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Pharmacology: Pharmacodynamics: General Properties: Gemifloxacin is a synthetic antibacterial agent. Gemifloxacin is a fluoroquinolone antibiotic with a wide range of Gram-positive and Gram-negative pathogens.
Mode of Action: The mode of action is by inhibiting DNA synthesis through the inhibition of both bacterial DNA gyrase and topoisomerase. Gemifloxacin is highly selective for bacterial rather than human topoisomerase II, having strong affinity for bacterial topoisomerases II (DNA gyrase) and IV, which are essential enzymes that play a decisive part in the replication, transcription and repair of bacterial DNA.
Susceptible Micro-organisms: Aerobic Gram-positive: Streptococcus pneumoniae (including multi-drug resistant MDRSP*); Streptoccocus pyogenes (including macrolide resistant); Streptococcus viridans; Streptococcus agalactiae; Streptococcus milleri; Streptococcus anginosius; Streptococcus constellatus; Streptococcus mitis; etc., Streptococcus species; Staphylococcus aureus (methicillin sensitive); Staphylococcus epidermidis; Staphylococcus saprophyticus; Staphylococcus haemolyticus; etc., Staphylococcus species; Enterococcus faecalis; Enterococcus faecium; etc., Enterococcus species.
*MDRSP, Multi-drug resistant Streptococcus pneumoniae includes isolates previously known as PRSP (penicillin-resistant Streptococcus pneumoniae), and are strains resistant to two or more of the following antibiotics: penicillin, 2nd generation cephalosporins, e.g., cefuroxime, macrolides, tetracyclines and trimethoprim/sulfamethoxazole.
Aerobic Gram-negative: Haemophilus influenzae (beta lactamase positive and negative); Haemophilus parainfluenzae; etc., Haemophilus species; Moraxella catarrhalis (beta lactamase positive and negative); etc., Moraxella species; Klebsiella pneumoniae; Klebsiella oxytoca; etc., Klebsiella species; Escherichia coli; Neisseria gonorrhoeae; etc., Neisseria species; Acinetobacter lwoffi; Acinetobacter anitratus; Acinetobacter calcoaceticus; Acinetobacter haemolyticus; etc., Acinetobacter species; Citrobacter freundii; Citrobacter koseri; etc., Citrobacter species; Salmonella species; Shigella species; Enterobacter cloacae; Enterobacter aerogenes; etc., Enterobacter species; Serratia marcescens; etc., Serratia species; Proteus mirabilis; Proteus vulgaris; etc., Proteus species; Providencia species; Morganella morganii; etc., Morganella species; Yersinia species; Pseudomonas aeruginosa; etc., Pseudomonas species; Bordetella pertussis; etc., Bordetella species.
Atypicals: Coxiella burnetti; etc., Coxiella species; Mycoplasma pneumoniae; etc., Mycoplasma species; Legionella pneumophila; etc., Legionella species; Chlamydia pneumoniae; etc., Chlamydia species.
Anaerobes: Peptostreptococcus species; Clostridium non-perfringens; Clostridium perfringens; etc., Clostridium species; Fusobacterium species; Porphyromonas species; Prevotella species.
Pharmacokinetics: The pharmacokinetics of gemifloxacin are approximately linear over the dose range from 40 mg to 640 mg. There was minimal accumulation of gemifloxacin following multiple oral doses up to 640 mg a day for 7 days (mean accumulation <20%). Following repeat oral administration of 320 mg gemifloxacin once daily, steady state is achieved by the third day of dosing.
Absorption and Bioavailability: Gemifloxacin, given as an oral tablet, is rapidly absorbed from the gastrointestinal tract. Peak plasma concentrations of gemifloxacin were observed between 0.5 and 2 hours following oral tablet administration and the absolute bioavailability of the 320 mg tablet averaged approximately 71% (95% CI 60%-84%). Following repeat oral doses of 320 mg to healthy subjects, the mean ± SD maximal gemifloxacin plasma concentrations (Cmax) and systemic drug exposure (AUC (0-24)) were 1.61 ± 0.51 μg/mL (range 0.70-2.62 μg/mL) and 9.93 ± 3.07 μg·hr/mL (range 4.71-20.1 μg·hr/mL), respectively. In patients with respiratory and urinary tract infections (n=1423), similar estimates of systemic drug exposure were determined using a population pharmacokinetics analysis (geometric mean AUC (0-24), 8.36 μg·hr/mL; range 3.2 - 47.7 μg·hr/mL. The pharmacokinetics of gemifloxacin was not significantly altered when a 320 mg dose was administered with a high-fat meal. Therefore Factive may be administered without regard to meals.
Distribution: In vitro binding of gemifloxacin to plasma proteins in healthy subjects is approximately 60 to 70% and is concentration independent. After repeated doses, the in vivo plasma protein binding in healthy elderly and young subjects ranged from 55% to 73% and was unaffected by age. Renal impairment does not significantly affect the protein binding of gemifloxacin. The blood-to-plasma concentration ratio of gemifloxacin was 1.2:1. The geometric mean for Vdss/F is 4.18 L/kg (range, 1.66 - 12.12 L/kg). Gemifloxacin is widely distributed throughout the body after oral administration. Concentrations of gemifloxacin in bronchoalveolar lavage fluid exceed those in the plasma. Gemifloxacin penetrates well into lung tissue and fluids. After five daily doses of 320 mg gemifloxacin, concentrations in plasma, bronchoalveolar macrophages, epithelial lining fluid and bronchial mucosa at approximately 2 hours are indicated in table as follows. (See Table 1.)
Click on icon to see table/diagram/imageMetabolism: Gemifloxacin is metabolized to a limited extent by the liver. The unchanged compound is the predominant drug-related component detected in plasma (approximately 65%) up to 4 hours after dosing. All metabolites formed are minor (<10% of the administered oral dose); the principal ones are N-acetyl gemifloxacin, the E-isomer of gemifloxacin and the carbamyl glucuronide of gemifloxacin. Cytochrome P450 enzymes do not play an important role in gemifloxacin metabolism, and the metabolic activity of these enzymes is not significantly inhibited by gemifloxacin.
Elimination: Gemifloxacin and its metabolites are excreted via dual routes of excretion. Following oral administration of gemifloxacin to healthy subjects, a mean (± SD) of 61 ± 9.5% of the dose was excreted in the feces and 36 ± 9.3% in the urine as unchanged drug and metabolites. The mean (± SD) renal clearance following repeat doses of 320 mg was approximately 11.6 ± 3.9 L/hr (range 4.6-17.6 L/hr), which indicates active secretion is involved in the renal excretion of gemifloxacin. The mean (± SD) plasma elimination half-life at steady state following 320 mg to healthy subjects was approximately 7 ± 2 hours (range 4-12 hours).
Photosensitivity Potential: In a study of the skin response to ultraviolet and visible radiation conducted in 40 healthy volunteers, the minimum erythematous dose (MED) was assessed following administration of either gemifloxacin 160 mg once daily, gemifloxacin 320 mg once daily, ciprofloxacin 500 mg BID, or placebo for 7 days. At 5 of the 6 wavelengths tested (295-430 nm), the photosensitivity potential of gemifloxacin was not statistically different from placebo. At 365 nm (UVA region), gemifloxacin showed a photosensitivity potential similar to that of ciprofloxacin 500 mg BID and the photosensitivity potential for both drugs were statistically greater than that of placebo. Photosensitivity reactions were reported rarely in clinical trials with gemifloxacin (0.039%).
It is difficult to ascribe relative photosensitivity/phototoxicity among various fluoroquinolones during actual patient use because other factors play a role in determining a subject's susceptibility to this adverse event such as: a patient's skin pigmentation, frequency and duration of sun and artificial ultraviolet light (UV) exposure, wearing of sun screen and protective clothing, the use of other concomitant drugs and the dosage and duration of fluoroquinolone therapy.
Special Population: Geriatric: In adult subjects, the pharmacokinetics of gemifloxacin are not affected by age.
Gender: There are no significant differences between gemifloxacin pharmacokinetics in males and females when differences in body weight are taken into account. Population pharmacokinetic studies indicated that following administration of 320 mg gemifloxacin, AUC values were approximately 10% higher in healthy female patients compared to males. No gemifloxacin dosage adjustment based on gender is necessary.
Renal Insufficiency: Results from population pharmacokinetic and clinical pharmacology studies with repeated 320 mg doses indicate the clearance of gemifloxacin is reduced and the plasma elimination is prolonged, leading to an average increase in AUC values of approximately 70% in patients with renal insufficiency. In the pharmacokinetic studies, gemifloxacin Cmax was not significantly altered in subjects with renal insufficiency. Dose adjustment in patients with creatinine clearance ≥40 mL/min is not required. Modification of the dosage is recommended for patients with creatinine clearance <40 mL/min.
Hepatic Insufficiency: The pharmacokinetics following a single 320 mg dose of gemifloxacin were studied in patients with mild to severe hepatic impairments. There was a mean increase in AUC and in Cmax in these subjects with hepatic impairment compared to healthy volunteers. These average pharmacokinetic increases are not considered to be clinically significant. There was no significant change in plasma elimination half-life in the mild, moderate or severe hepatic impairment patients. No dosage adjustment is recommended in patients with mild, moderate or severe hepatic impairment (Child-Pugh A, B and C).
Toxicology: Preclinical safety data: Genotoxicity: Gemifloxacin was not mutagenic in the bacterial strains used in an Ames Salmonella reversion assay. It did not induce either micronuclei in the bone marrow of mice following intraperitoneal doses nor unscheduled DNA synthesis in hepatocytes from rats. Gemifloxacin was clastogenic in vitro in the mouse lymphoma and human lymphocyte chromosome aberration assays. It was clastogenic in vivo in the rat micronucleus assay at oral and intravenous dose levels that produced bone marrow toxicity.
Carcinogenesis: Long term studies in animals to determine the carcinogenic potential of gemifloxacin have not been conducted.
Gemifloxacin was administered orally, by gavage, 5 days per week for 12 months, to hairless mice at doses up to 100 mg/kg/day and mice were exposed to UV radiation. Gemifloxacin did not induce development of UVR-induced skin tumor. In phototoxicity studies, gemifloxacin demonstrated either the least or no phototoxic effects.
Gemifloxacin was reported to have antigenic potential in animal studies.
Impairment of Fertility: Gemifloxacin did not affect the fertility of male or female rats at AUC levels following oral administration that were approximately 3- to 4-fold higher than the AUC levels at the clinically recommended dose.
