Ethambutol [100] 2 4 2 3 6
Ethionamide [100] 1 2 2 2 4
Streptomycin [200] 0.5 3 6 2 8
Amikacin [200] 1 30 30 2 12
Kanamycin [200] 6 30 5 2 6
Sparfloxacin [50] 0.12 2.8 5.6 5 18
Ofloxacin [200] 1.0 10 20 7 35
Linezolid [50] 17.7 1.4
PNU-100480 [50] 7 0.7
Pharmocokinetic Properties of Anti-mycobacterial Drugs
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Effect of Chemotherapy on Survival - Kradolfer et al
Design• Intravenous infection with M. bovis Ravenal strain
• Oral administration of drugs - day 11 & 12 post infection (Sm - s.c.)
• Minimal effect: Prolonging the survival of 50% mice in the treated groups - ED50
1 10 100 10002
3
4
5
6
7
Dose [mg/kg]
Prob
it
H R E A S
Data from: Kradolfer, F. 1970. Antibiotica et Chemotherapia. 16:352-360
ED50 [mg/kg]
Isoniazid (H) 2.7 - 3.4
Rifampicin (R) 4.5 - 6.5
Ethambutol (E) 35 - 55
Ethionamide (A) 75 - 107
Streptomycin (S) 75 - 108
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Bactericidal Effect of Chemotherapy - Kradolfer et al
Design• Intravenous infection with M. bovis Ravenal strain• Bactericidal effect: Culture negativity after prolonged oral treatment
Ref: Kradolfer, F & Schnell, R. 1971. Chemotherapy. 16:173-182
0 1500
1
2
3
4
5
6
7
8
Rif 40
Inh 25
Rif 40 + Inh 25
Rif 40 + Emb 150Rif 40 + Sm 250 s.c
200 250
Days
Log
10
cfu
/ lun
gs
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Bactericidal Effect: An Initial Measure for Comparison
Iv infection (~107 cfu); treatment by gavage started 1 wk pi., for 4 wks.
• Cynamon, M. H., Klemens, S. P., Sharpe, C. A., Chase, S. 1999. A. A. C. T. 43:1189-1191
• Klemens, S. P., Grossi, M. A., Cynamon, M. H. 1994. A. A. C. T. 38: 2245-2248
0
1
2
3
4
5
6
7
8
9
Ctrl Rif20
Rbt20
Rlz20
Inh25
Pza150
Emb125
Lev200
Log
10
cfu
/ lu
ngs
Isoniazid, Rifamycins
2
3
4
5
6
7
8
9
Ctrl Inh25
100480100
Lin100
Epre100
Oxazolidinones
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• Baohong Ji, Lounis, N., Truffot-Pernot C., Grosset,
J. 1995. A. A. C. T. 39: 1341 - 1344
• Lounis, N., Baohong Ji, Truffot-Pernot C., Grosset,
J. 1997. A. A. C. T. 41: 607 - 610
Aminoglycosides & Quinolones
Iv infection (~107 cfu); treatment by gavage started 1 day pi., for 4 wks.
0
1
2
3
4
5
6
7
Ctrl Inh25
Sm200
Kan200
Ami200
Ise200
Spf50
Ofl200
Lev200
Log
10
cfu
/ spl
een
Bactericidal Effect: An Initial Measure for Comparison
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Bactericidal Effect: Infection Dose As a VariableTreatment by gavage started 1 day pi., for 4 wks.
0
1
2
3
4
5
6 Lungs
Spleen
Ctrl Inh25
Mox100
Inh25Mox 100
Log
10
cfu
/ org
an
iv infection (~105 cfu) iv infection (~107 cfu)
0
1
2
3
4
5
6
7
8 Lungs
Spleen
Ctrl Mox100
Inh25Mox 100
Log
10
cfu
/ org
an
• Miyazaki, E., R. E., Bishai, W. R. et al. 1999. A. A. C. T. 43: 85-89
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PK Parameters Significant bactericidal activity in mice
H >>> Z > Emb > Eth [Cmax, T > MIC] H > Z > Emb > Eth
Rfp = Rlz = Rbu > Rif [Cmax, T > MIC] Rlz = Rfp > Rbu > Rif
Ami > Sm = Kan [Cmax] Ami > Sm = Kan
Spar > Lev = Ofla [Cmax] Spar > Lev = Ofla
H > Linezolid > PNU100480 [?] H > PNU100480 > Linezolid
No single parameter can independently Rlz = Rfp > Rbu > Rif = Spar > H
predict across drug classes H > PNU100480> Lin > Z
Z = Ofla > Emb > Eth
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Clinical Efficacy in Tuberculosis
• Early Bactericidal Activity
• Sputum Conversion
• Emergence of resistance
• Relapse Rates
Markers Factors
• Combination Regimen
• Duration of Rx
• Frequency of Dosing
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Inh, Rif, Emb
Pza
Rif
[Early Bactericidal Activity]
[Sterilizing Activity]
108
107
106
105
104
103
102
2 4 6
Cfu
/ml i
n s
pu
tum
Time (months)
Why combination is needed and why is it at least six months long?
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Drug
Isoniazid +++ +
Rifampicin ++ +++
Pyrazinamide + +++
Ethambutol + -
Streptomycin + -
Early Bactericidal Activity [EBA]
Sterilizing Activity
Measured byCfu from sputum for 1st 2 days after onset
of treatment
Relapse rates, 30 mo. after onset of
treatment
Importance Community Individual
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Model for the Initial and Continuation Phases of Rx
Initial Phase Log10 cfu /spleen Spontaneous Relapse
[once daily for 2 months] (6 mo. post)
Untreated 0 6.65 ± 0.19
Inh+Rif 25 + 10 3.00 0.54
Rif+PZA 10 + 150 0.86 0.44
*Inh+Rif+PZA 25 + 10+ 150 2.79 0.73
Continuation Phase % mice with [once daily for 4 months] +ve spleen cultures
*+* 25+10+150 0 35%
*+Inh+Rif 25+10 0 38%
*+Rif+PZA 10+150 0 9%
Ref: J. Grosset, Truffot-Pernot, C., Lacroix, C., Ji. B. 1992. A.A.C.T. 36: 548-551
iv infection (107 cfu/animal) Rx: Oral gavage started 14 days pi.
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Shortened Course - Daily Treatment with Rifapentine
0 4 8 12 16 20 24 280
1
2
3
4
5
6
7
8
9
Inh + Pza +Rfp 20
Inh 25 + Rif 20
Inh + Rif +Pza 150
0 4 8 12 16 20 24 280
1
2
3
4
5
6
7
8
9L
og10
cfu
/ or
gan
Spleen Lungs
Inh+Rif
Inh+Rif+Pza
Inh+Pza+Rfp
7/7
6/7
0/8
7/7
7/7
3/8
7/7
6/7
0/8
7/7
7/7
3/8
Ref: Cynamon, M. H. et al. 1999. A. A. C. T. 43: 2356-2360
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Intermittent treatment with Rifapentine
0
1
2
3
SpleenLungs
ctrl Rfp2H2
Rfp1H1
Rfp2HZ2
4
6
8
Rfp1HZ1
Rx 12 weeks
iv. infection ~107 cfu / animal
Cynamon, M. H. et al. 1999.
A. A. C. T. 43: 2356-2360
Rx 8 weeks
0
1
2
3
4
5
6
7
8
Ctrl Rif6 Rfp1 Rif6HZ6
Rfp1HZ6
Rfp1HZ1
Spleen
Lungs
Log
10 c
fu /
orga
n
47%
Rifr mice
61%
Grosset J. et al. 1998. Am J Respir
Crit Care Med. 157:1436-1440
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0 5 10 15 200
1
2
3
4
5
6
7
untreated
Rb (6/wk)
H (6/wk)HRb (2/wk)
HRb (1/wk)
unvaccinated
Weeks post vaccination
Log
10 c
fu /
sple
en0
BCG Infection
28
Dosing
44 100 128
8 wk12 wk
Prophylaxis
Ref: Jabes, D., Bruna, C. D., Rossi, R., Olliaro, P.
1994. A. A. C. T. 38:2346-2350
*
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Cornell Model for Effect on Reactivation Disease
Inh+Pza7 wks
Test Rx6 wks
Infect iv8.8x105
Cort3 wks
Sac
Cort3 wks
Sac
2 9 15 23 26 32 35Wks.
• Question: After the initial phase, what confers sterilization?• Test regimens were R [15mg/kg]; RH [H25]; RZ [Z150]; RHZ• % positive organs : R 81; RH 63; RZ 65; RHZ 71 [p = 0.3]• However, trend chi-square suggested than addition of H or Z
improved the sterilization effect of R • Answer: At least in the Cornell model, none of the existing
regimens confer complete sterilization
Ref: Dhillon, J., Dickinson, J. M., Sole, K., Mitchison, D. A. 1996. A. A. C. T. 40: 552-555
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Cornell Model for Effect on Reactivation Disease
Inh+Pza12 wks
NoRx
Test Rx18 wks
NoRx
NoRx
Cort
Infect iv3.95x105
Sac
0 12 16 34
Culture -veorgans
41 44 48
Treatment Dosing % Positive Log10cfu Log10cfuorgans spleen lungs
Placebo 100 3.242.2 5.770.11
Inh 25 daily 50 1.932.11 0.711.34
Rif 10 twice weekly 100 4.110.40 5.390.49
Rpt 10 once weekly 100 3.631.18 4.672.35
Inh+Rpt once weekly 37.5 1.462.04 1.782.49
Ref: Miyazaki, E., Chaisson, R. E., Bishai, W.R. 1999. A. A. C. T. 43:2126-2130
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RifapentineAnimal Data
• Daily dosing with Rfp offers the possibility of reduced Rx.
• However, due to long half life, possibility of accumulation
• Based on animal studies, twice weekly better than once weekly
• Based on daily dosing in animals, HZRfp > HZRif (relapse rates)
• However, relapse rates not determined in the case of intermittent Rx!)
• Intermittent Rfp approved by FDA in 1988 (1st in >15 yrs for TB)
Clinical Trial data (surprises!)
• 2HRZ/4H2R2 better than 2HRpZ/H1Rp1, based on relapse data
• 4/5 HIV+ patients in 2HRpZ/H1Rp1 developed Rifres
Ref: Vernon, A. et al. 1998. Am. J. Resp. Crit. Care. Med. 157: A467
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ROUTE OF INFECTION AS A VARIABLE
• Infection Route Intravenous Respiratory
• Infection Dose 106 cfu/animal 10
cfu/animal
• Quantitation cfu / spleen cfu / lungs
• Infrastructure Simple Specialized
Tuberculosis Genitourinary 16.0%
Peritoneal 3.7%Meningeal 4.2%Bone/Joint 8.5%
Other 9.3%
Miliary 9.8%
Pleural 21.5%
Lymphatic 27.0%
Pu
lmon
ary
84.5
%
14.6%
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0 50 100 150 200 2500
2
4
6
8
i.v.
resp.
Time (days)
Log
10cf
u/l
un
gs
Comparison of M. tuberculosis iv. vs. Respiratory Infection in Mice
Ref:1. Robert J. North. 1995. Mycobacterium tuberculosis is strikingly more virulent for mice when given via therespiratory route than via the intravenous route. J. Inf. Dis. 172:1550-1553.
2. Orme, I. M. & F. M. Collins. 1994. Mouse Model of Tuberculosis. In:Bloom, B. R. (ed) Tuberculosis:Pathogenesis, Protection and Control. ASM, Washington D.C., pp113-134.
0 25 50 75 100 1251
2
3
4
5
6
resp.
i.v.
Time (days)
Lungs Spleen
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1 151
2
3
4
5
6
7
untreated
Rif 25 mg/kg
18 21 24 27 30 330 28 56 840
2
4
6
8
10
untreated
Rif 20 mg/kg
*
Model for Evaluating Primary Efficacy
Time (days)
84
Respiratory Challenge(10 cfu / animal)
Infect with M. tuberculosis
Intravenous Challenge (106 cfu / animal)
Log
10 c
fu /
lun
gs
14
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350 20 40 60
0
2
4
6
8 CSU 93L
un
gs
0 20 40 600
2
4
6
8 Erdman
0 20 40 600
2
4
6
8 CSU 93
Sp
leen
0 20 40 600
2
4
6
8 Erdman
Untreated
Inh+Rif
Inh+Rbt
Inh+Rpt
Inh+Rlz
Log
10cf
u /
orga
n
Days
• Resp infection (100 cfu / animal)• Once a week oral Rx
Brooks, J & Orme, I. 1998. A. A. C. T. 42: 3047-3048
1/wk; 5 wks (resp) vs
6/wk;12 wks (iv)
Similar results
Combination Rx in the Respiratory Infection Model
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Infect with M. tuberculosis
0 56 112-2
0
2
4
6
8
10
Untreated
Rif+PZA
126 133 140
[Untreated+Cortisone]
[Test Compound+Cortisone]
Days
Log
10cf
u /
lun
gs
RZ:8wk Test 3wk. 1wk
Model for Evaluating Sterilization [20 wk. assay]
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Bactericidal Effect Determined in Guinea Pigs
0 28 56 84 112 1400
1
2
3
4
5
6
Untreated
Inh+Rif
Days
Log
10cf
u/pr
imar
y le
sion
Ref: Smith, D. W., Balasubramanian, V., Wiegeshaus, E. H. 1991. Tubercle. 72:223-2310
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Culture negativity
•Limitation: poor thera. Index•Not predictable from PK/PD
Relapse rates
2HRZ/4RZ > 6HRZ > 2HRZ/4HR [8%] [34%] [38%]
Towards clinical use...
•No drug given singly •HRZ > HR > RZ > HZ•RE, RS, HE, not effective
•In humans 2HRZ/4HR = 6HRZ [~8%].•2HRZ/4RZ not given due to Z toxicity
• Rlz = Rfp > Rbu > Rif = Spar > H
• H > PNU100480 > Lin > Z = Ofla = Lev
• Z > Emb > Eth
• All significantly better than untreated control
Compounds exhibiting statistically significant reduction in cfu
PK predictive of efficacy within
but not across
Clinical Trial?
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Clues from Animal Efficacy for Clinical Efficacy
• EBA
• Sputum conversion
• Drug resistance
• Relapse rates @ 30 mo.
• Duration of Rx
• Frequency of Rx
Humans• ??
• Rate of culture negativity
• Resistance of survivors
• Relapse rates @ 6 mo.
• Time to culture negativity +
relapse rates @ 6 mo.
• PK profiles such as T1/2
Expt. animals
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Efficacy Models During the Course of Development
• Effect (singly or combination) during early phase of infection
* Survival
* Bacterial counts
• Spontaneous Relapse after initial and continuation phase
• Reactivation following immunosuppression - Cornell
• Prophylaxis
• Effect on immunocompromised hosts
• All of the above in animals infected via the airway will be more
efficient and relevant
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Variables Bactericidal effect Spontaneous relapse*
Vaccination - -
Vaccination-infection interval - -
Route of infection i.v. or resp i.v. or (resp)
Infection inoculum ~107cfu or 100 cfu ~107cfu or (100 cfu)
Infection-Drug interval 2-4 weeks 2-4 weeks
Duration of initial treatment 8 wks (iv); 2 wks (resp) 8 wks; (4 wks)
Duration of continuation Rx - 16 wks; (8 wks)
Duration of immunosuppression - -
Post treatment interval 1 day 1 day, 3 & 6 months
Measure of efficacy Cfu / spleen or lungs Cfu / spleen or lungs
% mice with +ve organ cultures
*conditions shown in parentheses not yet established
Summary of important variables for the different efficacy models
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Variables Sterilization* Prophylaxis
Vaccination - BCG
Vaccination-infection interval - 4 weeks
Route of infection i.v. or (resp) i.v. or resp
Infection inoculum ~107cfu or (100 cfu) ~107cfu or 100 cfu
Infection-Drug interval 2-4 weeks 2-4 weeks
Duration of initial treatment 12 weeks 8-12 weeks
Duration of continuation Rx 12 weeks -
Duration of immunosuppression 3 weeks -
Post treatment interval 1 day, 2-4 weeks 1 day
Measure of efficacy Cfu / spleen or lungs Cfu / spleen or lungs
% mice with +ve organ cultures
*conditions shown in parentheses not yet established
Summary of important variables for the different efficacy models