Bioavailability and pharmacokinetics of ofloxacin in healthy volunteers

The bioequivalence of oral and intravenous ofloxacin was investigated after the administration of multiple doses of 400 mg every 12 h to 20 healthy male volunteers in a randomized, crossover, open-label study. Ofloxacin concentrations in plasma were evaluated after 4 days of oral or intravenous (1-h infusion) dosing with a 3-day wash-out period between regimens. As expected, delivery to the systemic circulation took slightly longer after the oral dosing (time to maximum concentration of drug in serum of 1.7 h) relative to the 1-h intravenous infusion, but the systemic availabilities of ofloxacin by the two routes of administration were equivalent (area under the concentration-time curve from 0 to 12 h ratio of 95%). Since previous studies have not demonstrated any change in the bioavailability of ofloxacin in infectious disease patients, this study supports the interchangeability of these dosing regimens.Ofloxacin is a synthetic carboxyquinolone antimicrobial agent with potent broad-spectrum bactericidal activity against gram-positive and gram-negative aerobic and facultatively anaerobic bacteria (8 Washout was performed during days 6 to 8. On day 9, the crossover took place and subjects again received p.o. or i.v. ofloxacin (400 mg ql2h) during days 9 to 12. On day 13, they received the last p.o. or i.v. morning dose. All subjects entered the study center at least 12 h prior to administration of the first dose and remained at the center until the last procedure was completed. Subjects were not allowed to eat within 2 h of a dose. For the morning doses, subjects fasted from at least midnight of the previous day. On days 5 and 13, food was not consumed after the prior evening meal until 2 h after the morning dose. Venous blood samples (5 ml) were drawn from each volunteer immediately prior to each dose on days 1, 3, 4, 9, 11, and 12. On days 5 and 13, blood samples were drawn immediately prior to dosing and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 9, 12, 16, and 24 h after dosing began.Analytical procedures. Plasma samples were analyzed for ofloxacin by a sensitive and specific high-pressure liquid chromatographic method previously described (3). After extraction at pH 7 with dichloromethane, the extract was injected onto a C18 ,uBondapak column (25 cm by 4.6 mm [inner diameter]; Waters Associates Inc., Milford, Mass.). The mobile phase consisted of 1.74 g of potassium dihydrogen phosphate and 20 mg of 1-hexanesulfonic sodium salt (Eastman Kodak Co., Rochester, N.Y.) dissolved in 650 ml of distilled water, combined with 350 ml of methanol, and adjusted to pH 3 with phosphoric acid. The imidazolic derivative of ofloxacin (Daiichi Seiyaku) was used as the internal standard. Detection was done with a UV detector at 313 nm. The limit of quantitation was 0.01 mg/liter, and the extraction efficiency was more than 75%. The assay was linear over the concentration range of 0.025 to 9 mg/liter. The intra-and interday coefficients of variation ranged from 3 to 6% over the standard curve concentration range of 0.025 to 9 mg/liter.

Section: Methodssupporting

confidence: 56%

Section: Methodsmentioning

confidence: 82%

Bioequivalence of oral and intravenous ofloxacin after multiple-dose administration to healthy male volunteers

Flor¹,

Rogge²,

Chow³

1993

“…However, because preliminary studies indicated that the pharmacokinetic properties of LVFX in healthy volunteers and presumably also in mice were very similar to those of OFLO (14) and because there is no evidence that the adverse reactions to fluoroquinolones are correlated with their anti-DNA gyrase activities, it is likely that the maximal clinically tolerated dosage of LVFX is similar to that of OFLO, i.e., 800 mg per day (5,9). Since the half-life of OFLO in humans (2,8,24) is significantly longer than that in mice (19), there is a very significant accumulation effect after multiple doses in healthy human volunteers (8) but probably not in mice; therefore, to extrapolate the results of the mouse experiments for the treatment of humans, it is appropriate to take into account the pharmacokinetic data for OFLO and LVFX in humans after multiple doses. Because the area under the concentration-time curve, 48.8 g ⅐ h/ml, for mice treated with a single dose of OFLO at 150 mg/kg (19) is very similar to the area under the concentration-time of 48.1 (8) or 41.20 Ϯ 6.98 (2) g ⅐ h/ml for humans treated with multiple doses of OFLO at 400 mg every 12 h, it is reasonable to estimate that in terms of the area under the concentration-time curve, OFLO at 300 mg/kg in mice is equivalent to OFLO at 800 mg, or the maximal clinically tolerated dosage, in humans.…”

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo activities of levofloxacin against Mycobacterium tuberculosis

Lounis

Truffot-Pernot

et al. 1995

101

In tests with 18 drug-susceptible strains of Mycobacterium tuberculosis, the MIC at which 50% of the strains are inhibited by levofloxacin (LVFX) was one dilution less than that at which 50% of the strains are inhibited by ofloxacin (OFLO), but the MICs at which 90% of the strains are inhibited were similar. The in vivo activity of LVFX against M. tuberculosis was compared with the activities of isoniazid, OFLO, and sparfloxacin (SPFX). Mice were inoculated intravenously with 1.74 ؋ 10 6 CFU of H37Rv, and treatments began the next day and were carried out six times weekly for 4 weeks. The severity of infection and effectiveness of treatment were assessed by survival rate, spleen weights, gross lung lesions, and enumeration of CFU in the spleen. In terms of CFU counts, the ranking of the anti-M. tuberculosis activities of the treatments used ran in the following order: LVFX (300 mg/kg of body weight) ‫؍‬ SPFX (100 mg/kg) > isoniazid > SPFX (50 mg/kg) > OFLO (300 mg/kg) ‫؍‬ LVFX (150 mg/kg) > OFLO (150 mg/kg) ‫؍‬ LVFX (50 mg/kg). It seems, therefore, that the in vivo activity of LVFX is comparable to that produced by a twofold-greater dosage of OFLO. It is assumed that the maximal clinically tolerated dosage of LVFX is similar to that of OFLO, i.e., 800 mg daily, which is equivalent to 300 mg of LVFX per kg in mice. Because LVFX displayed powerful bactericidal activity, promising effects against human tuberculosis may be achieved if patients are treated with the maximal clinically tolerated dosage of LVFX.Today, one-third of the world's population is infected with Mycobacterium tuberculosis, and pulmonary tuberculosis is one of the most serious public health problems in both developing and developed countries (17). Furthermore, M. tuberculosis isolates that are resistant to multiple drugs, especially to isoniazid (INH) and rifampin, are increasing (1, 22); for those multidrug-resistant patients, only a limited number of alternative chemotherapeutic regimens are available, none of them is very effective, and the mortality is high (22). Therefore, effective new antituberculosis drugs with bactericidal mechanisms different from those of the presently available agents, i.e., INH, rifampin, pyrazinamide, ethambutol, and streptomycin, are urgently needed.Our previous experiments demonstrated that among the major commercially available fluoroquinolones, ofloxacin (OFLO) seemed to be the only compound active against M. tuberculosis both in vitro and in vivo (19). The MIC of OFLO at which 90% of the clinical isolates of M. tuberculosis, either susceptible or resistant to both INH and rifampin, are inhibited (MIC 90 ) was 2 g/ml on Löwenstein-Jensen medium (19) or 7H11 agar (10), well below its achievable peak level in serum in mice or humans. The activity of OFLO in mice was dosage related: a dosage of 150 mg/kg of body weight six times weekly displayed only a modest degree of activity against M. tuberculosis, whereas the activity of a dosage of 300 mg/kg six times weekly was moderate (12,19). The pharmacokinetic studies t...

“…Coadministration of moxifloxacin with rifapentine (enzyme and transporter inducer) gave 17.2% (8) and 8% (13) decreases in moxifloxacin exposure in healthy volunteers (dosed three times a week) and tuberculosis patients (dosed once or twice weekly), respectively. Ofloxacin is rapidly absorbed, with peak concentrations reached within 2 h and with a half-life of 6 h, and those characteristics are comparable between healthy volunteers (14) and infected patients (15). Ofloxacin is primarily renally eliminated (16); its concentrations were reported to increase linearly with dose, but elimination of ofloxacin decreases with declining renal function and increasing age (17).…”

mentioning

confidence: 99%

Moxifloxacin Population Pharmacokinetics and Model-Based Comparison of Efficacy between Moxifloxacin and Ofloxacin in African Patients

Zvada

Denti

Sirgel

et al. 2014

h Pharmacokinetic exposure and the MIC of fluoroquinolones are important determinants of their efficacy against Mycobacterium tuberculosis. Population modeling was used to describe the steady-state plasma pharmacokinetics of moxifloxacin in 241 tuberculosis (TB) patients in southern Africa. Monte Carlo simulations were applied to obtain the area under the unbound concentration-time curve from 0 to 24 h (fAUC 0 -24 ) after daily doses of 400 mg or 800 mg moxifloxacin and 800 mg ofloxacin. The MIC distributions of ofloxacin and moxifloxacin were determined for 197 drug-resistant clinical isolates of Mycobacterium tuberculosis. For a specific MIC, the probability of target attainment (PTA) was determined for target fAUC 0 -24 /MIC ratios of >53 and >100. The PTAs were combined with the MIC distributions to calculate the cumulative fraction of response (CFR) for multidrug-resistant (MDR) Mycobacterium tuberculosis strains. Even with the less stringent target ratio of >53, moxifloxacin at 400 mg and ofloxacin at 800 mg achieved CFRs of only 84% and 58% for multidrug-resistant isolates with resistance to an injectable drug, while the 800-mg moxifloxacin dose achieved a CFR of 98%. Using a target ratio of >100 for multidrug-resistant strains (without resistance to injectable agents or fluoroquinolones), the CFR was 88% for moxifloxacin and only 43% for ofloxacin, and the higher dose of 800 mg moxifloxacin was needed to achieve a CFR target of >90%. Our results indicate that moxifloxacin is more efficacious than ofloxacin in the treatment of MDR-TB. Further studies should determine the optimal pharmacodynamic target for moxifloxacin in a multidrug regimen and clarify safety issues when it is administered at higher doses.