Dec 7, 1990 - University of Connecticut, Farmington, Connecticut 060325. Received 12 June ... An ac- curate determination of bioavailability is necessary for.
Vol. 35, No. 2
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Feb. 1991, p. 384-386
00664804/91/020384-03$02.00/0 Copyright © 1991, American Society for Microbiology
Bioavailability and Pharmacokinetics of Ofloxacin in Healthy Volunteers JAE H. YUK,1 CHARLES H. NIGHTINGALE,2,3* RICHARD QUINTILIANI,4'5 AND KEVIN R. SWEENEY2'3 Pharmacy Services, The Methodist Hospital, Houston, Texas 770301; Department of Pharmacy Services2 and Department of Medicine, Division of Infectious Diseases,4 Hartford Hospital, Hartford, Connecticut 06115;
School of Pharmacy, University of Connecticut, Storrs, Connecticut 062683; and School of Medicine. University of Connecticut, Farmington, Connecticut 060325 Received 12 June 1990/Accepted 7 December 1990
The pharmacokinetics and bioavailabiity of ofloxacin in 20 healthy male volunteers were studied in an open-label, randomized, two-way crossover study. Ofloxacin (400 mg) was administered either as a 1-h infusion or as an oral tablet. The mean peak concentration after intravenous infusion was 4.30 0.69 ,ug/ml, and that after oral administration was 3.14 ± 0.53 ,ug/mI, occurring 1.74 + 0.57 h after dosing. The bioavailability (F) of the oral dosage form of ofloxacin was virtuaUy identical to that of the intravenous form (F = 105% 7%). This complete bioavailability of ofloxacin is supportive of the use of the oral dosage form for the treatment of infections in hospitalized patients either as a replacement for intravenous ofloxacin therapy or in streamlining therapy from the intravenous to the oral route.
Ofloxacin is a synthetic, fluorinated carboxyquinolone active against members of the family Enterobactericeae and gram-positive organisms. Its favorable pharmacokinetic features include good oral absorption and lack of metabolism resulting in decreased drug interaction. The presence of the methyl piperazine ring in ofloxacin probably leads to enhanced oral absorption and a long half-life (properties shown by other quinolones such as pefloxacin, fleroxacin, and difloxacin). Pharmacokinetic disposition and bioavailability have been previously studied in different study populations, and the bioavailability of ofloxacin has been reported to be 80 to 90% (1, 2, 4, 5, 7). There is a paucity of data, however, directly comparing oral (p.o.) and intravenous (i.v.) dosage forms in the same population. The present study was undertaken to evaluate the bioavailabilities of orally and parenterally administered ofloxacin in normal volunteers. An accurate determination of bioavailability is necessary for considering the use of oral ofloxacin in place of the parenteral form in the treatment of hospitalized patients. On the basis of laboratory tests (serum chemistry, hematology, urinalysis), medical history, and physical examination, 20 healthy male volunteers (age, 25 ± 4.6 years; weight, 74.5 ± 7.87 kg; height, 178.3 ± 5.92 cm [mean ± standard deviation]) were enrolled in this study after giving written informed consent. No alcohol or concomitant medication was allowed 72 h prior to the initial administration of the dose and for the entire duration of the study. All subjects reported to the study site at least 12 h prior to the administration of the initial dose, remained within the facility for 36 h after each dose, and returned to the study site for the 48-h scheduled blood draw. Subjects were dosed in the mornings of day 1 and day 8. Subjects fasted at least 8 h prior to each dose and remained fasted for 2 h postdose. Water was permitted ad lib until 2 h prior to and 2 h after dosing. Tablets containing 400 mg of ofloxacin (FD 18489-BS-22) and 10-ml single-dose vials containing 400 mg of ofloxacin (FD 18489*
BR-45) for parenteral use were provided by Ortho Pharmaceutical Corporation. The tablets were administered with 8 oz (ca. 240 ml) of water. The subjects were maintained in an upright position for the first 2 h after oral dosing. For i.v. administration, 10 ml of the ofloxacin solution was mixed with 100 ml of DSW, and 100 ml of the mixed solution was delivered to the subjects over 60 min. Since only 360 mg was infused in this manner, the values obtained were corrected to represent those expected from 400 mg. Blood samples (5 ml) were obtained in heparinized tubes by venipuncture prior to dosing and at 5, 10, 20, 30, 45, 60, 75, and 90 min and 2, 3, 4, 6, 9, 12, 24, 36, and 48 h after initiation of drug administration. This schedule was the same for both routes of ofloxacin administration. Urine samples were collected 8 h prior to dosing and 0 to 6, 6 to 12, 12 to 24, and 24 to 36 h postdose until the subjects were dismissed from the study site. A standard lunch was provided 4 h after each dose. Vital signs were monitored throughout the study, and the laboratory tests were repeated immediately prior to and 24 h after each dose. Ofloxacin concentrations in plasma and in urine samples were determined by using a high-performance liquid chromatographic method by Ortho Pharmaceutical Corporation (3). Briefly, samples were analyzed by using a C18 ,uBondapak column after extraction at pH 7 with dichloromethane. The mobile phase consisted of 1.74 g of potassium dihydrogen phosphate and 20 mg of 1-hexanesulfonic sodium salt dissolved in 650 ml of distilled water, combined with 350 ml of methanol, and adjusted to pH 3 with phosphoric acid. The imidazole derivative of ofloxacin was used as an internal standard. The limit of detection was 0.01 ,ugIml, and the reproducibility was more than 95%. The maximum concentration in plasma and time to peak concentration in plasma were determined by inspection of the observed concentrations in plasma. The area under the plasma concentration-time curve from time zero to infinity (AUC0,) was calculated by the linear trapezoidal rule from time zero to the last measured time plus the residual trape-
Corresponding author. 384
VOL. 35, 1991
zoid area, determined by dividing the last detectable concentration by the terminal elimination rate constant obtained These calcuby the linear least-squares regression analysis. lated AUCs were compared with AUCs obtained from fittingo the data to a pharmacokinetic model. The analysis of variance was used for statistical comparisons and an alpha level of 36 was the amount of drug excreted in the urine during the collection period. The absolute oral bioavailability (F) was calculated as F =
>. ( , = 3 0
_ C 3 o. o 1+ R H M ,_ £ w 0 ,, C
3 a3 >
rY . _ 8 (0
constant to obtain better volume of
distribution and absorption rate constant estimates. Plasma half-life, distribution- and terminal-phase elimination rate constants, volume of distribution, and total systemic clearance were estimated from the fitting. Ofloxacin was well tolerated in most subjects, with the exception of two subjects who experienced nausea after p.o. administration. The statistical analysis of data was conducted excluding data from one subject who experienced emesis following the p.o. dose. The repeated laboratory tests and physical examinations all remained within normal range. The pharmacokinetic parameters after parenteral and p.o. administration are presented in Table 1. The mean (± standard deviation) half-lives following the i.v. infusion and p.o. administration were 5.79 + 0.73 and 5.59 ± 0.81 h, respectively, and no significant difference was found among terminal rate constants from different study days. The volume of distribution and clearance after i.v. and p.o. administration were also similar. These values are in good agreement with previous reports (4, 6). Bioavailabilities calculated from computed modeled AUCs were very close to those obtained from the trapezoidal method. A mean peak (+ standard deviation) concentration of 4.30 ± 0.69 ,ug/ml was observed following i.v. infusion, while the mean peak (_ standard deviation) concentration of 3.14 + 0.53 p,g/ml was achieved 1.74 ± 0.57 h following p.o. administration. The mean AUC.O0 value of the p.o. tablet dose was 105% ± 7% of that of the i.v. infusion dose (Fig. 1). The mean total amounts excreted during the 36-h period following i.v. and p.o. administration of 400 mg of ofloxacin were 257.03 ± 65.40 (64.26% + 16.35%) and 257 + 31.65 (64.35% + 7.91%) mg, respectively. The mean total amount excreted in the urine following the p.o. dose was 100.1% of that of the i.v. dose, which was not significantly different. The estimated renal clearance was also found to be equivalent. The absorption of ofloxacin when administered in our young study volunteers was virtually complete. The maximum concentration in plasma and time to peak concentration in plasma of the oral dosage form were statistically significantly different, as indicated by analysis of variance (P > 0.05) and the two one-sided t test 90% confidence intervals (66.16 to 79.88% and 166.30 to 211.74%, respectively), from the i.v. dosage form. This is not unexpected. Because of a small intrasubject variability (coefficient of variation, 4.5%) in the AUC values, the difference in the plasma AUC values
o ' >.
/AUCi.J (dosei.v./dosep.o.)(AUCp For compartmental pharmacokinetic analysis of the data, unweighted, open, two- and one-compartmental models with
first order absorption and zero order infusion and elimination (PCNONLIN)(6) were fitted to the infusion and p.o. administration data, respectively. For p.o. administration, the data were fitted holding the terminal elimination rate constant and
l . 3
X_ + c0. C)t - -, ,
- E5 5 0 C, o 1+ I+ I+ ' r , -
0 . g BX 1+ g M 0o~~~~~~~~~n o + C --. 2
B. m 3 _
33 co ° 0 #Q X
ANTIMICROB. AGENTS CHEMOTHER. 54
Sw L 4.C
FIG. 1. Mean concentrations of ofloxacin in plasma of 19 male subjects following 400-mg i.v. (0) and p.o. (-) administrations.
between the p.o. and i.v. doses (4.7%) was found to be statistically significant (P < 0.05), with the p.o. dosage form having the larger AUC. However, this difference can be considered clinically insignificant since the 90% confidence intervals (101 to 108%) around the mean AUC value for the p.o. dose was within 100% ± 20% bounds for bioequivalence to the reference i.v. dose. When one is managing infections caused by bacterial strains with relatively high MICs, being able to integrate the pharmacokinetic properties and microbiological activities to evaluate and predict the overall therapeutic response is critical. Being able to achieve reliably good oral absorption is an important property of the quinolones, especially considering the possibility of streamlining i.v. to p.o. therapy and the potential role of oral formulation in the management of rather difficult to treat infections. The small variation in AUCs after p.o. administration seen in our study also implies a very reliable absorption, which is an important aspect in the treatment of patients with acute, severe infection. Further studies, however, are needed to characterize the absorption of this compound in a patient population. The reliable and complete oral absorption of ofloxacin is supportive of the use of the p.o. dosage form for the treatment of infections in hospitalized patients either as a replacement for i.v. ofloxacin therapy or in streamlining therapy from the i.v. to the p.o. route.
We greatly appreciate Pamela L. Henderson and the other members of the pharmacy research laboratory at Hartford Hospital for their invaluable assistance in the conducting of the study. This study was supported by grants from Ortho Pharmaceutical
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