Zagam Pharmacology, Pharmacokinetics, Studies, Metabolism - Sparfloxacin

Zagam Pharmacology, Pharmacokinetics, Studies, Metabolism - Sparfloxacin

CLINICAL PHARMACOLOGY

Absorption :   Sparfloxacin is well absorbed following oral administration with an absolute oral bioavailability of 92%. The mean maximum plasma sparfloxacin concentration following a single 400-mg oral dose was approximately 1.3 (±0.2) µg/mL. The area under the curve (mean AUC _{O ->(infinity)} ) following a single 400-mg oral dose was approximately 34 (±6.8) µg·hr/mL.

Steady-state plasma concentration was achieved on the first day by giving a loading dose that was double the daily dose. Mean (±SD) pharmacokinetic parameters observed for the 24-hour dosing interval with the recommended dosing regimen are shown below:

Maximum plasma concentrations for the initial oral 400-mg loading dose were typically achieved between 3 to 6 hours following administration with a mean value of approximately 4 hours. Maximum plasma concentrations for a 200-mg dose were also achieved between 3 to 6 hours after administration with a mean of about 4 hours.

Oral absorption of sparfloxacin is unaffected by administration with milk or food, including high fat meals. Concurrent administration of antacids containing magnesium hydroxide and aluminum hydroxide reduces the oral bioavailability of sparfloxacin by as much as 50%. (See PRECAUTIONS , Information for Patients , and Drug Interactions .)

Distribution:   Upon reaching general circulation, sparfloxacin distributes well into the body, as reflected by the large mean steady-state volume of distribution (Vd _ss ) of 3.9 (±0.8) L/kg. Sparfloxacin exhibits low plasma protein binding in serum at about 45%.

Sparfloxacin penetrates well into body fluids and tissues. Results of tissue and body fluid distribution studies demonstrated that oral administration of sparfloxacin produces sustained concentrations and that sparfloxacin concentrations in lower respiratory tract tissues and fluids generally exceed the corresponding plasma concentrations. The concentration of sparfloxacin in respiratory tissues (pulmonary parenchyma, bronchial wall, and bronchial mucosa) at 2 to 6 hours following standard oral dosing was approximately 3 to 6 times greater than the corresponding concentration in plasma. Concentrations in these respiratory tissues increase at up to 24 hours following dosing. Sparfloxacin is also highly concentrated into alveolar macrophages compared to plasma. Tissue or fluid to plasma sparfloxacin concentration ratios for respiratory tissues and fluids are:

Mean pleural effusion to plasma concentration ratios were 0.34 and 0.69 at 4 and 20 hours postdose, respectively.

Metabolism:   Sparfloxacin is metabolized by the liver, primarily by phase II glucuronidation, to form a glucuronide conjugate. Its metabolism does not utilize or interfere with cytochrome-mediated oxidation, in particular cytochrome P450.

Excretion:   The total body clearance and renal clearance of sparfloxacin were 11.4 (±3.5) and 1.5 (±0.5) L/hr, respectively. Sparfloxacin is excreted in both the feces (50%) and urine (50%). Approximately 10% of an orally administered dose is excreted in the urine as unchanged drug in patients with normal renal function. Following a 400-mg loading dose of sparfloxacin, the mean urine concentration 4 hours postdose was in excess of 12.0 µg/mL, and measurable concentrations of active drug persisted through six days for subjects with normal renal function.

The terminal elimination phase half-life (t _{1 / 2} ) of sparfloxacin in plasma generally varies between 16 and 30 hours, with a mean t _{1 / 2} of approximately 20 hours. The t _{1 / 2} is independent of the administered dose, suggesting that sparfloxacin elimination kinetics are linear.

Special Populations

Geriatric:   The pharmacokinetics of sparfloxacin are not altered in the elderly with normal renal function.

Pediatric:   The pharmacokinetics of sparfloxacin in pediatric subjects have not been studied.

Gender:   There are no gender differences in the pharmacokinetics of sparfloxacin.

Renal insufficiency:   In patients with renal impairment (creatinine clearance <50 mL/min), the terminal elimination half-life of sparfloxacin is lengthened. Single or multiple doses of sparfloxacin in patients with varying degrees of renal impairment typically produce plasma concentrations that are twice those observed in subjects with normal renal function. (See PRECAUTIONS : General and DOSAGE AND ADMINISTRATION .)

Hepatic insufficiency:   The pharmacokinetics of sparfloxacin are not altered in patients with mild or moderate hepatic impairment without cholestasis.

MICROBIOLOGY

Sparfloxacin has in vitro activity against a wide range of gram-negative and gram-positive microorganisms. Sparfloxacin exerts its antibacterial activity by inhibiting DNA gyrase, a bacterial topoisomerase. DNA gyrase is an essential enzyme which controls DNA topology and assists in DNA replication, repair, deactivation, and transcription.

Quinolones differ in chemical structure and mode of action from (beta)-lactam antibiotics. Quinolones may, therefore, be active against bacteria resistant to (beta)-lactam antibiotics.

Although cross-resistance has been observed between sparfloxacin and other fluoroquinolones, some microorganisms resistant to other fluoroquinolones may be susceptible to sparfloxacin.

In vitro tests show that the combination of sparfloxacin and rifampin is antagonistic against Staphylococcus aureus.

Sparfloxacin 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

Staphylococcus aureus

Streptococcus pneumoniae (penicillin-susceptible strains)

Aerobic gram-negative microorganisms

Enterobacter cloacae

Haemophilus influenzae

Haemophilus parainfluenzae

Klebsiella pneumoniae

Moraxella catarrhalis

Other microorganisms

Chlamydia pneumoniae

Mycoplasma pneumoniae

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

Sparfloxacin exhibits in vitro minimal inhibitory concentrations (MIC's) of 1 µg/mL or less against most (>/=90%) strains of the following microorganisms; however, the safety and effectiveness of sparfloxacin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Aerobic gram-positive microorganisms

Streptococcus agalactiae

Streptococcus pneumoniae (penicillin-resistant strains)

Streptococcus pyogenes

Viridans group streptococci

Aerobic gram-negative microorganisms

Acinetobacter anitratus

Acinetobacter lwoffi

Citrobacter diversus

Enterobacter aerogenes

Klebsiella oxytoca

Legionella pneumophila

Morganella morganii

Proteus mirabilis

Proteus vulgaris

SUSCEPTIBILITY TESTS

Dilution techniques:    Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MIC's). These MIC's provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MIC's should be determined using a standardized procedure. Standardized procedures are based on a dilution method ¹ (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of sparfloxacin powder. The MIC values should be interpreted according to the following criteria:

For testing aerobic microorganisms other than Haemophilus influenzae, Haemophilus parainfluenzae, and Streptococcus pneumoniae:

For testing Haemophilus influenzae and Haemophilus parainfluenzae: ^a

^a These interpretive standards are applicable only to broth microdilution susceptibility testing with Haemophilus influenzae and Haemophilus parainfluenzae using Haemophilus Test Medium ¹ .

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 Streptococcus pneumoniae: ^b

^b These interpretive standards are applicable only to broth microdilution susceptibility tests using cation-adjusted Mueller-Hinton broth with 2-5% 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.

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 sparfloxacin powder should provide the following MIC values:

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 procedure ² requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 5-µg sparfloxacin to test the susceptibility of microorganisms to sparfloxacin.

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

For aerobic microorganisms other than Haemophilus influenzae, Haemophilus parainfluenzae , and Streptococcus pneumoniae:

Haemophilus influenzae and Haemophilus parainfluenzae should not be tested by diffusion techniques. An MIC should be determined for these isolates.

For Streptococcus pneumoniae: ^a

^a These zone diameter standards for Streptococcus pneumoniae apply only to tests performed using Mueller-Hinton agar supplemented with 5% sheep blood and incubated in 5% CO ₂ .

The current absence of data on resistant strains precludes any category 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 sparfloxacin.

As with standard 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 sparfloxacin disk should provide the following zone diameters in these laboratory quality control strains:

ANIMAL PHARMACOLOGY

Sparfloxacin and other quinolones have been shown to cause arthropathy in juvenile animals of most species tested. (See WARNINGS.)

Sparfloxacin had no convulsive activity in mice when administered alone or in combination with the nonsteroidal anti-inflammatory agents ketoprofen, or naproxen.