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CLINICAL PHARMACOLOGY

Absorption

Grepafloxacin is rapidly and extensively absorbed following oral administration of RAXAR (grepafloxacin) Tablets Bioavailability of the tablet is equivalent to the bioavailability of an oral solution of grepafloxacin. The absolute bioavailability of RAXAR (grepafloxacin) Tablets was estimated by comparing the areas under the plasma grepafloxacin concentration versus time curve (AUC) after intravenous and oral administration of grepafloxacin in separate studies. The absolute bioavailability is approximately 70%.

Single-dose and steady-state pharmacokinetic parameters following administration of 400 mg and 600 mg doses to healthy adult males are displayed in Table 1.

Table 1
Single-dose and Steady-state Pharmacokinetic Parameters in Healthy Adult Males

Parameter
Single-dose Pharmacokinetic
Parameters
Steady-state Pharmacokinetic Parameters
 
400 mg (n=40)
600 mg (n=31)
400 mg (n=10)
600 mg (n=46)
*AUC (µgh/mL)
12.27 ± 3.81
22.66 ± 5.65
14.08 ± 2.80
27.51 ± 6.95
Cmax (µg/mL)
1.11 ± 0.34
1.58 ± 0.37
1.35 ± 0.25
2.25 ± 0.48
Trough (µg/mL)
not applicable
not applicable
0.21 ± 0.08
0.55 ± 0.22

    *AUC=AUC¥ for single-dose; AUC0-24 for steady-state.

On average, the peak plasma drug concentration (Cmax) is achieved 2 to 3 hours after dosing. Steady-state concentrations of grepafloxacin are achieved within 7 days of once a day dosing.

Grepafloxacin pharmacokinetic parameters were determined following administration of 600 mg grepafloxacin immediately following a high fat meal (1000 kcal, 67 grams fat, 38 grams protein, 63 grams carbohydrates) and administration in the fasted state (n=29). There was no difference in grepafloxacin pharmacokinetic parameters between the fasted and fed treatments. Milk had no effect on the Cmax, Tmax, or AUC of grepafloxacin after oral administration. Neutralization of gastric acidity by intravenous administration of the histamine type-2 receptor antagonist famotidine did not affect the absorption or other pharmacokinetic properties of RAXAR (grepafloxacin) Tablets

Distribution

The apparent volume of distribution after oral administration of grepafloxacin 400 mg was 5.07 ± 0.95 L/kg, suggesting that grepafloxacin distributes widely into extravascular spaces. Binding of grepafloxacin to human plasma proteins is low (approximately 50%).

Table 2 summarizes the concentrations of grepafloxacin in fluids and tissues compared with serum drug concentration.

Table 2
Distribution of Grepafloxacin into Tissues and Fluids After Oral Administration n=number of subjects

 
Concentration Mean ± SD
Tissue or Fluid
Oral Dose (mg)
Hours Post-Dose
n
Serum
(µg/mL)
Tissue or Fluid
(µg/mL or µg/g)
Ratio
Alveolar lining fluid
400
4-5
5
1.76
27.1
15.4
Alveolar macrophages
400
4-5
5
1.76
278
158
Cervix uteri
100
4-5
5
1.23 ± 0.26
3.42 ± 0.65
2.8
Portio vaginalis
100
4-5
5
1.23 ± 0.26
2.58 ± 0.69
2.1
Sputum
200
4
7
0.47 ± 0.11
1.04 ± 0.48
2.2

Metabolism and Excretion

The plasma elimination half-life of grepafloxacin at steady-state was 15.7 ± 4.2 hours Grepafloxacin is eliminated predominantly through hepatic metabolism and biliary excretion. Less than 10% of an oral dose is excreted as unchanged grepafloxacin in urine. Approximately 88% of an oral dose of radiolabeled grepafloxacin 400 mg was recovered in urine (38%) and feces (50%) over 7 days post dose. Approximately one half of the AUC in plasma for the 12 hours after dosing was due to unchanged grepafloxacin; 68% of AUC in plasma for 12 hours after dosing was due to unchanged grepafloxacin plus known metabolites. Unchanged grepafloxacin (6% of dose) and several metabolites (in amounts ranging from 0.08% to 5.57% of dose) were recovered in urine. Unchanged grepafloxacin (27% of dose) and several metabolites (in amounts ranging from 1.83% to 3.91% of dose) were recovered in feces. Grepafloxacin metabolites include glucuronide (major metabolite) and sulfate conjugates and oxidative metabolites. The oxidative metabolites are formed mainly by cytochrome P450 1A2 (CYP1A2), while the cytochrome P450 3A4 (CYP3A4) has minor involvement. The nonconjugated metabolites have little antimicrobial activity compared with the parent drug. The conjugated metabolites have no antimicrobial activity.

Special Populations

Gender: Following administration of RAXAR (grepafloxacin) 600 mg daily for 7 days, Cmax was approximately 30% to 50% higher and AUC was approximately 20% to 50% higher in females compared to males. The observed differences appear to be due mainly to differences in body weight. Total clearance (per unit body weight), renal clearance (per unit body weight), and half-life did not differ between males and females. The observed differences in pharmacokinetic properties by gender do not necessitate any difference between males and females in dosage and administration.

Geriatric: There are no significant differences in grepafloxacin pharmacokinetics between young and elderly subjects.

Pediatric: Grepafloxacin has not been evaluated in pediatric patients.

Hepatic Insufficiency: Two studies were performed to assess the effect of hepatic failure on grepafloxacin pharmacokinetics. Both studies evaluated subjects with normal hepatic function, with mild (Child-Pugh class A) hepatic failure, or moderate hepatic failure (Child-Pugh class B). In one study, oral clearance was reduced by approximately 50% in patients with mild hepatic failure (n=5)relative to subjects with normal hepatic function (n=6). In the second study oral clearance was reduced by approximately 15% in subjects with mild hepatic failure (n=5)relative to subjects with normal hepatic function (n=8). Due to the different results for the two studies, it is not possible to determine an appropriate dose adjustment for subjects with mild hepatic failure. In both studies oral clearance was decreased by >50% in subjects with moderate hepatic failure (n=9, n=3) compared to subjects with normal hepatic function (n=6, n=8). RAXAR (grepafloxacin) Tablets are contraindicated for use in patients with hepatic failure (see DOSAGE AND ADMINISTRATION .)

Renal Insufficiency: Renal clearance of grepafloxacin was 0.458 ± 0.04 mL/min per kg in adults with normal renal function. The effect of varying degrees of renal function on the pharmacokinetics of grepafloxacin was assessed in 15 patients with impaired renal function (creatinine clearances ranging from 7.5 to 64 mL/min) compared with five adults with normal renal function. Varying degrees of renal function did not substantially affect the pharmacokinetic properties of grepafloxacin

Smokers: In a population pharmacokinetics study of grepafloxacin in patients with acute bacterial exacerbations of chronic bronchitis grepafloxacin clearance was 35% to 43% faster in patients who smoked relative to patients who did not smoke. This observation is consistent with the involvement of C.P.A. in the metabolism of grepafloxacin and the known induction of this enzyme in smokers. However, in the pivotal clinical trials, smoking did not have an effect on clinical efficacy.

Drug Interactions

(See also PRECAUTIONS, DRUG INTERACTIONS).

Antacids: Following administration of 200 mg grepafloxacin with 1 gram aluminum hydroxide, grepafloxacin AUC and Cmax were both decreased by approximately 60% relative to administration of grepafloxacin alone (n=6) (see PRECAUTIONS, DRUG INTERACTIONS).

Probenecid: Administration of 200 mg grepafloxacin with 500 mg probenecid followed by 500 mg probenecid every 12 hours for three doses did not alter grepafloxacin pharmacokinetics (n=6).

Theophylline: Grepafloxacin is a competitive inhibitor of theophylline metabolism. Twelve healthy subjects received an individualized regimen of sustained-release theophylline alone for 7 days, followed by coadministration of the theophylline regimen with 600 mg grepafloxacin once daily for 10 days. Following the addition of grepafloxacin, theophylline clearance decreased by approximately 50%, from 0.78 ± 0.25 to 0.40 ± 0.08 mL/min per kg. Steady-state peak theophylline concentration increased from 8.30 ± 1.54 µg/mL to 15.12 ± 3.69 µg/mL (see PRECAUTIONS, DRUG INTERACTIONS).

Warfarin: Fourteen healthy subjects received an individualized regimen of warfarin alone for 14 days, followed by coadministration of the warfarin regimen with 600 mg grepafloxacin once daily for 10 days. Grepafloxacin did not alter the anticoagulant effect of warfarin. Other quinolones have been reported to enhance the anticoagulant effects of warfarin (see PRECAUTIONS, DRUG INTERACTIONS).

Microbiology

Grepafloxacin has in vitro activity against a wide range of gram-positive and gram-negative aerobic microorganisms, as well as some atypical microorganisms. Grepafloxacin exerts its antibacterial activity by inhibiting bacterial topoisomerase II (DNA gyrase) and topoisomerase IV, essential enzymes for duplication, transcription, and repair of bacterial DNA. Beta-lactamase production has no effect on grepafloxacin activity and penicillin-resistant Streptococcus pneumoniae strains have undiminished in vitro susceptibility to grepafloxacin. Grepafloxacin is bactericidal at concentrations equal to or slightly greater than minimum inhibitory concentrations (MICs).

Resistance to grepafloxacin through spontaneous mutation in vitro occurs at a low frequency (10-8 to 10-10). As with other fluoroquinolones, the mutation frequency was higher for Pseudomonas species and Stenotrophomonas maltophilia than for other microorganisms. When resistance develops, it does so through slow stepwise increases in MICs. In clinical trials, grepafloxacin-resistant mutants were rarely encountered during the treatment of infections caused by susceptible isolates When they did occur, they were usually Pseudomonas species isolates.

Although cross-resistance has been observed between grepafloxacin and some other fluoroquinolones, some organisms resistant to other quinolones are susceptible to grepafloxacin.

Quinolones differ in chemical structure and mode of action from other classes of antimicrobial agents, including beta-lactam antibiotics and aminoglycosides; therefore, microorganisms resistant to these other classes of drugs may be susceptible to grepafloxacin and other quinolones.

In vitro tests show that grepafloxacin has reduced activity against some gram-positive microorganisms when combined with rifampin.

Grepafloxacin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section:

    Aerobic Gram positive Microorganisms:
    Aerobic Gram negative Microorganisms:
      Haemophilus influenzae
      Moraxella catarrhalis
      Neisseria gonorrhoeae
    Other Microorganisms:

The following in vitro data are available, but their clinical significance is unknown.

Grepafloxacin exhibits in vitro MICs of 1 µg/mL or less against most (³90%) strains of the following microorganisms; however, the safety and effectiveness of grepafloxacin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

    Aerobic Gram positive Microorganisms:
      Staphylococcus aureus (methicillin-susceptible strains)
      Staphylococcus epidermidis (methicillin-susceptible strains)
      Streptococcus agalactiae
      Streptococcus pneumoniae (penicillin-resistant strains)
      Streptococcus pyogenes.
    Aerobic Gram negative Microorganisms:
      Citrobacter freundii
      Citrobacter (diversus) koseri
      Enterobacter aerogenes
      Enterobacter cloacae
      Escherichia coli
      Haemophilus parainfluenzae
      Klebsiella oxytoca
      Klebsiella pneumoniae
      Morganella morganii
      Proteus mirabilis
      Proteus vulgaris
    Other Microorganisms

Susceptibility Tests

Dilution Techniques: Quantitative methods are used to determine MICs. These M.C. provide estimates of the susceptibility of bacteria to antimicrobial compounds. The M.C. should be determined using a standardized procedure. Standardized procedures are based on a dilution method1 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of grepafloxacin powder. The MIC values should be interpreted according to the following criteria:

For testing aerobic organisms other than Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria gonorrhoeae:

MIC (µg/mL)
Interpretation
£ 1
Susceptible (S)
2
Intermediate (I)
³ 4
Resistant (R)

For testing Streptococcus pneumoniae:a

MIC (µg/mL)
Interpretation
£ 1
Susceptible (S)

    a These interpretive standards are applicable only to broth microdilution susceptibility tests using cation-adjusted Mueller-Hinton broth with 2% to 5% lysed horse blood.

The current absence of data on resistant strains precludes defining any categories other than "Susceptible". Strains yielding MIC results suggestive of a "Nonsusceptible" category should be submitted to a reference laboratory for further testing.

For testing Haemophilus influenzae:b

MIC (µg/mL)
Interpretation
£ 0.25
Susceptible (S)

    b These interpretive standards are applicable only to broth microdilution susceptibility testing with Haemophilus influenzae using Haemophilus Test Medium HTM1.

The current absence of data on resistant strains precludes defining any categories other than "Susceptible". Strains yielding MIC results suggestive of a "Nonsusceptible" category should be submitted to a reference laboratory for further testing.

    For testing Neisseria gonorrhoeae:c

MIC (µg/mL)
Interpretation
£ 0.06
Susceptible (S)

    c These interpretive standards are applicable only to agar dilution tests with GC agar base and 1% defined growth supplement.

The current absence of data on resistant strains precludes defining any categories other than "Susceptible". Strains yielding MIC results suggestive of a "Nonsusceptible" category should be submitted to a reference laboratory for further testing.

A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentration usually achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard grepafloxacin powder should provide the following MIC values:

Microorganism
MIC Range (µg/mL)
Escherichia coli ATCC 25922
0.004-0.03
Haemophilus influenzae ATCC 49247a
0.002-0.016
Neisseria gonorrhoeae ATCC 49226b
0.004-0.03
Staphylococcus aureus ATCC 29213
0.03-0.12
Streptococcus pneumoniae ATCC 49619c
0.06-0.5
    a This quality control range is applicable only to H influenzae ATCC 49247 tested by a broth microdilution procedure using HTM.1
    b This quality control range is applicable only to N gonorrhoeae ATCC 49226 tested by agar dilution using GC agar base with 1% defined growth supplement.
    c This quality control range is applicable only to S pneumoniae ATCC 49619 tested by a broth microdilution procedure using cation-adjusted Mueller-Hinton broth with 2 to 5 lysed horse blood.

Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 5-µg grepafloxacin to test the susceptibility of microorganisms to grepafloxacin.

Reports from the laboratory providing results of the standard single disk susceptibility test with a 5-µg disk should be interpreted according to the following criteria:

For aerobic organisms other than Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria gonorrhoeae:

Zone Diameter (mm)
Interpretation
³ 18
Susceptible (S)
15-17
Intermediate (I)
£ 14
Resistant (R)

For testing Streptococcus pneumoniae:a

Zone Diameter (mm)
Interpretation
³ 19
Susceptible (S)

    a These zone diameter standards for Streptococcus pneumoniae are applicable only to tests performed using Mueller-Hinton agar supplemented with 5% sheep blood and incubated in 5% CO2.

The current absence of data on resistant strains precludes defining any categories other than "Susceptible". Strains yielding zone diameter results suggestive of a "Nonsusceptible" category should be submitted to a reference laboratory for further testing.

For testing Haemophilus influenzae:b

Zone Diameter (mm)
Interpretation
³ 24
Susceptible (S)

    b These zone diameter standards are applicable only to disk diffusion testing with Haemophilus influenzae using HTM2.

The current absence of data on resistant strains precludes defining any categories other than "Susceptible". Strains yielding zone diameter results suggestive of a "Nonsusceptible" category should be submitted to a reference laboratory for further testing.

For testing Neisseria gonorrhoeae:c

Zone Diameter (mm)
Interpretation
³ 37
Susceptible (S)

    c These zone diameter standards for Neisseria gonorrhoeae are applicable only to disk diffusion tests with GC agar base and 1% growth supplement.

The current absence of data on resistant strains precludes defining any categories other than "Susceptible." Strains yielding zone diameter results suggestive of a "Nonsusceptible" category should be submitted to a reference laboratory for further testing.

Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for grepafloxacin.

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 5-µg grepafloxacin disk should provide the following zone diameters in these laboratory test quality control strains:

Microorganism
Zone Diameter (mm)
Escherichia coli ATCC 25922
28-36
Haemophilus influenzae ATCC 49247a
32-39
Neisseria gonorrhoeae ATCC 49226b
44-52
Staphylococcus aureus ATCC 25923
26-31
Streptococcus pneumoniae ATCC 49619c
21-28
    a This quality control range is applicable only to H. influenzae ATCC 49247 tested by a disk diffusion procedure using HTM.2
    b This quality control range is applicable only to N. gonorrhoeae ATCC 49226 tested by a disk diffusion procedure using GC agar base with 1% defined growth supplement.
    c This quality control range is applicable only to S. pneumoniae ATCC 49619 tested by a disk diffusion procedure using Mueller-Hinton agar supplemented with 5% sheep blood and incubated in 5% CO2.


CLINICAL STUDIES

Acute Bacterial Exacerbations of Chronic Bronchitis

Two separate controlled randomized trials of grepafloxacin in the treatment of acute bacterial exacerbations of chronic bronchitis yielded overall efficacy rates of grepafloxacin 400 mg and grepafloxacin 600 mg which demonstrated equivalence to comparators. However, these studies suggest that grepafloxacin 400 mg once daily for 10 days may be less effective against S. pneumoniae than grepafloxacin 600 mg once daily for 10 days or comparator for 10 days. These studies excluded patients whose respiratory status required the initiation of steroid therapy or an increase in maintenance steroid doses greater than prednisone 10 mg per day (or its equivalent). Clinical success at end of treatment did not always predict clinical success at follow-up. Table 6 presents efficacy data from these two trials at end of treatment (1 to 5 days posttreatment) and at follow-up (14 to 28 days posttreatment).

Table 6
Clinical Efficacy in Studies of Acute Bacterial Exacerbations of Chronic Bronchitis 

Study 106-92-301
End of Treatment (1-3 Days Posttreatment)
Follow-up (14 Days Posttreatment)
 
Grepafloxacin 400 mg q.d.
Grepafloxacin 600 mg q.d.
Comparator
Grepafloxacin 400 mg q.d.
Grepafloxacin 600 mg q.d.
Comparator
Overall Efficacy
142/57
(90.4%)
140/150
(93.3%)
152/161
(94.4%)
123/153
(80.4%)
124/149
(83.2%)
137/161
(85.1%)
Efficacy by Individual Organism:
S. pneumoniae
36/42
(85.7%)
40/41
(97.6%)
43/44
(97.7%)
29/40
(72.5%)
35/41
(85.4%)
38/44
(86.4%)
H. influenzae
63/68
(92.6%)
61/68
(89.7%)
84/90
(93.3%)
55/67
(82.1%)
51/67
(76.1%)
76/90
(84.4%)
M. catarrhalis
41/43
(95.3%)
32/32
(100%)
29/30
(96.7%)
38/42
(90.5%)
31/32
(96.9%)
26/30
(86.7%)
Study 106-92-206
End of Treatment (3-5 Days Posttreatment)
Follow-up (14-28 Days Posttreatment)
 
Grepafloxacin 400 mg q.d.
Grepafloxacin 600 mg q.d.
Comparator
Grepafloxacin 400 mg q.d.
Grepafloxacin 600 mg q.d.
Comparator
Overall Efficacy
66/72 (91.7%)
66/71 (93.0%)
65/70 (92.9%)
58/71 (81.7%)
61/71 (85.9%)
54/66
(81.8 %)
Efficacy by Individual Organism:
S. pneumoniae
8/8
(100%)
8/9
(88.9%)
3/5
(60%)
7/8
(87.5%)
6/9
(66.7%)
3/5
(60%)
H. influenzae
18/19 (94.7%)
15/16 (93.8%)
17/18 (94.4%)
17/19 (89.5%)
14/16 (87.5%)
15/18 (83.3%)
M. catarrhalis
20/21 (95.2%)
20/21 (95.2%)
18/19 (94.7%)
19/21 (90.5%)
18/21 (85.7%)
15/16 (93.8%)

Community-acquired Pneumonia

The two pivotal clinical trials that assessed the efficacy of grepafloxacin in the treatment of community-acquired pneumonia excluded patients whose respiratory status required the initiation of steroid therapy or an increase in maintenance steroid doses greater than prednisone 10 mg per day (or its equivalent). Study 106-92-302 was a randomized controlled study that assessed the efficacy of grepafloxacin 600 mg once daily for 10 days compared with comparator for 10 days. Study 106-92-205 was an open study that assessed clinical efficacy of grepafloxacin 600 mg once daily for 10 days. Table 7 presents efficacy results from the two pivotal studies:

Table 7
Clinical Efficacy in Community-acquired Pneumonia in Two Pivotal Studies
     
    Grepafloxacin 600 mg q.d.
    Comparator
    Study 106-92-302
    Success
    89/110 (80.9%)
    94/117 (80.3%)
    Failure
    21/110 (19.1%)
    23/117 (19.7%)
    Study 106-92-205
    Success
    116/125 (92.8%)
     
    Failure
    9/125 (7.2%)
     

ANIMAL PHARMACOLOGY

Quinolones have been shown to cause arthropathies in juvenile rats and dogs. In addition, these drugs are associated with an increased incidence of osteochondrosis in rats as compared with the incidence in vehicle-treated rats. Grepafloxacin-associated joint toxicity (cavitation with loss of cartilaginous matrix and chondrocytes with cartilage fibrillation) was observed in juvenile dogs receiving 100 mg/kg by intravenous or subcutaneous injection for 1 week. Grepafloxacin associated joint toxicity (blisters of the articular cartilage) was observed in juvenile dogs given oral doses of 80 mg/kg per day (approximately 4.3 times the recommended maximum daily human dose on a mg/m2 basis for 4 weeks. No joint toxicity was observed at lower oral doses of 60 mg/kg per day approximately 3.2 times the recommended maximum daily human dose on a mg/m2 basis) for 4 weeks. The clinical relevance of these observations is unknown.

In the dog, oral doses of 30 mg/kg and above ( ³ 1.5 times the maximum human dose on a mg/m2 basis) caused prolongation of the QT interval, although the results were variable. Intravenous administration of grepafloxacin at 10 mg/kg elicited a moderate hypotension in anesthetized dogs and rabbits.

In phototoxicity tests, mice exposed to ultraviolet A radiation (similar to that used in tanning booths, sunlight contains a wider spectrum of UV radiation) after administration of grepafloxacin as a single 200 mg/kg oral dose (1.6 times the highest recommended human dose based upon body surface area) showed a mild redness on the ears. Phototoxic reactions such as this have been reported with other quinolones.

Lenticular opacities, sometimes observed after long-term, high-dose use with other quinolones, were not observed with grepafloxacin in a 52-week study in monkeys.

Drug interactions resulting in seizures have been reported between some quinolones and NSAIDs. Grepafloxacin did not induce seizures when administered with a variety of NSAIDs. in rats. The NSAIDs. studied were fenbufen, flurbiprofen, indomethacin, phenylbutazone, ibuprofen, and diflunisal.

Last reviewed on RxList: 12/8/2004
This monograph has been modified to include the generic and brand name in many instances.

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