Pharmacokinetics and body fluid penetration of fleroxacin in healthy volunteers

In this open-label study, the disposition of fleroxacin in liver disease in 12 healthy male volunteers, 6 male cirrhotics without ascites (group A), and 6 male cirrhotics with ascites (group B) was evaluated. Fleroxacin (400 mg) was administered orally and intravenously to each subject in a random crossover fashion. Fleroxacin was completely absorbed and achieved similar peak concentrations in plasma in all three study groups (P > 0.05).The volume of distribution exceeded 1 liter/kg in healthy controls and was not affected by liver impairment (P > 0.05). Only group B demonstrated differences in the pharmacokinetic parameters evaluated: the systemic and renal clearances of fleroxacin and the renal clearances and clearances of the two major metabolites of fleroxacin formed, N-demethyl fleroxacin and fleroxacin N-oxide, were significantly lower and the half-lives of the parent drug and its metabolites were significantly longer in group B than in healthy controls and group A (P < 0.05). The elimination of the two metabolites appeared to be formation rate limited in all three study groups. It was concluded from this study that a 50% reduction in the fleroxacin maintenance dose in patients with liver disease appears justified only in patients with ascites. However, no change in the fleroxacin loading dose is needed in patients with compromised liver function.Fleroxacin [6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-quinoline-3-carboxylic acid; AM-833; Ro 23-6240] is a new fluoroquinolone derivative. It possesses a broad antibacterial spectrum and potent activity in vitro against gram-positive and gram-negative bacteria (MIC for 90% of isolates, <0.05 to 2 mg/liter), including Pseudomonas aeruginosa, methicillin-resistant staphylococci (MIC for 90% of isolates, .0.5 to 4.0 mg/liter), and ,B-lactamase-producing bacteria resistant to broad-spectrum cephalosporins (16). The overall activity of fleroxacin is roughly comparable to those of norfloxacin, enoxacin, lomefloxacin, ofloxacin, and pefloxacin (1, 3, 5).

Section: Resultsmentioning

confidence: 99%

“…Fleroxacin is well distributed into interstitial fluid and various tissues (20,21,26,30). Fleroxacin is primarily renally eliminated, with 50 to 60% of the drug being excreted unchanged.…”

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confidence: 99%

Fleroxacin pharmacokinetics in patients with liver cirrhosis

Blouin

Hamelin

Smith

et al. 1992

“…Pharmacokinetic studies in humans have demonstrated that fleroxacin is rapidly and completely absorbed from the gastrointestinal tract, achieving a high concentration in the plasma after either oral or intravenous therapy, is metabolized to a minor extent, and has a long elimination half-life, making once-a-day therapy possible (8,21,39,49,51,52,54). Animal studies have suggested that there is excellent penetration of drug into most tissues (5, 18, 30-34, 41, 49, 53), but only limited information on tissue penetration of fleroxacin in humans is available (22,26,41,44,53).…”

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confidence: 99%

Pharmacokinetics of [18F]fleroxacin in healthy human subjects studied by using positron emission tomography

Fischman

Livni

Babich

et al. 1993

Positron emission tomography (PET) with [18Fjfleroxacin was used to study the pharmacokinetics of fleroxacin, a new broad-spectrum fluoroquinolone, in 12 healthy volunteers (9 men and 3 women). The subjects were infused with a standard therapeutic dose of fleroxacin (400 mg) supplemented with -20 mCi of[18F]fleroxacin. Serial PET images were made and blood samples were collected for 8 h, starting at the initiation of the infusion. The subjects were then treated with unlabeled drug for 3 days (400 mg/day). On the fifth day, infusion of radiolabeled drug, PET imaging, and blood collection were repeated. In most organs, there was rapid accumulation of radiolabeled drug, with stable levels achieved within 1 h after completion of the infusion.Especially high peak concentrations (in micrograms per gram) were achieved in the kidney (>34), liver (>25), lung (>20), myocardium (>19), and spleen (>18). Peak concentrations of drug more than two times the MIC for 90% of Enterobacteriaceae strains tested (>10-fold for most organisms) were achieved in all tissues except the brain and remained above this level for more than 6 to 8 h. The plateau concentrations in tissues (2 to 8 h, in micrograms per gram ± standard error of the mean) of drug were as follows: brain, 0.

“…It is eliminated primarily by renal clearance, with about 60 to 70% of a dose being recovered unchanged in the urine within 96 h (53-55). These pharmacokinetic properties associated with a wide antibacterial spectrum (5,7,24,35,37,55,56) and a high degree of penetration into body fluids and tissues (12,26,27,36,44,52) allow a once-a-day oral administration. The pharmacokinetic parameters of fleroxacin in healthy young volunteers are well known (33,44,53,54).…”

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confidence: 99%

“…These pharmacokinetic properties associated with a wide antibacterial spectrum (5,7,24,35,37,55,56) and a high degree of penetration into body fluids and tissues (12,26,27,36,44,52) allow a once-a-day oral administration. The pharmacokinetic parameters of fleroxacin in healthy young volunteers are well known (33,44,53,54). However, serious infections may lead to changes in these parameters through various mechanisms (1,2,4,6,13,28,49,50).…”

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confidence: 99%

Single-dose pharmacokinetics of oral fleroxacin in bacteremic patients

Schrenzel

Cerruti

Herrmann

et al. 1994

Fleroxacin is a new broad-spectrum quinolone which can be given by the oral route. The present study was designed to assess the influence of bacteremia on the pharmacokinetics of a single oral dose of fleroxacin. Thirteen patients with proven bacteremia (one or more pairs of positive blood cultures, no hypotension) were given a single 400-mg fleroxacin dose orally on two occasions while also receiving standard antibiotic therapy.The first dose was administered 12 to 36 h after the last positive blood culture was drawn (day 1), and a second dose was administered 7 days later (day 7 + 2) to compare the pharmacokinetics between the acute and the convalescent phases of the disease. Following each administration of fleroxacin, serial plasma samples were collected for up to 72 h and were analyzed for unchanged drug by a reversed phase high-pressure liquid chromatography technique. There were no significant changes in the following pharmacokinetic parameters (mean standard deviation) the maximum concentration of drug in serum (6.4 ± 1.5 versus 6.7 + 1.9 mg/liter), the minimum concentration of drug in serum, defined as the concentration of drug in serum at 24 h postdose (3.0 ± 1.7 versus 2.5 ± 1.2 mg/liter), the time to the maximum concentration of drug in serum (2.3 + 1.4 versus 2.0 ± 1.2 h), and the elimination half-life (19.7 ± 8.0 versus 17.9 ± 6.9 h). Fleroxacin clearances were compared for each individual patient. A positive correlation (R2 = 0.787) was found between the values measured on day 1 and day 7. Oral clearance of fleroxacin (CL = CL/F, where F is bioavailability) was slightly, but not significantly, reduced during the bacteremic phase (oral clearance, 43.8 + 23.5 versus 48.5 + 17.5 ml/min).When compared with previous results obtained in healthy young subjects, longer times to the maximum concentration of drug in serum and elimination half-lives and higher areas under the curve were observed. This could be due to the bacteremic state, the old age of the patients (mean, 66 years), and the low renal clearance (mean calculated creatinine clearance, 71.1 ml/min). A single oral dose of 400 mg of fleroxacin provides sufficient levels in serum to cover susceptible microorganisms for at least 24 h in bacteremic patients. Renal function appeared to be the key element that had to be taken into consideration to adapt fleroxacin dosage profiles in our patient population. Bacteremia itself appeared to amplify that phenomenon, but to a much lesser extent than renal function did.Fleroxacin is a new trifluorinated quinolone that differs from most other quinolones by its excellent bioavailability (reaching almost 100%) and a longer terminal half-life (t112,; 10 h) following oral administration (53, 54). It is eliminated primarily by renal clearance, with about 60 to 70% of a dose being recovered unchanged in the urine within 96 h (53-55). These pharmacokinetic properties associated with a wide antibacterial spectrum (5,7,24,35,37,55,56) and a high degree of penetration into body fluids and tissues (12,26,27,36,44,52) all...