Transcript GROSSET_TBETHICS

Ongoing trials with new drugs/regimens:
the fluoroquinolone case
J. Grosset, E. Nuermberger & R.Chaisson
Center for TB Research, Johns Hopkins University
1. What are fluoroquinolones ?
2. What is the experimental antituberculosis
activity of fluoroquinolones ?
3. What information is available on the
antituberculosis activity of fluoroquinolones
in humans ?
4. What are the ethical issues in clinical trials
with fluoroquinolones?
1. Fluoroquinolones
Fluoroquinolones are synthetic antimicrobial agents
derived from nalidixic acid and characterized by a
fluorine atom at position 6 :
- Ciprofloxacin (C)
- Ofloxacin (O)
- Levofloxacin (L)
- Sparfloxacin (S)
- Moxifloxacin (M)
- Gatifloxacin (G)
2
µg/ml
2.1. MICs (μg/ml) of main quinolones
against M. tuberculosis
2.2. Comparative pharmacokinetics and pharmacodynamics of fluoroquinolones after single oral dose in humans*
Drug
Pharmacokinetics
Pharmacodynamics
Dose
(mg/kg)
Cmax
(µg/ml)
AUC24
(mg.h/L)
MIC90
(µg/ml)
CMax/MIC90
AUC24/MIC90
Ciprofloxacin
250 (4.1)
500 (8.3)
1.5 ± 0.43
1.9 ± 2.9
5.75 ± 1.25
10-19
1.0
1-2
2-3
5-6
10-20
Ofloxacin
400 (6.6)
600 (10)
4
11
48
58
2.0
2
5
24
29
Levofloxacin
500 (8.3)
6.21 ±1.34
44.8
1.0
5.7
40-50
Sparfloxacin
200 (3.3)
400(6.6)
0.70
1.18
18.7
33
0.5
2
2-4
40
66
Moxifloxacin
100 (1.4)
400 (6.6)
0.43 ±1.23
4.34 ± 1.61
6.18 ± 1.18
39.3 ± 5.35
0.5
1
9
12-15
80
Gatifloxacin
400 (6.6)
3.42 ± 0.74
30 ± 3.8
0.5
7
60
* from Hooper et Wolfson, 1985; Siefert et al., 1999; Hooper, 2000; Lubasch et al., 2000; Wright et al., 2000;
Schentag et al., 2001.
2.3. Antituberculosis activity of
fluoroquinolones in mice
Change in log10 spleen CFU
Bactericidal activity of fluoroquinolones
alone against M. tuberculosis in mice
1.5
1
0.5
0
-0.5
-1
-1.5
-2
-2.5
-3
-3.5
Control
INH 25
INH 25
O 150
Levo 150
Spar 50
Spar 50
Moxi 100
0
1
2
3
4
Weeks of treatment
Ji et al, AAC (1995); 39:1341
Ji et al, AAC (1998); 42:2066
2.4. Conclusions from experimental data
1. Among all fluoroquinolones, MXF has the
most favorable PK/PD parameters
2. Used alone in the mouse model, MXF has the
most potent bactericidal activity among all
fluoroquinolones
3. The bactericidal activity of MXF is close to
that of INH
3a.Activity of fluoroquinolones in humans
• In 1985, Tsukamura et al., treated 19 patients with
ofloxacin alone for 6 to 9 months: 5 became culture
negative. No side-effect.
• Many anecdotal reports confirmed these findings.
• In 1993, ATS and CDC noted that fluoroquinolones
might be active for MDR-TB treatment.
• In 2003, ATS/CDC guidelines recommended
fluoroquinolones for MDR-TB treatment but not as
first-line agents. Why?
3b.Why fluoroquinolones were not
recommended as first-line agents?
• All EBA study with fluoroquinolones other than
MXF failed to demonstrate powerful activity
• The addition of a fluoroquinolone to the standard
regimen failed to demonstrate benefit in terms of
time to culture conversion and relapse rate.
• However, in a trial (TRC Chennai 2002),the
addition of ofloxacin to the standard regimen and
the shortening of treatment duration to 4 and 5
months was gave positive results. But this trial
raised ethical issues.
4. Ethical Rules for Clinical Trials
• Autonomy - consent of the patient
• Beneficence – the patients should benefit, or at
least not suffer, from being in the trial
• Equipoise – when randomizing, the
investigators must be equally comfortable with
the alternative treatment arms
• Justice – the benefits and burdens of research
should be shared fairly to the extent possible
In practice
1. Basic fact: the present 6-month standard regimen
CAN cure 100% of newly diagnosed patients with
drug susceptible organisms and regular intake of
drugs
2. Consequently,
1st. Patients should not be deprived of a 100% active
treatment
2nd. Patients should not be exposed to undue risks of
toxicity
3rd. The trial should be scientifically founded
(prerequisite experimental & clinical evidence)
4th. The trial should be scientifically designed and
performed
4.1. No risk of depriving patients
from an active treatment
Any deviation in the drug content and the duration of the
standard treatment is unacceptable without solid
scientific experimental/clinical evidence .
For example, there is no evidence* that
(i) the duration of treatment might be reduced, and
(ii) the time to smear and culture conversion is shortened
with the use of any new drug
* Possibility is not evidence
4.2. No exposition to undue risk of
toxicity
• Except in a 6-month study conducted in Italy
with no side effect (Valerio et al., 2003), MXF
has not been given for several weeks or
months
• Therefore, preliminary studies in which MXF
is substituted for ethambutol are now in
progress (CDC, Johns Hopkins) with two
primary end-points: culture conversion
within two months and safety/tolerability.
4.3. The trial should be scientifically
founded
• On experimental data
• On clinical data
Both should provide rationale for
undertaking of the trial
Moxifloxacin (MXF) in combination
with first-line agents
Aim of the experiment: determine the effect of
1. The addition of MXF to the standard
regimen, 2RHZ/4RH.
2. The substitution of MXF for each of the
individual components of the standard
regimen.
L
1
u
n
g
C
F
U
c
o
u
n
t
s
0
9
8
7
U
n
2
2
t
r
e
a
t
R
H
Z
+
R
H
Z
M
e
d
4MRH
+
2 RM
Z+
4 RM
2 Z
M
H+
4 M
H
6
4
R
+
H
4
R
H
M
5
2
R
H
4
3
Log CFU in entire lung
2
1
0
0
1
D
u
r
2
a
t
i
o
n
3
o
f
t
r
e
a
4
t
m
e
n
5
t
(
m
o
s
6
.
)
Results of log10 CFU counts from lung homogenates.
Early Bactericidal Activity (EBA) of Drugs in
Pulmonary Tuberculosis
(Fall in log10 CFU counts during the first 2 days)
Authors
INH
RIF
MXF
Hafner et
al.,1997
Gosling et
al., 2003
Pletz et
al., 2003
0.57
-
-
0.77
0.28
0.53
0.40
-
0.54
Consequences of scientific foundation
• CDC is working with the Russian Research
Institute for Phthisio-pulmonology to
implement a phase II to evaluate MXF in
place of isoniazid in the initial phase of
treatment (Time to culture conversion,
Safety/tolerability)
• Investigators at Johns Hopkins are also
developing a similar approach
4.4. The trial should be scientifically
designed and performed
The protocol should follow the rules of
controlled clinical trial :
- Control group
- Adequate number of patients to obtain
significant results
- Adequate organization of drug intake, and
clinical and laboratory monitoring
- Definition of primary and secondary end- point
Conclusions
• At long last (R. O’Brien, 2003),
improving treatment of tuberculosis
is more than a distant dream.
• For such a dream not to be a
nightmare for some patients, all
investigators should comply with
ethical rules.
Alligato gozaimasu
FIN
END