Treatment of Pneumonic Plague:
Medical Utility of Ciprofloxacin
Robert Johnson, Ph.D.
Director Office of Regulatory Affairs
Director,
Affairs,
Division of Microbiology and
Infectious Diseases
NIAID NIH,
NIAID,
NIH DHHS
April
p 3, 2012
Proposed Indication
 The proposed indication for ciprofloxacin is
the treatment of pneumonic plague in adult
patients at an intravenous dose of 400 mg
every 12 hours for 14 days.
 The treatment of pneumonic plague in
pediatric patients (age 1-17 yrs) at an IV
dose of 6
6-10
10 mg/kg (not to exceed 400
mg/dose) every 8 hours for 10-21 days.
2
Ciprofloxacin PIND 113289
Regulatory Pathway
 NIAID does not hold a license for
g or distribution of any
y drug,
g,
manufacturing
including ciprofloxacin.
 NIAID is seeking a decision on whether
this data package could be used by
product manufacturers to support their
own labeling supplemental application(s).
3
Ciprofloxacin PIND 113289
Regulatory Pathway
 A favorable FDA decision that the NIAID
data package will support a labeling
supplement would be shared with all
generic manufacturers of ciprofloxacin.
 This is similar to the approach taken for
doxycycline and penicillin G for inhalation
anthrax (post-exposure),
(post exposure) where FDA’s
FDA s
decision was published in the Federal
Register.
Register
4
Ciprofloxacin PIND 113289
Speaker Topics
 Efficacy of ciprofloxacin in treatment of
pneumonic plague in the African Green
Monkey (AGM) model
 Pharmacokinetics in the AGM and
translation to human dosing
 Unmet medical need
 Benefit/risk of use of ciprofloxacin for
treatment of pneumonic plague
5
Ciprofloxacin PIND 113289
Agenda
Treatment of Pneumonic
Plague: Medical Utility of
Ciprofloxacin
Robert Johnson, Ph.D.
Director, Office of Regulatory Affairs (ORA)
Division of Microbiology and Infectious Diseases (DMID)
National Institute of Allergy and Infectious Diseases (NIAID)
Efficacy of Ciprofloxacin
Therapy for Pneumonic
Plague
M. Louise M.
M
M Pitt,
Pitt Ph
Ph.D.
D
Chief, Virology
United States Army Medical Research Institute of Infectious
Diseases (USAMRIID)
Nonclinical Pharmacokinetics
and Translation to Human
Dosing
Blaire Osborn, Ph.D.
Pharmacokineticist
ORA/DMID/NIAID
Safety and Benefit/Risk of the
Use of Ciprofloxacin for
Treatment of Pneumonic
Plague
Richard Gorman, M.D.
Associate Director for Clinical Research
DMID/NIAID
Summary
Robert Johnson, Ph.D.
Director, Office of Regulatory Affairs
DMID/NIAID
6
USAMRIID
Efficacy off Ciprofloxacin
Effi
Ci
fl
i Therapy
Th
for
f
Pneumonic Plague in the African Green
M k
Monkey
M. Louise M. Pitt, Ph.D.
United States Army Medical Research Institute of
Infectious Diseases
3 April 2012
“Biodefense solutions to protect our nation”
7
Presentation Outline
•
•
•
•
AGM
Challenge Strain
Study Design
Results
Conclusion
Human
“Biodefense solutions to protect our nation”
8
Bacterial Strain
• Yersinia pestis strain Colorado 92 (CO92)
– Biovar Orientalis
– Fatal human case of pneumonic plague
– Obtained from T Quan,
Quan CDC,
CDC Fort Collins,
Collins CO
– Passaged in mouse prior to preparation of the master
seed
– Master seed prepared in 1993 at USAMRIID
S
 Used for all model development and vaccine and
therapeutic efficacy studies
– Working stock frozen (-70oC) in potassium phosphate
buffered glycerol
“Biodefense solutions to protect our nation”
9
Challenge
g Material Preparation
p
• Tryptose blood agar base (TBAB) culture slants are inoculated
with Y.
Y pestis
pestis, CO92.
CO92
• Incubated for two days at 26 – 30 ºC.
• Each slant culture is suspended in 11-22 ml of Heart Infusion
Broth (HIB).
• Suspensions from the slants are pooled, vortexed for approx.
10 sec
sec.
• Optical density (O.D.) of the suspension is determined at 620
nm. (1 unit equates to a Y. pestis concentration of 109 cfu/ml).
• Suspensions diluted with HIB to desired concentration.
– For a 100 LD50 target, a concentration of 3 X 106 cfu/ml
“Biodefense solutions to protect our nation”
10
Study Design
• Species: Chlorocebus aethiops / African
Green monkey (AGM)
• Source: St. Kitts, West Indies
• Vendor: Three Springs Scientific, Inc.
• Health Status: Released from colonyy for studyy
by veterinarian
– Screened for TB,, SA8,, Measles,, STLV-1,,
SA-11, SIV, SRV-VI
“Biodefense solutions to protect our nation”
11
Study Design
• Animals: 12 adults
– (50% ffemale
l / 50% male)
l )
– Weight Range: 3.0 – 6.0 kg
• Study: 2 Iterations
– 10 Treated and 2 Aerosol placebo treated
controls
 5 Treated and 1 Control / iteration
– Randomization stratified by sex and
challenge day
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12
Study Design
• Aerosol Challenge: Head – only (Mass Median Aerosol
Diameter ~1
1.5
5 µm)
•
•
•
•
Challenge Strain: Y. pestis CO92
Target Inhaled Dose: 100 ± 50 LD50
Central Venous Catheters
Telemetry: implants DSI temperature-pulse-pressure
Telemetr
temperat re p lse press re
(TL11M2-D70-PCT)
– Every 30 minutes
– Fever criteria: ≥ 1.5 oC increase over baseline
“Biodefense solutions to protect our nation”
13
Study Design
• Treatment initiation: Fever for 2 hours in the majority
of the animals
• Ciprofloxacin dose: 15 mg/kg IV BID (60-min IV
infusion) for 10 days
– Recommended by the FDA
•
•
•
•
•
Ciprofloxacin levels in sera: reversed phase HPLC
Subjective clinical signs
Manual respiratory rate
Euthanasia criteria established in the protocol
Not blinded
“Biodefense solutions to protect our nation”
14
Clinical Assessments and Euthanasia
Criteria
Score / category
Activity
Behavior
Stimuli Response
Breathing
5
Normal
Normal
Normal
Normal
4
Active
Anti‐social
Enter room
Rapid 3
Slow Active
Depressed
Approach cage
Abdominal breathing
2
Sluggish
Hunched
Rattle cage
Dyspnea
1
I ti
Inactive
I
Ignoring i
Pi h
Pinch
R l
Rales
Maximum Score = 20
• Euthanasia criteria
– A cumulative score of ≤ 5 OR
– Any of the following
 Comatose; loss of consciousness
 Convulsions
 Presence
P
off abdominal
bd i l respiration
i i
with
i h rales
l
“Biodefense solutions to protect our nation”
15
Study Design
Summary of blood draws
Time Post Exposure (days)
0
Treatment (day)
Treatment (day)
3
5
7
9
11
13
0
2
4
6
8
10
15
17
Culture
*
*
*
*
*
*
*
*
*
CBC
*
*
*
*
*
*
*
*
*
Chemistry Panel
Ciprofloxacin
(Peak / Trough)
*
*
*
*
*
*
*
“Biodefense solutions to protect our nation”
16
Simulated Ciprofloxacin Serum
Concentrations in AGMs
Provided by Francis Pelsor (FDA)
“Biodefense solutions to protect our nation”
17
Rationale for Treatment Study Design
Natural History Study of Pneumonic Plague Conclusions
– Fever is the most consistent sign
g of clinical illness
- When fever present, animals are bacteremic
– Y. pestis bacteremia is the gold standard for systemic disease
- Takes 2 days to confirm positive blood culture
– Fever therefore considered an appropriate marker of the
presence of illness
Initiation of Treatment Criteria
– D
Development
l
t off consistent
i t t fever
f
(≥ 1
1.5°C
5°C above
b
baseline
b
li
temperature x 2 hours) in the majority of animals
– Treated as a group
“Biodefense solutions to protect our nation”
18
Results
“Biodefense solutions to protect our nation”
19
Delivered Doses
Iteration #
Order
Animal #
Sex
Wt (kg)
MV (ml)
Dose (cfu)
LD50
1
V494
F
3.9
763
4.2 X 104
124
2
V463
M
5.0
991
3.1 X 104
92
3
V246
M
5.0
1033
4.3 X 104
127
4
V311
M
5.1
846
4.1 X 104
119
5
V527
F
3.4
581
3.3 X 104
97
6
W319
F
3.7
673
3.3 X 104
97
1
W318
F
3.8
600
3.3 X 104
96
2
V524
M
5.7
814
3.9 X 104
114
3
W161
F
3.3
711
3.8 X 104
110
4
V515
M
5.4
965
4.1 X 104
118
5
W352
F
4.3
597
3.8 X 104
110
6
V286
M
5.6
827
3.8 X 104
112
Mean
3.8 X 104
109.7
S.D.
4.1 X 103
11.7
1
2
“Biodefense solutions to protect our nation”
20
Study Outcome
Animal #
Group Outcome
Time to Death (hr)
V494
T
Live
V463
T
Live
V527
T
Live
W319
T
Li
Live
W318
T
Live
W524
T
Live
W161
T
Live
V515
T
Live
V286
T
Live
V246
TT*
Succumbed
248.5
W352
C
Succumbed 98.5
V311
C
Succumbed
99
T - Treated C – Control
•Animal received ~ 8 doses of ciprofloxacin – catheter failure
“Biodefense solutions to protect our nation”
21
Survival Curve
P = 0.0455
One-tailed Fisher’s
exact test
“Biodefense solutions to protect our nation”
22
Euthanized Control
Time of Placebo Initiation
40
Day
Time
Clinical Score
Respiratory Rate (rpm)
AM
20
36
PM
20
28
AM
20
24
PM
20
20
AM
19
24
PM
20
44
AM
17
102
PM
11
82
PM*
5
100
38
37
1
36
35
34
0
24
48
72
Hours Post Exposure
96
120
2
3
CBCs
%
Te
emperature (oC)
39
80
60
40
20
0
LY MO 0
1
2
3
GR Chemistry
Panel:
Normal
4
*Met criteria for euthanasia
Days Post Exposure
“Biodefense solutions to protect our nation”
23
Representative Survivor
Time of Treatment Initiation
Time of Last Treatment
CBCs
80
60
%
Chemistry Panel: Within normal
range throughout study
40
LY
20
MO
0
GR 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Days Post Exposure
“Biodefense solutions to protect our nation”
24
Representative Control and Survivor
Co pa so
Comparison
Time of Treatment Initiation
Time of Last Treatment
40
Tempera
ature (oC)
39
38
37
36
35
34
0
24
48
72
96
120 144 168 192 216 240 264 288 312 336 360 384 408 432 456 480 504 528 552 576 600 624 648 672 696 720
Hours Post Exposure
“Biodefense solutions to protect our nation”
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Temperature (C)
AGM with Catheter Failure
Day
Time
Clinical Score
Respiratory Rate (rpm)
1
AM
20
32
PM
20
24
AM
20
20
PM
20
24
AM
19
24
PM
20
60
AM
18
53
PM
18
44
AM
17
56
PM
17
64
AM
16
56
PM
17
44
AM
17
40
PM
15
52
AM
20
48
PM
16
52
AM
16
48
PM
10
100
AM
11
108
PM
10
112
AM*
11
120
Time of Treatment Initiation
41
40
39
38
37
36
35
34
Time of Last Treatment
* Animal met criteria
0
24
48
72
96
120
144
168
192
Hours Post Exposure
216
240
264
for euthanasia due to
abdominal breathing
with rales; was
anesthetized but
succumbed prior to
delivery of euthanasia
solution
2
3
4
5
6
%
CBCs
7
100
80
60
40
20
0
LY
MO 0
2
4
6
Days Post Exposure
8
10
GR 8
Ch i t Panel:
Chemistry
P
l
High LDH on day
7, otherwise normal
9
10
11
“Biodefense solutions to protect our nation”
26
Bacteremia Summary
Time Post Exposure (days)
Animal #
3
5
7
9
11
13
Treatment (days)
15
17
Terminal
Post Treatment
0
2
4
6
8
10
V494
2830
140
‐
‐
‐
‐
‐
‐
NA
V463
7170
‐
‐
‐
‐
‐
‐
‐
NA
V515
5730
‐
‐
‐
‐
‐
‐
‐
NA
V286
2430
‐
‐
‐
‐
‐
‐
‐
NA
V527
190
‐
‐
‐
‐
‐
‐
‐
NA
W319
5400
73
‐
‐
‐
‐
‐
‐
NA
W318
2900
‐
‐
‐
‐
‐
‐
‐
NA
V524
22000
30
‐
‐
‐
‐
‐
‐
NA
W161
1930
‐
‐
‐
‐
‐
‐
‐
NA
V246
1430
‐
‐
10
W352
993000
> 10E +08 (98.5 hr)
V311
30
2.3E +05 (99 hr)
0 (248.5 hr)
“Biodefense solutions to protect our nation”
27
Ciprofloxacin Peak and Trough Levels (µg/ml)
Day of Treatment
2
Animal #
6
10
Human Target Mean Cmax
Pk Tr
Pk
Tr
Pk
Tr
V494
2.93
<0.5
4.32
<0.5
6.29
<0.5
V463
3.69
<0.5
3.16
<0.5
3.16
<0.5
V515
3.92
<0.5
3.88
<0.5
3.21
<0.5
V286
3.75
<0.5
3.77
<0.5
3.13
<0.5
V527
2.93
<0.5
3.31
<0.5
3.33
<0.5
W319
2.77
<0.5
3.98
<0.5
5.90
<0.5
W318
3.38
<0.5
5.04
<0.5
3.87
<0.5
V524
3.82
<0.5
3.86
<0.5
3.33
<0.5
W161
4.34
<0.5
>ULOQ
<0.5
3.99
<0.5
V246
<0.5
<0.5
Mean
3.5*
3.92^
4.02
4.56
SD
0 53
0.53
0 58
0.58
1 22
1.22
NA
* Mean does not include V246
^ Mean does not include W161
“Biodefense solutions to protect our nation”
28
Pathology
• Necropsies and histopathological evaluations were
performed on the three monkeys that succumbed to
pneumonic plague,
plague
– 2 controls
– Animal with the failed catheter
• Both control monkeys had
– G
Gross evidence
id
off pneumonia
i with
ith fluid
fl id in
i the
th nares,
tracheal lumen and pleural cavity and mediastinal
lymphadenopathy.
– Gross and histological lesions and myriad bacilli consistent
with acute pneumonic plague.
– One had histologic evidence of disseminated intravascular
g
, which has been reported
p
as a sequela
q
to Y.
coagulation,
pestis infection in the AGM and man.
“Biodefense solutions to protect our nation”
29
Summary of Data for AGM with Failed Catheter (V246)
• Animal was given 8 doses of ciprofloxacin
• Drug level on day 2 (<0.5 µg/ml) of treatment suggests animal received
minimal amount of drug prior to complete catheter failure
– Documented continuous catheter issues
• ~ 48 hr after catheter removal animal bacteremic and fever present
• Succumbed within 48 hrs of reappearance of fever
• At d
death
th had
h d lesions
l i
consistent
i t t with
ith pneumonic
i plague
l
– Some resolution of initial pneumonia (fibrin organization, fibroblast
proliferation)
– Recr
Recrudescence
descence of ac
acute
te pne
pneumonic
monic plag
plague
e (al
(alveolar
eolar flooding
flooding, ne
neutrophil
trophil
infiltration and necrosis)
“Biodefense solutions to protect our nation”
30
Conclusion
• Ciprofloxacin is efficacious in the treatment
of p
pneumonic plague
p g in AGM
– 10 day regimen
– Dosage of 15 mg/kg delivered over 60 min twice a
day in AGM mimics the human regimen of 400 mg
IV twice a day in humans
“Biodefense solutions to protect our nation”
31
Acknowledgements
NIAID
Judith Hewitt
Kristin DeBord
USAMRIID
Personnel past and present
FDA
Lewis Schrager
Tracy Macgill
Tracy Macgill
Dianne Murphy
Mary Purucker
Brad Leissa
Francis Pelsor
Francis Pelsor
Janice Soreth
Susan Thompson
Mark Goldberger
William Rodriguez
William Rodriguez
Center for Aerobiological Sciences
Veterinary Medicine Division
Pathology Division
Biostatistics
The research described herein was sponsored by
FDA / NIAID / USAMRIID Interagency Agreements
“Biodefense solutions to protect our nation”
32
Disclaimer
Opinions, interpretations, conclusions, and recommendations are
those of the author and are not necessarily endorsed by the US Army.
All animal research was conducted in compliance with the Animal
Welfare Act and other federal statutes and regulations relating to
animals and experiments involving animals and adheres to principles
stated in the “Guide for the Care and Use of laboratory
Animals”,, Institute of Laboratory Animal Resources, Commission on
Animals
Life Sciences, National Research Council, National Academy
Press, Washington, DC, 1996. The USAMRIID facility, where the animal
research was conducted, is fully accredited by the Association for the
A
Assessment
t and
d Accreditation
A
dit ti off Laboratory
L b
t
Animal
A i l Care
C
International.
I t
ti
l
“Biodefense solutions to protect our nation”
33
Agenda
Treatment of Pneumonic
Plague: Medical Utility of
Ciprofloxacin
Robert Johnson, Ph.D.
Director, Office of Regulatory Affairs (ORA)
Division of Microbiology and Infectious Diseases (DMID)
National Institute of Allergy and Infectious Diseases (NIAID)
Efficacy of Ciprofloxacin
Therapy for Pneumonic
Plague
M. Louise M.
M
M Pitt,
Pitt Ph
Ph.D.
D
Chief, Virology
United States Army Medical Research Institute of Infectious
Diseases (USAMRIID)
Nonclinical Pharmacokinetics
and Translation to Human
Dosing
Blaire Osborn, Ph.D.
Pharmacokineticist
ORA/DMID/NIAID
Safety and Benefit/Risk of the
Use of Ciprofloxacin for
Treatment of Pneumonic
Plague
Richard Gorman, M.D.
Associate Director for Clinical Research
DMID/NIAID
Summary
Robert Johnson, Ph.D.
Director, Office of Regulatory Affairs
DMID/NIAID
Nonclinical Pharmacokinetics
and Translation to
Human Dosing
g
Blaire Osborn, Ph.D.
Office of Regulatory Affairs
Division of Microbiology and
Infectious Diseases
NIAID, NIH, DHHS
April 3, 2012
Approach to This Project
 Plasma concentration data provide the link
between the use of the drug in humans and
in the animal model for disease.
 Ciprofloxacin concentrations attained in
humans are documented in the product label.
 The label concentrations served as the target
for the animal exposures.
 The
Th route
t and
d schedule
h d l off administration
d i i t ti
used matched those approved in the product
label.
label
36
Ciprofloxacin PIND 113289
Ciprofloxacin
 Fluoroquinolone antibiotic
 Concentration-dependent bactericidal
activity
 Bactericidal activity is dependent on both
Cmax and
d AUC
 AUC0-24/MIC ~ 100-125 is associated with
activity against gram negative bacteria
(e.g. Yersinia pestis)
37
Ciprofloxacin PIND 113289
The Target:
g
Ciprofloxacin Concentrations Reported in Humans
A 500 mg oral dose given every 12 hours has been shown to produce an area
under the serum concentration time curve (AUC) equivalent to that produced
by an intravenous infusion of 400 mg ciprofloxacin given over 60 minutes
every 12 hours.
S
Source:
C
Cipro®
® Label - 2/11
/
38
Ciprofloxacin PIND 113289
Data Available
 Two studies of ciprofloxacin in AGMs
1) Pharmacokinetic study 126-03
• Provided pharmacokinetic data in healthy animals
animals.
• Pharmacokinetic modeling and simulation was
employed to select a dose and schedule for the
subsequent efficacy study.
2) Efficacy study A05-04G
• Evaluated the efficacy of the selected dose and
schedule in pneumonic plague-infected animals.
39
Ciprofloxacin PIND 113289
Pharmacokinetic Study
 6 healthy AGMs (3 of each sex)
– Single oral doses of 15, 20 and 25 mg/kg
– Single IV dose of 15 mg/kg
– IV doses of 20 mg/kg once daily for 14 days
 The same animals were used for all doses
following appropriate washout periods.
 Only the IV route was pursued in the
subsequent study, so only those data are
presented.
40
Ciprofloxacin PIND 113289
Mean ± SD Plasma Ciprofloxacin
Concentrations
0.33 hour IV infusion
41
Study SRI B126-03
Ciprofloxacin PIND 113289
First Hour of Study
0 33 hour IV infusion
0.33
42
Study SRI B126-03
Ciprofloxacin PIND 113289
IV Pharmacokinetic
Parameters
Ci
Ciprofloxacin
fl
i Dose
D
15 mg/kg
20 mg/kg
(1st dose)
20 mg/kg
(14th dose)
Cmax (µg/mL)
9.34 ± 0.89
11.7 ± 1.56
27.33 ± 23.95
tmax (h)
0.31 ± 0.06
0.3 ± 0.07
0.23 ± 0.08
6118 ± 991
5456 ± 802
4815 ± 779
AUC(0-t) (µg•h/mL)
(
h/ L)
12 12 ± 2.43
12.12
2 43
18 83 ± 3.22
18.83
3 22
17 82 ± 3.22
17.82
3 22
t1/2 (h)
3.37 ± 0.57
2.8 ± 0.33
2.36 ± 0.5
CL (mL/kg/h)
1277 ± 235
1361 ± 236
1447 ± 291
Parameter
Vz (mL/kg)
Ciprofloxacin PIND 113289
43
Exposure in Humans
and AGMs
Human
1 hr infusion
AGM
15 mg/kg 0.33 hr infusion
AGM AGM
20 mg/kg 0.33 hr infusion
Cmax
(µg/mL)
4.56
9.34
11.7
AUC
AUC (µg/mL•h)
12.7
12.1
18.8
Parameter
Conclusion
Human target Cmax exceeds target exposure based concentration
on label
AUC comparable to target exposure
target exposure
Ciprofloxacin PIND 113289
Cmax and AUC both exceed target exposure
44
Increasing the Infusion Time
0 33 h 1 h Reduces the Cmax
0.33
Concen
ntration (g/mL
L)
10
0.33 h infusion time
Exceeds Target C max
1
0.1
0
1
2
3
4
5
6
7
8
9
10
11
12
Hours
ou s
Con
ncentration (g
g/mL)
10
1 h infusion time
AchievesTarget C max
1
0.1
0
1
Ciprofloxacin PIND 113289
2
3
4
5
6
Hours
7
8
9
10
11
12
45
Simulated Serum Concentrations
i AGMs
in
AGM
Source: USAMRIID Final Report A05-04G: Ciprofloxacin Therapy for pneumonic plague in the
African Green Monkey
46
Ciprofloxacin PIND 113289
Efficacy Study
S d Design
Study
D i
 12 AGMs
 Exposure dose ~100 LD50s of Yersinia pestis
(CO92)
 10/12 given
i
ciprofloxacin
i fl
i (15 mg/kg
/k every 12
hr for 10 days).
 2/12 control group given 5% dextrose in saline
 Serum samples for ciprofloxacin concentration
y were obtained p
prior to dosing
g ((trough)
g )
analysis
and at the conclusion of the 1 hour infusion
(peak) on the 2nd, 6th and 10th day of drug
administration.
administration
47
Ciprofloxacin PIND 113289
PK Results – Efficacy Study
 No animal had q
quantifiable drug
g in trough
g
samples.
 Drug clears completely between doses.
 9/10 drug-treated
drug treated animals had ciprofloxacin in
peak samples.
 9/10 drug-treated animals survived pneumonic
plague.
l
 1/10 drug-treated animals had no detectable peak
ciprofloxacin
p
concentration. This animal had a
malfunctioning drug catheter and did not survive
plague exposure.
 2/2 control animals succumbed to pneumonic
plague.
48
Ciprofloxacin PIND 113289
No Quantifiable Serum Ciprofloxacin Trough
Concentrations in Plague-Infected AGMs
2
Malfunctioning
catheter
Animal ID
V494
V463
V515
V286
V527
W319
W318
V524
W161
V246
Day of Treatment
6
10
Serum Ciprofloxacin Concentrations (µg/mL)
<0.5
<0 5
<0.5
<0.5
<0.5
<0.5
<0.5
<0.5
<0.5
<0.5
<0.5
<0.5
<0 5
<0.5
<0.5
<0.5
<0.5
<0.5
<0.5
<0.5
<0.5
NS
<0.5
<0 5
<0.5
<0.5
<0.5
<0.5
<0.5
<0.5
<0.5
<0.5
NS
Dose and schedule: 15 mg/kg every 12 h as a 1 hour IV infusion for 10 days
Source: USAMRIID Final Report A05-04G: Ciprofloxacin Therapy for pneumonic plague in the African Green
Monkey
Ciprofloxacin PIND 113289
49
Mean Peak Serum Ciprofloxacin Concentrations
are Below the Average
g Human Cmax
in Plague-Infected AGMs
50
Ciprofloxacin PIND 113289
Efficacy Study
C
Conclusions
l i
 Ciprofloxacin-treated
Ciprofloxacin treated monkeys survived
and control monkeys did not.
 The mean Cmax in plague
plague-infected
infected AGMs
is 77-88% of the 4.56 µg/mL Cmax reported
for humans given 400 mg by IV infusion
infusion.
 AUC was not determined in this study,
h
however,
an estimate
ti t off AUC iin th
the FDA
dosing simulation is 12.6 µg•h/mL.
51
Ciprofloxacin PIND 113289
Pharmacodynamics in Adults
Parameter
Human
AGM
Cmax µg/mL
4.56
3.8†
AUC0-12 µg•h/mL
12.7
12.6‡
AUC/MIC
423
420
Cmax/MIC
152
127
• MIC = 0.03 µg/mL
• AUC/MIC ratio of 100 - 125 is associated with activity
against gram negative bacteria
• Cmax/MIC ratio of >10 is associated with activity against
gram negative bacteria
• †Mean peak data (all days)
• ‡Approximated
A
i t d ffrom th
the FDA dosing
d i prediction
di ti
52
Ciprofloxacin PIND 113289
Pediatric Patients
 Ciprofloxacin is approved for use in
pediatric patients for certain severe
infections (complicated urinary tract
tract,
pyelonephritis and anthrax)
 The dose is 6
6-10
10 mg/kg every 8 hours for
10-21 days
53
Ciprofloxacin PIND 113289
Pediatric Exposure
Dose
IV 1 h infusion
Cmax
(µg/mL)
AUC
(µg•h/mL)
<1 year
10 mg/kg
6.1
17.4
1-5 years
10 mg/kg
7.2
16.5
Age
Pediatric patients given 10 mg/kg have higher Cmax and larger
AUC than adults given 400 mg IV
54
Ciprofloxacin PIND 113289
Pharmacodynamics in
Children
Parameter
<1 year
1-5 years
Adults
AGM
Cmax µg/mL
6.1
7.2
4.56
3.8
AUC µg•h/mL
17.4
16.5
12.7
12.6
AUC/MIC
580
550
423
420
Cmax/MIC
203
240
152
127
• MIC = 0.03 µg/mL
• The predicted elimination half-life in children is similar to adults (4-5 hours)
• The
Th drug
d
iis llargely
l excreted
t d unchanged
h
d iin th
the urine
i iin adults.
d lt
55
Ciprofloxacin PIND 113289
Conclusions
 A dose of 15 mg
g ciprofloxacin/kg
p
g every
y 12 h is
sufficient to treat an otherwise lethal exposure to
pneumonic plague in AGMs
 The achieved Cmax in AGMs is ≤88% of that reported
for humans given 400 mg by IV infusion
 The Cmax/MIC ratio in AGMs is below that calculated
for humans (127 in AGMs vs. 152 in humans)
 Given the 400 mg dose in humans results in a
higher Cmax and a similar AUC compared to the
AGMs, a 400 mg IV dose should be sufficient to
treat pneumonic plague in adults
56
Ciprofloxacin PIND 113289
Conclusions continued
Conclusions,
 Pediatric p
patients g
given 10 mg/kg
g g IV every
y 8 hours
have a greater Cmax and AUC than adults given 400
mg IV every 12 hours
 Cmax in AGMs is 56
56-66%
66% of that reported for
pediatric patients given 10 mg/kg by IV infusion.
 The Cmax/MIC ratio in AGMs resulted in efficacy,
y but
is below that calculated for children (127 in AGMs
vs. 203-240 in pediatric patients)
 Given the greater Cmax and AUC in children
children, an IV
dose of 10 mg/kg every 8 h should be sufficient to
treat pneumonic plague in this population.
57
Ciprofloxacin PIND 113289
Agenda
Treatment of Pneumonic
Plague: Medical Utility of
Ciprofloxacin
Robert Johnson, Ph.D.
Director, Office of Regulatory Affairs (ORA)
Division of Microbiology and Infectious Diseases (DMID)
National Institute of Allergy and Infectious Diseases (NIAID)
Efficacy of Ciprofloxacin
Therapy for Pneumonic
Plague
M. Louise M.
M
M Pitt,
Pitt Ph
Ph.D.
D
Chief, Virology
United States Army Medical Research Institute of Infectious
Diseases (USAMRIID)
Nonclinical Pharmacokinetics
and Translation to Human
Dosing
Blaire Osborn, Ph.D.
Pharmacokineticist
ORA/DMID/NIAID
Safety and Benefit/Risk of the
Use of Ciprofloxacin for
Treatment of Pneumonic
Plague
Richard Gorman, M.D.
Associate Director for Clinical Research
DMID/NIAID
Summary
Robert Johnson, Ph.D.
Director, Office of Regulatory Affairs
DMID/NIAID
58
Ciprofloxacin for Pneumonic
Plague
Risks vs. Benefit
Richard L. Gorman, M.D.
Associate Director for Clinical Research
Division of Microbiology and
Infectious Diseases
NIAID, NIH, DHHS
April 3, 2012
Risk vs. Benefit
 Disclaimer:
– Almost everything you have heard about
ciprofloxacin for use in this treatment model
for pneumonic plague is based on intravenous
dosing.
g
– Almost everything
y
g yyou will hear about safety,
y,
efficacy and indications for ciprofloxacin in
this presentation is based on oral dosing.
60
Ciprofloxacin PIND 113289
The Target:
g
Ciprofloxacin Concentrations Reported in Humans
≈
A 500 mg oral dose given every 12 hours has been shown to produce an area
under the serum concentration time curve (AUC) equivalent to that produced
by an intravenous infusion of 400 mg ciprofloxacin given over 60 minutes
every 12 hours.
S
Source:
C
Cipro®
® Label - 2/11
/
Ciprofloxacin PIND 113289
61
Drug Description
 A synthetic broad spectrum antimicrobial agent
 Mechanisms of Action
– Bactericidal
– Inhibits topoisomerase II and topoisomerase IV
– Both are DNA – gyrases enzymes that are involved in
replicating and repairing genetic material
 Mechanisms of Resistance
– Decrease membrane permeability
– Increase drug efflux
– DNA gyrase mutations
62
Ciprofloxacin PIND 113289
Clinical Pharmacology
 Absorption
• Well absorbed orally
• 500 mg orally equivalent to 400 mg IV
• Little first pass metabolism
 Distribution
Di t ib ti
• 20% to 40% protein bound
• Tissue levels often higher than serum levels
 Metabolism
M t b li
• Inhibits human cytochrome P450 1A2 (CYP1A2)
• 4 metabolites in urine: all have weak antimicrobial activity
 Excretion
E
ti
• Renal excretion: 50% unchanged
• Serum half-life 4 hours
63
Ciprofloxacin PIND 113289
Regulatory History
 1987: Ciprofloxacin approved by the FDA for Gram
positive and Gram negative infections
 1991:
1991 IV fformulation
l ti approved
d
 1994: Expanded indications to include
uncomplicated gonorrhea and typhoid fever
 1996: FDA publishes warning about acute tendon
rupture in FDA Medical Bulletin
 1997: Precautions added for CNS events:
convulsion, increases in intracranial pressure
64
Ciprofloxacin PIND 113289
Regulatory History
 1998: Safety information from a pediatric trial added
 2000: Anti- Infective Advisory Committee
recommends and FDA approves indications
for inhalation anthrax: Not by “Animal Rule”
 2004: Pediatric indication for complicated UTI and
pyelonephritis
 2008: Black box warning for acute tendon rupture
 2011: Black box warning for exacerbation of
Myasthenia Gravis
65
Ciprofloxacin PIND 113289
Black Box Warning presently on the Package Insert
66
Ciprofloxacin PIND 113289
Acute Tendon Rupture
 Signal Detected in FDA Adverse Event Reporting System
(AERS)
 Different age
• “Athletically” induced 35 years
• “Ciprofloxacin” induced 64 years
 Estimated
E i
dF
Frequency off ciprofloxacin
i fl
i iinduced
d
d6
6-37/100,000
3 /100 000
• ~ 90% are Achilles Tendons
 Odds Ratio: ciprofloxacin induced:naturally occurring
• 4 X age matched controls
• 46 X age matched controls on corticosteroids
67
Ciprofloxacin PIND 113289
Contraindications
Hypersensitivity to any quinolone
Concomitant administration of
tizanidine
– Tizanidine: decreases muscle tone and spasms in
multiple sclerosis
68
Ciprofloxacin PIND 113289
Warnings
•
•
•
•
•
•
•
•
•
Tendon rupture
Exacerbation of Myasthenia Gravis
Hypersensitivity reactions
Pregnant/Lactating women
Theophylline
Central nervous system effects
C difficile-associated
C.
diffi il
i t d di
diarrhea
h
Peripheral neuropathy
Musculoskeletal disorders in pediatric patients and
arthropathic effects in animals
• Prolongation of the QT interval
Cytochrome
o e P450
50 (C
(CYP450)
50) d
drug
ug interactions
te act o s
• Cytoc
69
Ciprofloxacin PIND 113289
Drug Interactions
• Tizanidine
• Theophylline
• Other Xanthine
Derivatives: Caffeine
• Methotrexate
• Duloxetine
• Oral Anti-coagulants
Anti coagulants
• Ropinirole
• Sildenafil
• Class 1A and III
Antiarrhythmics
• Chelation Complex
Formation
• Omeprazole
• Phenytoin
y
• Glyburide
• Metronidazole
• Cyclosporine
• Probenecid
• Metoclopramide
• Lidocaine
• Clozapine
70
Ciprofloxacin PIND 113289
Special Populations
 Pediatrics
– Multiple pediatric and adult studies demonstrate increased adverse
events related to joints and surrounding tissues
– Preclinical studies: lameness in immature dog
g
• Histopathology: Persistent lesions in the cartilage
 Pregnancy
– Animal reproductive studies have shown adverse effect on fetus
– Multiple limited studies in pregnant women did not demonstrate risk
 Lactation
– No toxicityy signal
g
 Geriatrics
– Acute tendon rupture
 Renal Failure
– Dose adjustment if creatinine clearance ≤ 50 mL/min
Ciprofloxacin PIND 113289
71
Usage
 1987: Declared “safe and effective” by the FDA
 1999
1999: Ci
Ciprofloxacin
fl
i # 11 in
i scripts
i t and
d # 20 iin
dollars spent in the USA. Estimated market ~$1
Billion
 2010: The fourth most commonlyy prescribed
p
antibiotic after amoxicillin, azithromycin and
cephalexin
72
Ciprofloxacin PIND 113289
The Target:
g
Ciprofloxacin Concentrations Reported in Humans
≈
A 500 mg oral dose given every 12 hours has been shown to produce an area
under the serum concentration time curve (AUC) equivalent to that produced
by an intravenous infusion of 400 mg ciprofloxacin given over 60 minutes
every 12 hours.
S
Source:
C
Cipro®
® Label - 2/11
/
73
Ciprofloxacin PIND 113289
Selected Indications
Indication
Severity
Oral Dose (mg)
Duration (days)
Acute UTI
Uncomplicated
250
3
Lower Respiratory Tract
Lower Respiratory Tract
Mild /Moderate
Mild /Moderate
500
7 14
7 –
Chronic Prostatitis
Mild/Moderate
500
28
Bones and Joints
Severe/Complicated
750
28 – 42
500
60
Inhalation Anthrax
74
Ciprofloxacin PIND 113289
Selected Indications
Indication
Severity
Dose (mg)
Duration( days)
Acute UTI
Uncomplicated
250
3
Lower Respiratory Tract
Mild /Moderate
500
7 – 14
400 IV ≈ 500 PO
14
500
28
Pneumonic Plague
Chronic Prostatitis
Mild/Moderate
Bones and Joints
Bones and Joints
Severe/Complicated 750
Inhalation Anthrax
500
28 – 42
28 60
75
Ciprofloxacin PIND 113289
Restatement of Issue
 The mortalityy rate of untreated p
pneumonic p
plague
g is
close to 100%.
 There is presently no antibiotic with a labeled indication
for pneumonic plague.
76
Ciprofloxacin PIND 113289
Conclusion
 Ciprofloxacin has been widely used and is well
understood.
 Ciprofloxacin is labeled safe and effective for similar
infections with similar doses and duration of
treatment.
 Ciprofloxacin is labeled safe and effective for other
infections with both higher doses and longer
duration.
77
Ciprofloxacin PIND 113289
Agenda
Treatment of Pneumonic
Plague: Medical Utility of
Ciprofloxacin
Robert Johnson, Ph.D.
Director, Office of Regulatory Affairs (ORA)
Division of Microbiology and Infectious Diseases (DMID)
National Institute of Allergy and Infectious Diseases (NIAID)
Efficacy of Ciprofloxacin
Therapy for Pneumonic
Plague
M. Louise M.
M
M Pitt,
Pitt Ph
Ph.D.
D
Chief, Virology
United States Army Medical Research Institute of Infectious
Diseases (USAMRIID)
Nonclinical Pharmacokinetics
and Translation to Human
Dosing
Blaire Osborn, Ph.D.
Pharmacokineticist
ORA/DMID/NIAID
Safety and Benefit/Risk of the
Use of Ciprofloxacin for
Treatment of Pneumonic
Plague
Richard Gorman, M.D.
Associate Director for Clinical Research
DMID/NIAID
Summary
Robert Johnson, Ph.D.
Director, Office of Regulatory Affairs
DMID/NIAID
Treatment of Pneumonic
Plague: Medical Utility of
Ciprofloxacin
p
Robert Johnson, Ph.D.
Director Office of Regulatory Affairs
Director,
Affairs,
Division of Microbiology and Infectious
Diseases
NIAID NIH,
NIAID,
NIH DHHS
April 3, 2012
79
Summary
 The efficacy study demonstrated that
p
cured p
pneumonic p
plague
g in
ciprofloxacin
the African Green Monkey model.
 The achieved serum concentrations in the
AGM aligned with those achieved in
humans following doses of 400 mg IV
every 12 hours
hours.
80
Ciprofloxacin PIND 113289
Summary
 Based on the safety profile of ciprofloxacin
and mortality associated with untreated
pneumonic plague
plague, the risk:benefit of the
proposed dosing regimen is comparable to
that of other approved indications of
ciprofloxacin.
 Currently,
Currently there are no licensed antibiotics
with an indication for treatment of
pneumonic plague
plague.
81
Ciprofloxacin PIND 113289
Thank you
y
82