Ongoing trials with new drugs/regimens: the fluoroquinolone case J. Grosset, E. Nuermberger &...
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![Page 1: Ongoing trials with new drugs/regimens: the fluoroquinolone case J. Grosset, E. Nuermberger & R.Chaisson Center for TB Research, Johns Hopkins University.](https://reader035.fdocuments.net/reader035/viewer/2022062315/56649eab5503460f94bb179d/html5/thumbnails/1.jpg)
Ongoing trials with new drugs/regimens: the fluoroquinolone case
J. Grosset, E. Nuermberger & R.ChaissonCenter 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?
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1. FluoroquinolonesFluoroquinolones 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
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2.1. MICs (μg/ml) of main quinolones against M. tuberculosis
C 0 L S M
0.12
0.25
0.5
8
1
2
4
Fluoroquinolones
range
MIC 90
µg
/ml
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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 ± 0.431.9 ± 2.9
5.75 ± 1.2510-19
1.0 1-22-3
5-610-20
Ofloxacin 400 (6.6)600 (10)
411
4858
2.0 25
2429
Levofloxacin 500 (8.3) 6.21 ±1.34 44.8 1.0 5.7 40-50
Sparfloxacin 200 (3.3)400(6.6)
0.701.18
18.733
0.5 22-4
4066
Moxifloxacin 100 (1.4)400 (6.6)
0.43 ±1.234.34 ± 1.61
6.18 ± 1.1839.3 ± 5.35
0.5 19
12-1580
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.
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2.3. Antituberculosis activity of fluoroquinolones in mice
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Bactericidal activity of fluoroquinolones alone against M. tuberculosis in mice
-3.5-3
-2.5-2
-1.5-1
-0.50
0.51
1.5
0 1 2 3 4
Change in log10 spleen CFU
ControlINH 25INH 25O 150Levo 150Spar 50Spar 50Moxi 100
Ji et al, AAC (1995); 39:1341
Ji et al, AAC (1998); 42:2066
Weeks of treatment
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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
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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?
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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.
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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
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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
toxicity3rd. The trial should be scientifically founded
(prerequisite experimental & clinical evidence)4th. The trial should be scientifically designed and
performed
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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
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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.
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4.3. The trial should be scientifically founded
• On experimental data
• On clinical data
Both should provide rationale for undertaking of the trial
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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.
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L u n g C F U c o u n t s
0
1
2
3
4
5
6
7
8
9
1 0
0 1 2 3 4 5 6
D u r a t i o n o f t r e a t m e n t ( m o s . )
Lo
g C
FU
in e
nti
re lu
ng
U n t r e a t e d
2 R H Z + 4 R H
2 R H Z M + 4 R H M
2 R H
M+4 RH2 RMZ+4 RM2 MHZ+4 M
H
Results of log10 CFU counts from lung homogenates.
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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
0.57 - -
Gosling et al., 2003
0.77 0.28 0.53
Pletz et al., 2003
0.40 - 0.54
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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
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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
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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.
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Alligato gozaimasu
FINEND