Single- and multiple-dose pharmacokinetics of fleroxacin, a trifluorinated quinolone, in humans

The multiple-dose pharmacokinetics and tolerance of temafloxacin, a new fluoroquinolone antibacterial agent, were evaluated in healthy volunteers. Temafloxacin was found to be well tolerated when administered orally every 12 h for 7 days at doses of 100, 200, 300, 400, 600, and 800 mg. Steady-state maximum and minimum concentrations in plasma were proportional to dose, averaging slightly over 1.0 and 0.5 microgram/ml/100 mg administered. Analyses of variance found no significant differences among the dosage groups in total apparent clearances (CLT/F), renal clearances (CLR), or nonrenal clearances, which averaged 197, 119, and 78 ml/min, respectively. The half-life increased slightly with dose, averaging 8.4 h overall. The extent of absorption of temafloxacin was quite reproducible, with day-to-day intrasubject variability in minima averaging under 10%. Renal glomerular filtration of unbound drug was the dominant elimination process; however, tubular secretion and reabsorption also appear to occur. Secretion was estimated to account for about 12% of CLT/F during a regimen of 600 mg every 12 h. CLR was relatively constant for urine flow rates above 1 ml/min, but reabsorption appeared to occur under low-flow conditions, resulting in day-versus-night differences in CLR. Intersubject variability in CLT/F over the eightfold range in dosage was only 20%, and 60% of this variance was accounted for by differences in body surface area (or lean body mass), concentration in plasma, and urine flow rate. Overall, it appears that the pharmacokinetics of temafloxacin are essentially linear, reproducible within a subject, and predictable among subjects.

Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 90%

Pharmacokinetics of temafloxacin in humans after multiple oral doses

Granneman

Carpentier

Morrison

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).…”

mentioning

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 (CLR), about 60 to 70% of a dose being recovered unchanged in the urine within 96 h. The terminal half-life (t112,3) reaches approximately 13 h. Two major metabolites in urine have been identified, N-oxide-fleroxacin and N-demethyl-fleroxacin. They amount to approximately 5 to 10% and 7%, respectively, in healthy subjects (47).…”

mentioning

confidence: 99%

Influence of rifampin on fleroxacin pharmacokinetics

Schrenzel

Dayer

Leemann

et al. 1993

Self Cite

Staphylococcus aureus infections have been successfully treated in animal models with the combination of fleroxacin and rifampin. We studied the influence of rifampin, a potent cytochrome P-450 inducer, on the pharmacokinetics and biotransformation of fleroxacin in 14 healthy young male volunteers. Subjects were given 400 mg of fleroxacin orally once a day for 3 days to reach steady state. After a wash-out period of 2 days, the same subjects received 600 mg of rifampin orally once daily for 7 days. On days 5 to 7 of rifampin treatment, 400 mg of fleroxacin was again administered once daily. Concentrations of fleroxacin as well as its two major urinary metabolites, N-demethyl-and N-oxide-fleroxacin, in plasma and urine were determined by reverse-phase high-performance liquid chromatography. The extent of hepatic enzyme induction by rifampin was confirmed by a significant increase of 6-13-hydroxycortisol urinary output from 160.8 ± 41.4 to 544.8 ± 120.7 ,ug/4 h. There were no significant changes in the peak fleroxacin concentration in plasma (6.3 ± 1.2 versus 6.2 ± 1.9 mg/liter), time to maximum concentration of fleroxacin in plasma (1.1 ± 0.9 versus 1.3 ± 1.1 h), or renal clearance (58.3 ± 16.4 versus 61.9 ± 19.2 mVmin). The area under the curve AUC (71.4 ± 15.8 versus 62.2 ± 13.7 mg. h/liter) and the terminal half-life of fleroxacin (11.4 ± 2.2 versus 9.2 + 1.1 h) decreased (P < 0.05), while the total plasma clearance increased from 97.7 ± 21.6 to 112.3 ± 25.8 ml/min (P < 0.01).Despite being statistically significant, this 15% increase in total plasma clearance does not appear to be clinically relevant. Metabolic clearance by N demethylation was increased (6.9 ± 2.4 versus 12.5 ± 3.2 ml/min; P < 0.01), whereas clearance by N oxidation did not change (5.8 ± 1.1 versus 5.8 ± 1.5 ml/min). Fleroxacin elimination was slightly increased (about 15%) through induction of metabolic clearance to N-demethylfleroxacin. Since fleroxacin levels remained above the MIC for 90%o of the tested isolates of methicillinsusceptible S. aureus for at least 24 h, dose adjustment does not appear necessary, at least for short-term treatments.Fluoroquinolones, including fleroxacin, have recently emerged as interesting antibacterial agents in the therapy of deep-seated infections. This is in part attributable to their antibacterial spectra, the extent of their oral absorption, and their high rate of penetration into biological fluids and tissues (45).Rifampin has long been used as an adjunctive treatment of staphylococcal infections because of its antibacterial effects on staphylococci and its extensive distribution into tissues. However, rifampin monotherapy almost invariably leads to failure due to development of resistance. The combined use of both families of antibacterial agents, fluoroquinolones and rifampin, has been advocated for the treatment of serious staphylococcal infections to avoid the emergence of resistant bacteria, especially in long-term treatments (3, 14-16, 22, 23, 25, 26, 28, 35, 38, 44, 48).The combination of fleroxa...