DESCRIPTION
Marbofloxacin is a synthetic broad-spectrum antibacterial agent from the fluoroquinolone class of chemotherapeutic agents. Marbofloxacin is the non-proprietary designation for 9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[3,2,1-ij][4,1,2] benzoxadiazine-6-carboxylic acid. The empirical formula is C17H19FN4O4 and the molecular weight is 362.36. The compound is soluble in water; however, solubility decreases in alkaline conditions. The N-octanol/water partition coefficient (Kow) is 0.835 measured at pH 7 and 25°C.
Figure 1: Chemical structure of marbofloxacin
CLINICAL PHARMACOLOGY
Marbofloxacin is rapidly and almost completely absorbed from the gastrointestinal tract following oral administration to fasted animals. Divalent cations are generally known to diminish the absorption of fluoroquinolones. The effects of concomitant feeding on the absorption of marbofloxacin have not been determined. (See Drug Interactions.) In the dog, approximately 40% of an oral dose of marbofloxacin is excreted unchanged in the urine1. Excretion in the feces, also as unchanged drug, is the other major route of elimination in dogs. Ten to 15% of marbofloxacin is metabolized by the liver in dogs.
In vitro plasma protein binding of marbofloxacin in dogs was 9.1% and in cats was 7.3%. In the cat, approximately 70% of an oral dose is excreted in the urine as marbofloxacin and metabolites with approximately 85% of the excreted material as unchanged drug. Pharmacokinetic parameters related to intravenous dosing were estimated in a study of 6 healthy adult beagle dogs, and are summarized in Table 1. The absolute bioavailability following dosing of oral tablets to the same animals was 94%.
Marbofloxacin plasma concentrations were determined over time in healthy adult beagle dogs (6 dogs per dosage group) following single oral doses of 1.25 mg/lb or 2.5 mg/lb. Absorption of orally administered marbofloxacin increases proportionally over the dose range of 1.25 to 2.5 mg/lb. Marbofloxacin plasma concentrations were determined over time in 7 healthy adult male cats following a single oral dose of 2.5 mg/lb. Plasma pharmacokinetic parameters following oral dosing of dogs and cats are summarized in Figures 2 and 3 and in Table 2. Based on the terminal elimination half-life and the dosing interval, steady-state levels are reached after the third dose and are expected to be approximately 25% greater in dogs and 35% greater in cats than those achieved after a single dose. Marbofloxacin is widely distributed in canine tissues. Tissue concentrations of marbofloxacin were determined in healthy male beagle dogs (4 dogs per time period) at 2, 18 and 24 hours after a single oral dose (1.25 or 2.5 mg/lb) and are summarized in Tables 3a and 3b.
Table 1: Mean pharmacokinetic parameters following intravenous administration of marbofloxacin to 6 adult beagle dogs at a dosage of 2.5 mg/lb.
|
Parameter
|
Estimate ± SD* n=6
|
|
Total body clearance, (mL/h•kg)
|
94 ± 8
|
|
Volume of distribution at steady state, Vss, (L/kg)
|
1.19 ± 0.08
|
|
AUC0-inf (μg•h/mL)
|
59 ± 5
|
|
Terminal plasma elimination half-life, t1/2(h)
|
9.5 ± 0.7
|
* SD = standard deviation
Table 2: Mean pharmacokinetic parameters following oral administration of marbofloxacin tablets to adult beagle dogs at a nominal dosage of 1.25 mg/lb or
2.5 mg/lb and to cats at 2.5 mg/lb.†
|
Parameters
|
Dog Estimate ± SD* (1.25 mg/lb) n=6
|
Dog Estimate ± SD* (2.5 mg/lb) n=6
|
Cat Estimate ± SD* (2.5 mg/lb) n=7
|
|
Time of maximum concentration, Tmax(h)
|
1.5 ± 0.3
|
1.8 ± 0.3
|
1.2 ± 0.6
|
|
Maximum concentration, Cmax, (μg/mL)
|
2.0 ± 0.2
|
4.2 ± 0.5
|
4.8 ± 0.7
|
|
AUC0-inf (μg•h/mL)
|
31.2 ± 1.6
|
64 ± 8
|
70 ± 6
|
|
Terminal plasma elimination half-life, t1/2(h)
|
10.7 ± 1.6
|
10.9 ± 0.6
|
12.7 ± 1.1
|
† mean actual dosages administered to dogs were 1.22 mg/lb and 2.56 mg/lb, respectively, and the mean
actual dosage administered to cats was 2.82 mg/lb.
* SD = standard deviation
Figure 2: Mean plasma concentrations (µg/mL) following single oral administration of marbofloxacin to adult beagle dogs at dosages of 1.25 mg/lb or 2.5 mg/lb.
* See Table 4 in Microbiology section for MIC data.
Figure 3: Mean plasma concentrations (µg/mL) following single oral administration of marbofloxacin to adult cats at a dosage of 2.5 mg/lb.
* See Table 5 in Microbiology section for MIC data.
Table 3a: Tissue distribution following a single oral administration of marbofloxacin tablets to adult beagle dogs at a dosage of 1.25 mg/lb*.
|
Tissue
|
Marbofloxacin 2 hours (n=4)
|
Concentrations 18 hours (n=4)
|
(μg/g ± SD) 24 hours (n=4)
|
|
bladder
|
4.8 ± 1.1
|
2.6 ± 1.5
|
1.11 ± 0.19
|
|
bone marrow
|
3.1 ± 0.5
|
1.5 ± 1.5
|
0.7 ± 0.2
|
|
feces
|
15 ± 9
|
48 ± 40
|
26 ± 11
|
|
jejunum
|
3.6 ± 0.5
|
1.3 ± 1.0
|
0.7 ± 0.3
|
|
kidney
|
7.1 ±1.7
|
1.4 ± 0.5
|
0.9 ± 0.3
|
|
lung
|
3.0 ± 0.5
|
0.8 ± 0.2
|
0.57 ± 0.19
|
|
lymph node
|
5.5 ± 1.1
|
1.3 ± 0.3
|
1.0 ± 0.3
|
|
muscle
|
4.1 ± 0.3
|
1.0 ± 0.3
|
0.7 ± 0.2
|
|
prostate
|
5.6 ± 1.4
|
1.8 ± 0.6
|
1.1 ± 0.4
|
|
skin
|
1.9 ± 0.6
|
0.41 ± 0.13
|
0.32 ± 0.08
|
* SD = standard deviation
Table 3b: Tissue distribution following a single oral administration of marbofloxacin tablets to adult beagle dogs at a dosage of 2.5 mg/lb.
|
Tissue
|
Marbofloxacin 2 hours (n=4)
|
Concentrations 18 hours (n=4)
|
(μg/g ± SD*) 24 hours (n=4)
|
|
bladder
|
12 ± 4
|
6 ± 7
|
1.8 ± 0.4
|
|
bone marrow
|
4.6 ± 1.5
|
1.28 ± 0.13
|
0.9 ± 0.3
|
|
feces
|
18 ± 3
|
52 ± 17
|
47 ± 28
|
|
jejunum
|
7.8 ± 1.1
|
2.0 ± 0.3
|
1.1 ± 0.3
|
|
kidney
|
12.7 ±1.7
|
2.7 ± 0.3
|
1.6 ± 0.2
|
|
lung
|
5.48 ± 0.17
|
1.45 ± 0.19
|
1.0 ± 0.2
|
|
lymph node
|
8.3 ± 0.7
|
2.3 ± 0.5
|
2.03 ± 0.06
|
|
muscle
|
7.5 ± 0.5
|
1.8 ± 0.3
|
1.20 ± 0.12
|
|
prostate
|
11 ± 3
|
2.7 ± 1.0
|
2.0 ± 0.5
|
|
skin
|
3.20 ± 0.33
|
0.705 ± 0.013
|
0.46 ± 0.09
|
* SD = standard deviation
Microbiology
The primary action of fluoroquinolones is to inhibit the bacterial enzyme, DNA gyrase. In susceptible organisms, fluoroquinolones are rapidly bactericidal at relatively low concentrations. Marbofloxacin is bactericidal against a broad range of gram-negative and gram-positive organisms. The minimum inhibitory concentrations (MICs) of pathogens isolated in clinical field studies performed in the United States were determined using National Committee for Clinical Laboratory Standards (NCCLS) standards, and are shown in Tables 4 and 5.
Table 4. MIC Values* (μg/mL) of marbofloxacin against pathogens isolated from skin, soft tissue and urinary tract infections in dogs enrolled in clinical studies conducted during 1994–1996.
|
Organism
|
No. of Isolates
|
MIC50
|
MIC90
|
MIC Range
|
|
Staphylococcus intermedius
|
135
|
0.25
|
0.25
|
0.125-2
|
|
Escherichia coli
|
61
|
0.03
|
0.06
|
0.015-2
|
|
Proteus mirabilis
|
35
|
0.06
|
0.125
|
0.03-0.25
|
|
Beta-hemolytic Streptococcus,
(not Group A or Group B)
|
25
|
1
|
2
|
0.5-16
|
|
Streptococcus,
Group D enterococcus
|
16
|
1
|
4
|
0.008-4
|
|
Pasteurella multocida
|
13
|
0.015
|
0.06
|
≤0.008-0.5
|
|
Staphylococcus aureus
|
12
|
0.25
|
0.25
|
0.25-0.5
|
|
Enterococcus faecalis
|
11
|
2
|
2
|
1-4
|
|
Klebsiella pneumonia
|
11
|
0.06
|
0.06
|
0.01-0.06
|
|
Pseudomonas spp.
|
9
|
**
|
**
|
0.06-1
|
|
Pseudomonas aeruginosa
|
7
|
**
|
**
|
0.25-1
|
* The correlation between in vitro susceptibility data (MIC) and clinical response has not been
determined.
** MIC50 and MIC90 not calculated due to insufficient number of isolates.
Table 5: MIC Values* (μg/mL) of marbofloxacin against pathogens isolated from
skin and soft tissue infections in cats enrolled in clinical studies conducted in 1995
and 1998.
|
Organism
|
No. of Isolates
|
MIC50
|
MIC90
|
MIC Range
|
|
Pasteurella multocida
|
135
|
0.03
|
0.06
|
≤0.008-0.25
|
|
Beta-hemolytic Streptococcus
|
22
|
1
|
1
|
0.06-1
|
|
Staphylococcus aureus
|
21
|
0.25
|
0.5
|
0.125-1
|
|
Corynebacterium spp.
|
14
|
0.5
|
1
|
0.25-2
|
|
Staphylococcus intermedius
|
11
|
0.25
|
0.5
|
0.03-0.5
|
|
Enterococcus faecalis
|
10
|
2.0
|
2.0
|
1.0-2.0
|
|
Escherichia coli
|
10
|
0.03
|
0.03
|
0.015-0.03
|
|
Bacillus spp.
|
10
|
0.25
|
0.25
|
0.125-0.25
|
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