![MOXI
Tuberculosis (2008) 88(2) 127–131
Moxifloxacin
Generic and additional names: Moxifloxacin Hydrochloride
CAS name: 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[(4aS,7aS)-
octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-4-oxo-3-quinolinecarboxylic
acid hydrochloride
CAS registry #: 186826-86-8
Molecular formula: C21H24FN3O4·HCl
Molecular weight: 437.89
Intellectual property rights: Bayer
N
CO2H
O
NHN
OMe
F
H
H
Brand names: Actimax (Sankyo); Actira (Bayer); Avelox (Bayer); Octegra (Bayer); Proflox (Esteve); Vigamox
(Alcon)
Derivatives: Moxifloxacin is a quinolone/fluoroquinolone antibiotic related to ciprofloxacin, enoxacin,
fleroxacin, gatifloxacin, gemifloxacin, grepafloxacin, levofloxacin, lomefloxacin, norfloxacin, ofloxacin,
pefloxacin, prulifloxacin, rufloxacin, sparfloxacin, temafloxacin, trovafloxacin, sitafloxacin
Solubility: Soluble in water
Polarity: Log P 2.033 [DrugBank]
Melting point: 238 242ºC [DrugBank]
Formulation and optimal human dosage: Avelox tablets: containing moxifloxacin hydrochloride (equivalent to
400 mg moxifloxacin).
Avelox i.v.: 250 ml latex-free flexibags as a sterile, preservative-free, 0.8% sodium chloride aqueous solution
of moxifloxacin hydrochloride (containing 400 mg moxifloxacin).
400 mg daily dose
Basic biology information
Drug target/mechanism: Moxifloxacin (MOXI: 8-meth-
oxy-quinolone), and quinolones in general, exert
their effects by trapping a DNA drug enzyme
complex and specifically inhibiting ATP-dependent
enzymes topoisomerase II (DNA gyrase) and topoi-
somerase IV. In most bacteria gyrase facilitates DNA
unwinding and topoisomerase IV activates decatena-
tion. DNA gyrase (reviewed in Champoux 20011
), an
essential enzyme involved in the replication, tran-
scription and repair of bacterial DNA, consists of two
components arranged in a GyrA2/GyrB2 complex en-
coded by the gyrA and gyrB genes. Topoisomerase IV,
encoded by parC and parE, appears to be absent
from Mycobacterium tuberculosis and from several
other bacteria including Helicobacter pylori and
Treponema palladium.2
Recently the single M. tuber-
culosis type II topoisomerase has been cloned into
Escherichia coli and exhibits classical supercoiling
activity as well as enhanced decatenation, cleavage
and relaxation activities.3
This is presumably the
single target for MOXI in the mycobacteria.
Drug resistance mechanism: Resistance to MOXI
occurs at a rate of 1.8×10 9
to <1×10 11
in vitro
for Gram-positive bacteria [FDA label]. There is
no known cross-resistance between MOXI and other
classes of antimicrobials, however cross-resistance
has been observed between MOXI and other
fluoroquinolones. Resistance (3 5-fold higher than
wild-type [WT]) can arise in M. tuberculosis from
changes in either gyrA or gyrB; furthermore specific
mutations in gyrA resulted in hypersensitivity to
quinolones.4
Most mutations conferring changes in
drug sensitivity occur in a quinolone-resistant region
in gyrA and more rarely in gyrB. Both resistance
and hypersensitivity were reflected in the IC50s of
DNA gyrase overexpressed and purified from the
concomitant M. tuberculosis strains.4
Many MDR
clinical strains are sensitive to MOXI (resistance
is defined as MIC > 2 mg/ml) even where they are
also resistant to ofloxacin (OFL); however several
strains in the same study were resistant to MOXI
and OFL and in these cases the mutation was often
in gyrA (A94G). The authors conclude that careful
1472-9792/$ - see front matter © 2008 TB Alliance. Published by Elsevier Ltd. All rights reserved.](https://image.slidesharecdn.com/moxig-150104111328-conversion-gate01/85/Moxi-g-1-320.jpg)
![128 Moxifloxacin
monitoring of resistance to MOXI is warranted in
clinical settings.5
In-vitro potency against MTB: M. tuberculosis H37Rv:
MIC 0.5 mg/ml.4
M. tuberculosis H37Rv comparative MICs for quino-
lones: ciprofloxacin 0.5 mg/ml, OFL 0.71 mg/ml,
levofloxacin (LEV) 0.35 mg/ml, MOXI 0.177 mg/ml,
gatifloxacin (GATI) 0.125 mg/ml.6
Spectrum of activity: MOXI has broad Gram-
positive and Gram-negative activity. It shows in-
vitro and clinical efficacy against Staphylococcus
aureus, Streptococcus pneumoniae, Str. pyogenes,
Haemophilus influenzae, H. parainfluenzae, Kleb-
siella pneumoniae, Moraxella catarrhalis, Chlamy-
dia pneumoniae and Mycoplasma pneumoniae. MOXI
has activity against mycobacteria in addition to
M. tuberculosis; MOXI is more active against
M. kansasii than M. avium complex: specifically MIC90
for M. avium > M. intracellulare > M. kansasii at 4,
2 and 2 mg/ml respectively. MIC90 for M. chelonae >
M. fortuitum at 16 and 0.5 mg/ml, respectively.7
Other in-vitro activity: MPC90 against M. tuberculo-
sis strains: MOXI 1 mg/ml, LEV 1 mg/ml, ciprofloxacin
4 mg/ml, OFL 2 mg/ml.8
MOXI, like other quinolones, is bactericidal. The
bactericidal activity of MOXI against M. tuberculosis
was decreased somewhat when ethambutol (ETH)
or high rifampin (RIF) and MOXI were tested
together, indicating some antagonism between these
drugs9
although this activity is not necessarily
reflected in vivo;10
antagonism between RIF or chlo-
ramphenicol and another quinolone (ciprofloxacin)
has been reported previously.11
A comparison of
quinolones, using an in-vitro model designed to
predict sterilizing activities, showed MOXI with
the greatest bactericidal effect against slow-
growing bacteria, and the best activity against
persistors.6
MOXI also outperformed other quino-
lones when the MPCs and MPC/AUC ratios were
compared.12
In-vivo efficacy in animal model: In a mouse
model designed to mimic human disease, regimens
containing MOXI/RIF/pyrazinamide (PZA) reduced
treatment time by up to 2 months compared to
regimens with isoniazid (INH)/RIF/PZA.13
Similar
results with a stable cure were reached after
4 months in mice treated twice weekly with
RIF/MOXI/PZA compared to cure in 6 months when
daily treated with RIF/INH/PZA.14
100 mg/kg MOXI
in mice gave activity comparable to INH; increased
dose in mice to 400 mg/kg MOXI daily resulted in
spleen CFU counts lower than for INH 25 mg/kg
(log CFU 1.4 for INH compared with log CFU 0.4
for MOXI) although the differences were not
statistically significant.15
AUC/MIC ratio correlated
best with in-vivo efficacy for the fluoroquinolones
in a mouse model of tuberculosis.16
MOXI in a pro-
drug formulation conjugated to danyl-carboxymethyl
glucan may have advantages in vivo if it can be
administered orally.17
Efficacy in humans
Human trials with MOXI show promise for shortening
treatment time and reducing toxicity.14
Using early
bactericidal activity (EBA) at 5 days as a com-
parator MOXI (400 mg/daily) is as efficacious as INH
(300 mg/daily) and better than RIF (600 mg/daily).
Using time to reduce viable counts by 50% (vt50) INH
outperformed MOXI and RIF (Rodr´ıguez et al. 2004,18
see also Lu and Drlica 200319
). In a similar study,
comparing MOXI or ETH combined with INH/RIF/PZA,
patients achieved negative culture status earlier
with the inclusion of MOXI.20
ADME data
See table 1 for main PK characteristics.
Other ADME data:
• Human: Bioavailability 90%. Alveolar macrophage/
plasma ratio ~21. MOXI is well absorbed from the
gastrointestinal tract. Food has little effect on
absorption. No significant differences in PK due
to gender, race or age are found; no specific
studies in pediatric patients have been reported
[FDA label].
Human metabolic pathway: Approximately 52% of
the oral or intravenous dose is metabolized via
glucuronide and sulphate conjugation. The sulphate
conjugate accounts for 38% of the dose, and the
glucuronide conjugate accounts for 14% of the
dose. Excretion as unchanged drug: 20% in urine
and 25% in faeces; 96±4% excretion as known
metabolites or parent drug. No changes in renal
excretion in patients with decreased renal function
[FDA label].
Safety and Tolerability
Animal drug drug interactions: The cytochrome
P450 system is not involved in metabolism of
MOXI. In-vitro studies indicate that MOXI does
not inhibit CYP3A4, CYP2D6, CYP2C9, CYP2C19 or
CYP1A2, indicating that MOXI is unlikely to alter
the pharmacokinetics of drugs metabolized by these
cytochrome P450 isozymes [FDA label].
Animal toxicity: The minimal lethal oral dose in
mice is 435 758 mg/kg but 1300 mg/kg for rat and
1500 mg/kg for cynomolgus monkey. Intravenous LD50
is 105 130 mg/kg for mice and 112 146 mg/kg for
rat. MOXI is considered moderately toxic after single
oral or i.v. doses.23
Arthropathy: quinolones have been implicated in
arthropathy in humans and animals; in juvenile dogs
arthropathy was observed at 30 mg/kg for 28 days](https://image.slidesharecdn.com/moxig-150104111328-conversion-gate01/85/Moxi-g-2-320.jpg)
![MOXI
Moxifloxacin 129
Table 1
Species Half-life
(h)
AUC
(mg·h/l)
Cmax
(mg/ml)
Volume
distribution
(l/kg)
Clearance
(ml/h)
PK methodology
Mouse 1.3* 184 norm* 137 norm* *9.2 mg/kg oral single dose; Cmax
and AUC normalized to a dose of
9.2 mg/kg21,22
Rat 1.3* 310 norm* 312 norm* *9.2 mg/kg oral single dose; Cmax
and AUC normalized to a dose of
9.2 mg/kg21,22
Dog 9* 4090 norm* 251 norm* *9.2 mg/kg oral single dose; Cmax
and AUC normalized to a dose of
9.2 mg/kg21,22
Monkey 7.2* 760 norm* 86 norm* *9.2 mg/kg oral single dose; Cmax
and AUC normalized to a dose of
9.2 mg/kg21,22
Human 12*,
11.5 15.6**
618 norm*,
36.1±9.1**
430 norm*,
3.1±1**
*1.4 mg/kg oral single dose; Cmax
and AUC normalized to a dose of
9.2 mg/kg,21,22
**Single 400 mg oral dose in healthy
young adults [FDA label]
(1.5× normal human dose) but similar symptoms
were not seen in adult rats and monkeys at up to
500 mg/kg and 135 mg/kg respectively.23
Ocular toxicity: Electroretinographic and histopatho-
logic changes were seen at 90 mg/kg/day in an
oral 4-week specialized lens study in beagle dogs
using slit lamp and biochemical investigations. No
adverse effects on the lens were observed in 6-month
chronic studies in rats or monkeys at doses as high
as 500 mg/kg or 250 mg/kg respectively.23
Generally MOXI shares liabilities with the other
quinolones but without the phototoxicity seen with
sparfloxacin.23
Animal safety pharmacology: Cardiovascular: there
were marginal effects on QT interval in dogs during
week 1 at a dose of 90 mg/kg/day.23
In monkeys using telemeterized evaluation, MOXI had
no significant effect on mean arterial pressure, heart
rate, PR or QRS intervals. MOXI produced significant
dose-related increases in QTc at doses of 30 mg/kg
(Cmax 5.5±0.6mM), 100 mg/kg (Cmax 16.5±1.6 mM),
and 175 mg/kg (Cmax 17.3±0.7 mM) with peak in-
creases of 22 (8%), 27 (10%), and 47 (18%) ms,
respectively.24
MOXI has an in-vitro human cardiac K channel hERG
IC50 of 129 mM, which is not as potent an inhibitor
of the hERG channel as some other quinolones such
as sparfloxacin (18mM) or grepafloxacin (50 mM), but
more potent than the hERG IC50 for LEV (915 mM) and
OFL (1420 mM).25
Human drug drug interactions: The only fluoro-
quinolone known to inhibit the P450 system is
ciprofloxacin inhibiting CYP1A2 (reviewed in Berning
200126
). Specifically, no changes were observed
in the metabolism of itraconazole, theophylline,
warfarin, digoxin, atenolol, oral contraceptives,
or glyburide. Itraconazole, theophylline, warfarin,
digoxin, probenecid, morphine, ranitidine, and
calcium did not significantly affect the pharmaco-
kinetics of MOXI [FDA label]. Antacids and iron-
containing products should be avoided 4 hours before
or after MOXI dosing due to the potential for
reduction in the AUC.
Human potential toxicity: Cardiovascular events: QT
prolongation was observed in 0.1 3% of patients;
drugs which exacerbate these symptoms such
as Solatol, a general antiarrhythmic should be
avoided [FDA label]. Prolongation of the QT interval
is a general feature of the fluoroquinolones and
MOXI does cause QT prolongation which limits
the maximum dose (reviewed in Falagas et al.
200727
). Torsades de pointes can be a result of
the prolongation in QTc (reviewed in Falagas et al.
200727
). Specifically, MOXI caused a QTc increase
when given once daily at 400 mg, whereas twice
daily doses of LEV and CIPRO had no effect on
this parameter. However at higher doses all the
fluoroquinolones cause an increase in the QTc
interval (reviewed in Falagas et al. 200727
). In
a clinical trial of more than 7900 patients no
cardiovascular morbidity or mortality attributable
to QTc prolongation occurred with MOXI treatment
[FDA label].
Arthropathy: quinolones are associated with specific
tendinitis-type events, and LEV seems to be
associated with the highest rates among these drugs.
MOXI is not recommended for treatment of athletes
in training. Cessation of treatment usually reverses](https://image.slidesharecdn.com/moxig-150104111328-conversion-gate01/85/Moxi-g-3-320.jpg)
![130 Moxifloxacin
these effects which may be more serious in the
elderly (reviewed in Owens and Ambrose 200528
).
Hypoglycaemia is mentioned as a possible side effect
[FDA label] although few events have been recorded
(reviewed in Owens and Ambrose 200528
).
Phototoxicity is not a clinically relevant event during
MOXI treatment (reviewed in Owens and Ambrose
200528
).
Human adverse reactions: In clinical trials with
6700 patients receiving the 400 mg dose, adverse
events reported in MOXI trials were described as
mild to moderate in severity. MOXI was discontinued
due to adverse reactions thought to be drug-
related in 3.6% of orally treated patients. Adverse
reactions, judged by investigators to be at least
possibly drug-related, occurring in greater than
or equal to 3% of MOXI-treated patients were
nausea (7%), diarrhoea (6%) and dizziness (3%).
Additional clinically relevant events that occurred in
0.1% to <3% of patients were:
body as a whole: abdominal pain, headache, as-
thenia, injection site reaction (including phlebitis),
malaise, moniliasis, pain, allergic reaction;
cardiovascular: tachycardia, palpitation, vasodila-
tion, QT interval prolonged;
digestive: vomiting, abnormal liver function test,
dyspepsia, dry mouth, flatulence, oral moniliasis,
constipation, GGTP increased, anorexia, stomati-
tis, glossitis;
haemic/lymphatic: leukopenia, eosinophilia, pro-
thrombin decrease (prothrombin time prolonged/
International Normalized Ratio (INR) increased),
thrombocythemia;
metabolic/nutritional: lactic dehydrogenase in-
creased, amylase increased;
muscular: arthralgia, myalgia;
CNS: insomnia, nervousness, vertigo, somnolence,
anxiety, tremor;
skin: rash (maculopapular, purpuric, pustular),
pruritus, sweating, urticaria;
special senses: taste perversion;
urogenital: vaginal moniliasis, vaginitis [FDA la-
bel].
References
1. Champoux J (2001) DNA topoisomerases: structure,
function, and mechanism. Annu Rev Biochem 70, 369
413.
2. Gordon S, et al. (2001) Genomics of Mycobacterium bovis.
Tuberculosis 81(1 2), 157 63.
3. Aubry A, et al. (2006) First functional characterization
of a singly expressed bacterial type II topoisomerase:
the enzyme from Mycobacterium tuberculosis. Biochem
Biophys Res Commun 348, 158 65.
4. Aubry A, et al. (2006) Novel gyrase mutations in
quinolone-resistant and -hypersusceptible clinical isolates
of Mycobacterium tuberculosis: functional analysis of
mutant enzymes. Antimicrob Agents Chemother 50,
104 12.
5. Kam K, et al. (2006) Stepwise decrease in moxifloxacin
susceptibility amongst clinical isolates of multidrug-
resistant Mycobacterium tuberculosis: correlation with
ofloxacin susceptibility. Microb Drug Res 12, 7 11.
6. Hu Y, et al. (2003) Sterilizing activities of fluoroquinolones
against rifampin-tolerant populations of Mycobacterium
tuberculosis. Antimicrob Agents Chemother 47, 653 7.
7. Rodriguez Diaz J, et al. (2003) In vitro activity of
new fluoroquinolones and linezolid against nontuberculous
mycobacteria. Int J Antimicrob Agents 21, 585 8.
8. Rodr´ıguez J, et al. (2001) In vitro activity of four
fluoroquinolones against Mycobacterium tuberculosis. Int
J Antimicrob Agents 17, 229 31.
9. Lu T, Drlica K (2003) In vitro activity of C-8-methoxy
fluoroquinolones against mycobacteria when combined
with anti-tuberculosis agents. J Antimicrob Chemother 52,
1025 8.
10. Alvirez-Freites E, et al. (2002) In vitro and in vivo activities
of gatifloxacin against Mycobacterium tuberculosis.
Antimicrob Agents Chemother 46, 1022 5.
11. Gradelski E, et al. (2001) Activity of gatifloxacin and
ciprofloxacin in combination with other antimicrobial
agents. Int J Antimicrob Agents 17, 103 7.
12. Rodr´ıguez J, et al. (2004) Mutant prevention concentra-
tion: comparison of fluoroquinolones and linezolid with
Mycobacterium tuberculosis. J Antimicrob Chemother 53,
441 4.
13. Nuermberger E, et al. (2004) Moxifloxacin-containing
regimen greatly reduces time to culture conversion in
murine tuberculosis. Am J Respir Crit Care Med 169,
421 6.
14. Rosenthal I, et al. (2006) Potent twice-weekly rifapentine-
containing regimens in murine tuberculosis. Am J Respir
Crit Care Med 174, 94 101.
15. Yoshimatsu T, et al. (2002) Bactericidal activity of
increasing daily and weekly doses of moxifloxacin in
murine tuberculosis. Antimicrob Agents Chemother 46,
1875 9.
16. Shandil R, et al. (2007) Moxifloxacin, ofloxacin,
sparfloxacin, and ciprofloxacin against Mycobacterium
tuberculosis: evaluation of in vitro and pharmacodynamic
indices that best predict in vivo efficacy. Antimicrob
Agents Chemother 51, 576 82.
17. Schwartz Y, et al. (2006) Novel conjugate of moxifloxacin
and carboxymethylated glucan with enhanced activity
against Mycobacterium tuberculosis. Antimicrob Agents
Chemother 50, 1982 8.
18. Gosling R, et al. (2003) The bactericidal activity of
moxifloxacin in patients with pulmonary tuberculosis. Am
J Respir Crit Care Med 168, 1342 5.
19. Pletz M, et al. (2004) Early bactericidal activity of
moxifloxacin in treatment of pulmonary tuberculosis:
a prospective, randomized study. Antimicrob Agents
Chemother 48, 780 2.
20. Burman W, et al. (2006) Moxifloxacin versus ethambutol in
the first 2 months of treatment for pulmonary tuberculosis.
Am J Respir Crit Care Med 174, 331 8.
21. Siefert H, et al. (1999) Pharmacokinetics of the 8-
methoxyquinolone, moxifloxacin: tissue distribution in
male rats. J Antimicrob Chemother 43(Suppl B), 61 7.
22. Siefert H, et al. (1999) Pharmacokinetics of the 8-
methoxyquinolone, moxifloxacin: a comparison in human
and other mammalian species. J Antimicrob Chemother
43(Suppl B), 69 76.](https://image.slidesharecdn.com/moxig-150104111328-conversion-gate01/85/Moxi-g-4-320.jpg)
Moxi g
- 1. MOXI Tuberculosis (2008) 88(2) 127–131 Moxifloxacin Generic and additional names: Moxifloxacin Hydrochloride CAS name: 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[(4aS,7aS)- octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-4-oxo-3-quinolinecarboxylic acid hydrochloride CAS registry #: 186826-86-8 Molecular formula: C21H24FN3O4·HCl Molecular weight: 437.89 Intellectual property rights: Bayer N CO2H O NHN OMe F H H Brand names: Actimax (Sankyo); Actira (Bayer); Avelox (Bayer); Octegra (Bayer); Proflox (Esteve); Vigamox (Alcon) Derivatives: Moxifloxacin is a quinolone/fluoroquinolone antibiotic related to ciprofloxacin, enoxacin, fleroxacin, gatifloxacin, gemifloxacin, grepafloxacin, levofloxacin, lomefloxacin, norfloxacin, ofloxacin, pefloxacin, prulifloxacin, rufloxacin, sparfloxacin, temafloxacin, trovafloxacin, sitafloxacin Solubility: Soluble in water Polarity: Log P 2.033 [DrugBank] Melting point: 238 242ºC [DrugBank] Formulation and optimal human dosage: Avelox tablets: containing moxifloxacin hydrochloride (equivalent to 400 mg moxifloxacin). Avelox i.v.: 250 ml latex-free flexibags as a sterile, preservative-free, 0.8% sodium chloride aqueous solution of moxifloxacin hydrochloride (containing 400 mg moxifloxacin). 400 mg daily dose Basic biology information Drug target/mechanism: Moxifloxacin (MOXI: 8-meth- oxy-quinolone), and quinolones in general, exert their effects by trapping a DNA drug enzyme complex and specifically inhibiting ATP-dependent enzymes topoisomerase II (DNA gyrase) and topoi- somerase IV. In most bacteria gyrase facilitates DNA unwinding and topoisomerase IV activates decatena- tion. DNA gyrase (reviewed in Champoux 20011 ), an essential enzyme involved in the replication, tran- scription and repair of bacterial DNA, consists of two components arranged in a GyrA2/GyrB2 complex en- coded by the gyrA and gyrB genes. Topoisomerase IV, encoded by parC and parE, appears to be absent from Mycobacterium tuberculosis and from several other bacteria including Helicobacter pylori and Treponema palladium.2 Recently the single M. tuber- culosis type II topoisomerase has been cloned into Escherichia coli and exhibits classical supercoiling activity as well as enhanced decatenation, cleavage and relaxation activities.3 This is presumably the single target for MOXI in the mycobacteria. Drug resistance mechanism: Resistance to MOXI occurs at a rate of 1.8×10 9 to <1×10 11 in vitro for Gram-positive bacteria [FDA label]. There is no known cross-resistance between MOXI and other classes of antimicrobials, however cross-resistance has been observed between MOXI and other fluoroquinolones. Resistance (3 5-fold higher than wild-type [WT]) can arise in M. tuberculosis from changes in either gyrA or gyrB; furthermore specific mutations in gyrA resulted in hypersensitivity to quinolones.4 Most mutations conferring changes in drug sensitivity occur in a quinolone-resistant region in gyrA and more rarely in gyrB. Both resistance and hypersensitivity were reflected in the IC50s of DNA gyrase overexpressed and purified from the concomitant M. tuberculosis strains.4 Many MDR clinical strains are sensitive to MOXI (resistance is defined as MIC > 2 mg/ml) even where they are also resistant to ofloxacin (OFL); however several strains in the same study were resistant to MOXI and OFL and in these cases the mutation was often in gyrA (A94G). The authors conclude that careful 1472-9792/$ - see front matter © 2008 TB Alliance. Published by Elsevier Ltd. All rights reserved.
- 2. 128 Moxifloxacin monitoring of resistance to MOXI is warranted in clinical settings.5 In-vitro potency against MTB: M. tuberculosis H37Rv: MIC 0.5 mg/ml.4 M. tuberculosis H37Rv comparative MICs for quino- lones: ciprofloxacin 0.5 mg/ml, OFL 0.71 mg/ml, levofloxacin (LEV) 0.35 mg/ml, MOXI 0.177 mg/ml, gatifloxacin (GATI) 0.125 mg/ml.6 Spectrum of activity: MOXI has broad Gram- positive and Gram-negative activity. It shows in- vitro and clinical efficacy against Staphylococcus aureus, Streptococcus pneumoniae, Str. pyogenes, Haemophilus influenzae, H. parainfluenzae, Kleb- siella pneumoniae, Moraxella catarrhalis, Chlamy- dia pneumoniae and Mycoplasma pneumoniae. MOXI has activity against mycobacteria in addition to M. tuberculosis; MOXI is more active against M. kansasii than M. avium complex: specifically MIC90 for M. avium > M. intracellulare > M. kansasii at 4, 2 and 2 mg/ml respectively. MIC90 for M. chelonae > M. fortuitum at 16 and 0.5 mg/ml, respectively.7 Other in-vitro activity: MPC90 against M. tuberculo- sis strains: MOXI 1 mg/ml, LEV 1 mg/ml, ciprofloxacin 4 mg/ml, OFL 2 mg/ml.8 MOXI, like other quinolones, is bactericidal. The bactericidal activity of MOXI against M. tuberculosis was decreased somewhat when ethambutol (ETH) or high rifampin (RIF) and MOXI were tested together, indicating some antagonism between these drugs9 although this activity is not necessarily reflected in vivo;10 antagonism between RIF or chlo- ramphenicol and another quinolone (ciprofloxacin) has been reported previously.11 A comparison of quinolones, using an in-vitro model designed to predict sterilizing activities, showed MOXI with the greatest bactericidal effect against slow- growing bacteria, and the best activity against persistors.6 MOXI also outperformed other quino- lones when the MPCs and MPC/AUC ratios were compared.12 In-vivo efficacy in animal model: In a mouse model designed to mimic human disease, regimens containing MOXI/RIF/pyrazinamide (PZA) reduced treatment time by up to 2 months compared to regimens with isoniazid (INH)/RIF/PZA.13 Similar results with a stable cure were reached after 4 months in mice treated twice weekly with RIF/MOXI/PZA compared to cure in 6 months when daily treated with RIF/INH/PZA.14 100 mg/kg MOXI in mice gave activity comparable to INH; increased dose in mice to 400 mg/kg MOXI daily resulted in spleen CFU counts lower than for INH 25 mg/kg (log CFU 1.4 for INH compared with log CFU 0.4 for MOXI) although the differences were not statistically significant.15 AUC/MIC ratio correlated best with in-vivo efficacy for the fluoroquinolones in a mouse model of tuberculosis.16 MOXI in a pro- drug formulation conjugated to danyl-carboxymethyl glucan may have advantages in vivo if it can be administered orally.17 Efficacy in humans Human trials with MOXI show promise for shortening treatment time and reducing toxicity.14 Using early bactericidal activity (EBA) at 5 days as a com- parator MOXI (400 mg/daily) is as efficacious as INH (300 mg/daily) and better than RIF (600 mg/daily). Using time to reduce viable counts by 50% (vt50) INH outperformed MOXI and RIF (Rodr´ıguez et al. 2004,18 see also Lu and Drlica 200319 ). In a similar study, comparing MOXI or ETH combined with INH/RIF/PZA, patients achieved negative culture status earlier with the inclusion of MOXI.20 ADME data See table 1 for main PK characteristics. Other ADME data: • Human: Bioavailability 90%. Alveolar macrophage/ plasma ratio ~21. MOXI is well absorbed from the gastrointestinal tract. Food has little effect on absorption. No significant differences in PK due to gender, race or age are found; no specific studies in pediatric patients have been reported [FDA label]. Human metabolic pathway: Approximately 52% of the oral or intravenous dose is metabolized via glucuronide and sulphate conjugation. The sulphate conjugate accounts for 38% of the dose, and the glucuronide conjugate accounts for 14% of the dose. Excretion as unchanged drug: 20% in urine and 25% in faeces; 96±4% excretion as known metabolites or parent drug. No changes in renal excretion in patients with decreased renal function [FDA label]. Safety and Tolerability Animal drug drug interactions: The cytochrome P450 system is not involved in metabolism of MOXI. In-vitro studies indicate that MOXI does not inhibit CYP3A4, CYP2D6, CYP2C9, CYP2C19 or CYP1A2, indicating that MOXI is unlikely to alter the pharmacokinetics of drugs metabolized by these cytochrome P450 isozymes [FDA label]. Animal toxicity: The minimal lethal oral dose in mice is 435 758 mg/kg but 1300 mg/kg for rat and 1500 mg/kg for cynomolgus monkey. Intravenous LD50 is 105 130 mg/kg for mice and 112 146 mg/kg for rat. MOXI is considered moderately toxic after single oral or i.v. doses.23 Arthropathy: quinolones have been implicated in arthropathy in humans and animals; in juvenile dogs arthropathy was observed at 30 mg/kg for 28 days
- 3. MOXI Moxifloxacin 129 Table 1 Species Half-life (h) AUC (mg·h/l) Cmax (mg/ml) Volume distribution (l/kg) Clearance (ml/h) PK methodology Mouse 1.3* 184 norm* 137 norm* *9.2 mg/kg oral single dose; Cmax and AUC normalized to a dose of 9.2 mg/kg21,22 Rat 1.3* 310 norm* 312 norm* *9.2 mg/kg oral single dose; Cmax and AUC normalized to a dose of 9.2 mg/kg21,22 Dog 9* 4090 norm* 251 norm* *9.2 mg/kg oral single dose; Cmax and AUC normalized to a dose of 9.2 mg/kg21,22 Monkey 7.2* 760 norm* 86 norm* *9.2 mg/kg oral single dose; Cmax and AUC normalized to a dose of 9.2 mg/kg21,22 Human 12*, 11.5 15.6** 618 norm*, 36.1±9.1** 430 norm*, 3.1±1** *1.4 mg/kg oral single dose; Cmax and AUC normalized to a dose of 9.2 mg/kg,21,22 **Single 400 mg oral dose in healthy young adults [FDA label] (1.5× normal human dose) but similar symptoms were not seen in adult rats and monkeys at up to 500 mg/kg and 135 mg/kg respectively.23 Ocular toxicity: Electroretinographic and histopatho- logic changes were seen at 90 mg/kg/day in an oral 4-week specialized lens study in beagle dogs using slit lamp and biochemical investigations. No adverse effects on the lens were observed in 6-month chronic studies in rats or monkeys at doses as high as 500 mg/kg or 250 mg/kg respectively.23 Generally MOXI shares liabilities with the other quinolones but without the phototoxicity seen with sparfloxacin.23 Animal safety pharmacology: Cardiovascular: there were marginal effects on QT interval in dogs during week 1 at a dose of 90 mg/kg/day.23 In monkeys using telemeterized evaluation, MOXI had no significant effect on mean arterial pressure, heart rate, PR or QRS intervals. MOXI produced significant dose-related increases in QTc at doses of 30 mg/kg (Cmax 5.5±0.6mM), 100 mg/kg (Cmax 16.5±1.6 mM), and 175 mg/kg (Cmax 17.3±0.7 mM) with peak in- creases of 22 (8%), 27 (10%), and 47 (18%) ms, respectively.24 MOXI has an in-vitro human cardiac K channel hERG IC50 of 129 mM, which is not as potent an inhibitor of the hERG channel as some other quinolones such as sparfloxacin (18mM) or grepafloxacin (50 mM), but more potent than the hERG IC50 for LEV (915 mM) and OFL (1420 mM).25 Human drug drug interactions: The only fluoro- quinolone known to inhibit the P450 system is ciprofloxacin inhibiting CYP1A2 (reviewed in Berning 200126 ). Specifically, no changes were observed in the metabolism of itraconazole, theophylline, warfarin, digoxin, atenolol, oral contraceptives, or glyburide. Itraconazole, theophylline, warfarin, digoxin, probenecid, morphine, ranitidine, and calcium did not significantly affect the pharmaco- kinetics of MOXI [FDA label]. Antacids and iron- containing products should be avoided 4 hours before or after MOXI dosing due to the potential for reduction in the AUC. Human potential toxicity: Cardiovascular events: QT prolongation was observed in 0.1 3% of patients; drugs which exacerbate these symptoms such as Solatol, a general antiarrhythmic should be avoided [FDA label]. Prolongation of the QT interval is a general feature of the fluoroquinolones and MOXI does cause QT prolongation which limits the maximum dose (reviewed in Falagas et al. 200727 ). Torsades de pointes can be a result of the prolongation in QTc (reviewed in Falagas et al. 200727 ). Specifically, MOXI caused a QTc increase when given once daily at 400 mg, whereas twice daily doses of LEV and CIPRO had no effect on this parameter. However at higher doses all the fluoroquinolones cause an increase in the QTc interval (reviewed in Falagas et al. 200727 ). In a clinical trial of more than 7900 patients no cardiovascular morbidity or mortality attributable to QTc prolongation occurred with MOXI treatment [FDA label]. Arthropathy: quinolones are associated with specific tendinitis-type events, and LEV seems to be associated with the highest rates among these drugs. MOXI is not recommended for treatment of athletes in training. Cessation of treatment usually reverses
- 4. 130 Moxifloxacin these effects which may be more serious in the elderly (reviewed in Owens and Ambrose 200528 ). Hypoglycaemia is mentioned as a possible side effect [FDA label] although few events have been recorded (reviewed in Owens and Ambrose 200528 ). Phototoxicity is not a clinically relevant event during MOXI treatment (reviewed in Owens and Ambrose 200528 ). Human adverse reactions: In clinical trials with 6700 patients receiving the 400 mg dose, adverse events reported in MOXI trials were described as mild to moderate in severity. MOXI was discontinued due to adverse reactions thought to be drug- related in 3.6% of orally treated patients. Adverse reactions, judged by investigators to be at least possibly drug-related, occurring in greater than or equal to 3% of MOXI-treated patients were nausea (7%), diarrhoea (6%) and dizziness (3%). Additional clinically relevant events that occurred in 0.1% to <3% of patients were: body as a whole: abdominal pain, headache, as- thenia, injection site reaction (including phlebitis), malaise, moniliasis, pain, allergic reaction; cardiovascular: tachycardia, palpitation, vasodila- tion, QT interval prolonged; digestive: vomiting, abnormal liver function test, dyspepsia, dry mouth, flatulence, oral moniliasis, constipation, GGTP increased, anorexia, stomati- tis, glossitis; haemic/lymphatic: leukopenia, eosinophilia, pro- thrombin decrease (prothrombin time prolonged/ International Normalized Ratio (INR) increased), thrombocythemia; metabolic/nutritional: lactic dehydrogenase in- creased, amylase increased; muscular: arthralgia, myalgia; CNS: insomnia, nervousness, vertigo, somnolence, anxiety, tremor; skin: rash (maculopapular, purpuric, pustular), pruritus, sweating, urticaria; special senses: taste perversion; urogenital: vaginal moniliasis, vaginitis [FDA la- bel]. References 1. Champoux J (2001) DNA topoisomerases: structure, function, and mechanism. Annu Rev Biochem 70, 369 413. 2. Gordon S, et al. (2001) Genomics of Mycobacterium bovis. Tuberculosis 81(1 2), 157 63. 3. Aubry A, et al. (2006) First functional characterization of a singly expressed bacterial type II topoisomerase: the enzyme from Mycobacterium tuberculosis. Biochem Biophys Res Commun 348, 158 65. 4. Aubry A, et al. (2006) Novel gyrase mutations in quinolone-resistant and -hypersusceptible clinical isolates of Mycobacterium tuberculosis: functional analysis of mutant enzymes. Antimicrob Agents Chemother 50, 104 12. 5. Kam K, et al. (2006) Stepwise decrease in moxifloxacin susceptibility amongst clinical isolates of multidrug- resistant Mycobacterium tuberculosis: correlation with ofloxacin susceptibility. Microb Drug Res 12, 7 11. 6. Hu Y, et al. (2003) Sterilizing activities of fluoroquinolones against rifampin-tolerant populations of Mycobacterium tuberculosis. Antimicrob Agents Chemother 47, 653 7. 7. Rodriguez Diaz J, et al. (2003) In vitro activity of new fluoroquinolones and linezolid against nontuberculous mycobacteria. Int J Antimicrob Agents 21, 585 8. 8. Rodr´ıguez J, et al. (2001) In vitro activity of four fluoroquinolones against Mycobacterium tuberculosis. Int J Antimicrob Agents 17, 229 31. 9. Lu T, Drlica K (2003) In vitro activity of C-8-methoxy fluoroquinolones against mycobacteria when combined with anti-tuberculosis agents. J Antimicrob Chemother 52, 1025 8. 10. Alvirez-Freites E, et al. (2002) In vitro and in vivo activities of gatifloxacin against Mycobacterium tuberculosis. Antimicrob Agents Chemother 46, 1022 5. 11. Gradelski E, et al. (2001) Activity of gatifloxacin and ciprofloxacin in combination with other antimicrobial agents. Int J Antimicrob Agents 17, 103 7. 12. Rodr´ıguez J, et al. (2004) Mutant prevention concentra- tion: comparison of fluoroquinolones and linezolid with Mycobacterium tuberculosis. J Antimicrob Chemother 53, 441 4. 13. Nuermberger E, et al. (2004) Moxifloxacin-containing regimen greatly reduces time to culture conversion in murine tuberculosis. Am J Respir Crit Care Med 169, 421 6. 14. Rosenthal I, et al. (2006) Potent twice-weekly rifapentine- containing regimens in murine tuberculosis. Am J Respir Crit Care Med 174, 94 101. 15. Yoshimatsu T, et al. (2002) Bactericidal activity of increasing daily and weekly doses of moxifloxacin in murine tuberculosis. Antimicrob Agents Chemother 46, 1875 9. 16. Shandil R, et al. (2007) Moxifloxacin, ofloxacin, sparfloxacin, and ciprofloxacin against Mycobacterium tuberculosis: evaluation of in vitro and pharmacodynamic indices that best predict in vivo efficacy. Antimicrob Agents Chemother 51, 576 82. 17. Schwartz Y, et al. (2006) Novel conjugate of moxifloxacin and carboxymethylated glucan with enhanced activity against Mycobacterium tuberculosis. Antimicrob Agents Chemother 50, 1982 8. 18. Gosling R, et al. (2003) The bactericidal activity of moxifloxacin in patients with pulmonary tuberculosis. Am J Respir Crit Care Med 168, 1342 5. 19. Pletz M, et al. (2004) Early bactericidal activity of moxifloxacin in treatment of pulmonary tuberculosis: a prospective, randomized study. Antimicrob Agents Chemother 48, 780 2. 20. Burman W, et al. (2006) Moxifloxacin versus ethambutol in the first 2 months of treatment for pulmonary tuberculosis. Am J Respir Crit Care Med 174, 331 8. 21. Siefert H, et al. (1999) Pharmacokinetics of the 8- methoxyquinolone, moxifloxacin: tissue distribution in male rats. J Antimicrob Chemother 43(Suppl B), 61 7. 22. Siefert H, et al. (1999) Pharmacokinetics of the 8- methoxyquinolone, moxifloxacin: a comparison in human and other mammalian species. J Antimicrob Chemother 43(Suppl B), 69 76.
- 5. MOXI Moxifloxacin 131 23. von Keutz E, Schluter G (1999) Preclinical safety evaluation of moxifloxacin, a novel fluoroquinolone. J Antimicrob Chemother 43, 91 100. 24. Chaves A, et al. (2006) Cardiovascular monkey telemetry: Sensitivity to detect QT interval prolongation J Pharmacol Toxicol Methods 54, 150 8. 25. Kang J, et al. (2001) Interactions of a series of fluoroquinolone antibacterial drugs with the human cardiac K+ channel HERG. Mol Pharmacol 59, 122 6. 26. Berning S (2001) The role of fluoroquinolones in tuberculosis today. Drugs 61, 9 18. 27. Falagas M, et al. (2007) Arrhythmias associated with fluoroquinolone therapy. Int J Antimicrob Agents 29, 374 9. 28. Owens R, Ambrose P (2005) Antimicrobial safety: focus on fluoroquinolones. Clin Infect Dis 41(Suppl 2), S144 57.