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

Abstract

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.

Pharmacokinetics and safety of oral levofloxacin in human immunodeficiency virus-infected individuals receiving concomitant zidovudine

“…Elimination was assumed to be linear and first order. This model has been successfully applied to characterize the pharmacokinetics of levofloxacin in HIV-infected subjects and the pharmacokinetics of ofloxacin in healthy volunteers (2,5). Estimated pharmacokinetic parameters of levofloxacin included the area under the plasma concentration-time curve (AUC 0-t ) as measured by the trapezoidal summation method; AUC 0-ϱ calculated as AUC 0-last ϩ Cp last /k el , where Cp last is the last measurable plasma concentration and k el is the terminal elimination rate constant calculated as the slope of the terminal log-linear phase of the plasma concentration-time profile; apparent total body clearance (CL/F) calculated as dose/AUC 0-ϱ for a single dose and as dose/AUC 0-8 at steady state; and apparent volume of distribution (V/F) calculated as CL/F ⅐ (MRTϪT max /2), where MRT refers to the mean residence time following drug administration.…”

In vitro and in vivo activities of levofloxacin against Mycobacterium tuberculosis

“…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.…”

Quantification of the Impact of Partition Coefficient Prediction Methods on Physiologically Based Pharmacokinetic Model Output Using a Standardized Tissue Composition

“…The acids were thiopental and nifedipine (Nguyen et al, 1996;Ke et al, 2012). The neutrals were digoxin and artemether, and the zwitterion was ofloxacin (Sumner and Russell, 1976;Flor et al, 1993;Lin et al, 2016). The Schmitt and PK-Sim Standard methods recommended the use of membrane affinity (logMA) in place of logP (Willmann et al, 2005;Schmitt, 2008).…”

“…(Sumner and Russell, 1976), and (E) ofloxacin (400 mg, i.v.) (Flor et al, 1993). Dots indicate means, and error bars indicate S.D.…”