Synthetic broad-spectrum antibacterial agent for oral and i.v. administration.
Pharmacology: The main mechanism of action of levofloxacin is inhibition of DNA gyrase. It is 2-fold stronger than that of ofloxacin. There is not much difference between MIC and MBC. The activity of levofloxacin is bactericidal. In the observation of bacterial morphology, bacteriolysis can be seen in the concentration around MIC.
Cravit shows clinical efficacy on respiratory tract infections, genitourinary tract infections, biliary tract infections, intestinal tract infections and other various infections in the surgical, gynecological, dermatological, otorhinolaryngological, ophthalmological, and dental and oral surgery fields.
Pharmacokinetics: Absorption: Levofloxacin is rapidly and essentially completely absorbed after oral administration. Peak plasma concentrations are usually attained 1-2 hrs after oral dosing. The absolute bioavailability of a 500- and 750-mg tablet of levofloxacin are both approximately 99%, demonstrating complete oral absorption of levofloxacin. Following a single i.v. dose of levofloxacin to healthy volunteers, the mean ±SD peak plasma concentration attained was 6.2 ± 1.0 μg/mL after a 500-mg dose infused over 60 min and 11.5 ± 4.0 μg/mL after a 750-mg dose infused over 90 min.
Levofloxacin pharmacokinetics are linear and predictable after single and multiple oral or IV dosing regimens. Steady-state conditions are reached within 48 hrs following a 500- or 750-mg once-daily dosage regimen. The mean ±SD peak and trough plasma concentrations attained following multiple once-daily oral dosage regimens were approximately 5.7 ± 1.4 and 0.5 ± 0.2 μg/mL after the 500-mg doses, and 8.6 ± 1.9 and 1.1 ± 0.4 μg/mL after the 750-mg doses, respectively. The mean ±SD peak and trough plasma concentrations attained following multiple once-daily i.v. regimens were approximately 6.4 ± 0.8 and 0.6 ± 0.2 μg/mL after 500-mg doses, and 12.1 ± 4.1 and 1.3 ± 0.71 μg/mL after 750-mg doses, respectively.
Oral administration with food slightly prolongs the time to peak concentration by approximately 1 hr and slightly decreases the peak concentration by approximately 14%. Therefore, levofloxacin can be administered without regard to food.
The plasma concentration profile of levofloxacin after i.v. administration is similar and comparable in extent of exposure (AUC) to that observed for levofloxacin tablets when equal doses (mg/mg) are administered. Therefore, the oral and i.v. routes of administration can be considered interchangeable.
Distribution: The mean volume of distribution of levofloxacin generally ranges from 74-112 L after single and multiple 500- or 750-mg doses, indicating widespread distribution into body tissues. Levofloxacin reaches its peak levels in skin tissues and in blister fluid of healthy subjects at approximately 3 hrs after dosing. The skin tissue biopsy to plasma AUC ratio is approximately 2 and the blister fluid to plasma AUC ratio is approximately 1 following multiple once-daily oral administration of 750- and 500-mg levofloxacin, respectively, to healthy subjects. Levofloxacin also penetrates well into lung tissues. Lung tissue concentrations were generally 2- to 5-fold higher than plasma concentrations and ranged from approximately 2.4-11.3 μg/g over a 24-hr period after a single 500-mg oral dose.
In vitro, over a clinically relevant range (1-10 μg/mL) of serum/plasma levofloxacin concentrations, levofloxacin is approximately 24-38% bound to serum proteins across all species studied, as determined by the equilibrium dialysis method. Levofloxacin is mainly bound to serum albumin in humans. Levofloxacin binding to serum proteins is independent of the drug concentration.
Metabolism: Levofloxacin is stereochemically stable in plasma and urine and does not invert metabolically to its enantiomer, D-ofloxacin. Levofloxacin undergoes limited metabolism in humans and is primarily excreted as unchanged drug in the urine. Following oral administration, approximately 87% of an administered dose was recovered as unchanged drug in urine within 48 hrs, whereas <4% of the dose was recovered in feces in 72 hrs. Less than 5% of an administered dose was recovered in the urine as the desmethyl and N-oxide metabolites, the only metabolites identified in humans. These metabolites have little relevant pharmacological activity.
Excretion: Levofloxacin is excreted largely as unchanged drug in the urine. The mean terminal plasma elimination half-life of levofloxacin ranges from approximately 6-8 hrs following single or multiple doses of levofloxacin given orally or intravenously. The mean apparent total body clearance and renal clearance range from approximately 144-226 mL/min and 96-142 mL/min, respectively. Renal clearance in excess of the glomerular filtration rate suggests that tubular secretion of levofloxacin occurs in addition to its glomerular filtration. Concomitant administration of either cimetidine or probenecid results in approximately 24% and 35% reduction in the levofloxacin renal clearance; respectively, indicating that secretion of levofloxacin occurs in the renal proximal tubule. No levofloxacin crystals were found in any of the urine samples freshly collected from subjects receiving levofloxacin.
Special Populations: Geriatric: There are no significant differences in levofloxacin pharmacokinetics between young and elderly subjects when the subjects' differences in creatinine clearance are taken into consideration. Following a 500-mg oral dose of levofloxacin to healthy elderly subjects (66-80 years), the mean terminal plasma elimination half-life of levofloxacin was about 7.6 hrs, as compared to approximately 6 hrs in younger adults. The difference was attributable to the variation in renal function status of the subjects and was not believed to be clinically significant. Drug absorption appears to be unaffected by age. Levofloxacin dose adjustment based on age alone is not necessary.
Pediatric: The pharmacokinetics of levofloxacin in pediatric subjects have not been studied.
Gender: There are no significant differences in levofloxacin pharmacokinetics between male and female subjects when subjects' differences in creatinine clearance are taken into consideration. Following a 500-mg oral dose of levofloxacin to healthy male subjects, the mean terminal plasma elimination half-life of levofloxacin was about 7.5 hrs, as compared to approximately 6.1 hrs in female subjects. This difference was attributable to the variation in renal function status of the male and female subjects and was not believed to be clinically significant. Drug absorption appears to be unaffected by the gender of the subjects. Dose adjustments based on gender alone is not necessary.
Race: The effect of race on levofloxacin pharmacokinetics was examined through a covariate analysis performed on data from 72 subjects: 48 white and 24 nonwhite. The apparent total body clearance and apparent volume of distribution were not affected by the race of the subjects.
Renal Insufficiency: Clearance of levofloxacin is substantially reduced and plasma elimination half-life is substantially prolonged in patients with impaired renal function (creatinine clearance <50 mL/min), requiring dosage adjustment in such patients to avoid accumulation. Neither hemodialysis nor continuous ambulatory peritoneal dialysis (CAPD) is effective in removal of levofloxacin from the body, indicating that supplemental doses of levofloxacin are not required following hemodialysls or CAPD. (See Precautions and Dosage & Administration.)
Hepatic Insufficiency: Pharmacokinetic studies in hepatically impaired patients have not been conducted. Due to the limited extent of levofloxacin metabolism, the pharmacokinetics of levofloxacin are not expected to be affected by hepatic impairment.
Bacterial Infection: The pharmacokinetics of levofloxacin in patients with serious community-acquired bacterial infections are comparable to those observed in healthy subjects.
Drug-Drug Interactions: The potential for pharmacokinetic drug interactions between levofloxacin and theophylline, warfarin, cyclosporine, digoxin, probenecid, cimetidine, sucralfate and antacids has been evaluated. (See Interactions.)
Electrocardiogram: In a study of 48 healthy volunteers receiving single doses of levofloxacin 500, 1000 and 1500 mg and placebo, a dose-related increase from baseline to post-dose of average QTc was observed. These changes were not statistically significant from placebo for the 500-mg dose, variably statistically significant for the 1000-mg dose depending on the correction method used and statistically significant for the 1500-mg dose (see Precautions).
Microbiology: Cravit is a broad-spectrum quinolone antibacterial agent containing levofloxacin, optically active (-)-S-form of racemate ofloxacin synthesized by Daiichi Pharmaceutical Co., Ltd. Cravit shows broad and potent antibacterial activities against gram-positive bacteria, e.g. Staphylococcus sp, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus hemolyticus, Enterococcus sp, and gram-negative bacteria, e.g. E. coli, Klebsiella, Serratia, and Proteus spp, Pseudomonas aeruginosa, Haemophilus influenzae. Moreover, Cravit has antibacterial activities against Peptostreptococcus sp of anaerobic bacteria and Chlamydia trachomatis.