Curr Med Res Opin Downloaded from informahealthcare.com by University of California Irvine on 11/02/14 For personal use only.
Current Medical Research and Opinion
Vol. 12, No. 8,1991
Bioavailability and pharmacokinetics of oral ofloxacin formulations in normal subjects
Gary E. Stein, Pharm.D., Marc LeBel,' Pharm.D., Soledad C. Flor,**Ph.D., and
Miguel Zinny,***M.D. Department of Medicine, Michigan State University, East Lansing. MI, US.A.,*Laboratoire de Pharmacocinetique Clinique, Ecole de Pharmacie, Universitg Laval, Quebgc, Canada, **DrugMetabolism Division, Robert Wood Johnson Pharmaceutical Research Unit, Raritan, N.J., U.S.A.. and ***Medicaland Technical Research Associates, Jamaica Plain, MA. U.S.A.
Curr. Med. Res. Opin., (1991), 12,479.
Received: 6th August 1991
Summary The relative bioavailability and pharmacokinetics of ofloxacin tablets and a reference oral solution of ofloxacin were compared in 32 normal male subjects using a randomized two-way crossover design. After an overnight fast, subjects were randomized to receive a single 200 mg or 300 mg dose of ofloxacin (tablet or solution) and blood samples were obtained prior to and 0.5, I , 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, and 120 hours after the dose. After a 5-day wash-out period, subjects were administered the same dose but of the other formulation, and blood samples were collected in an identical manner: Plasma concentrations of ofloxacin were determined by high-pressure liquid chromatography. The results showed that ofloxacin tablets were more slowly absorbed when compared to the solution and mean peak plasma concentrations were obtained in about 1.5 hours for the tablet preparation. Maximum plasma concentrations were higher after administration of the solution (Cma,=2.24 pglml, 200 mg; Cma,=3.25 pglml, 300 mg) compared to the tablet (C,,,= 1.74 &ml, 200 mg; 2.61 pg/ml, 300 mg). The bioavailability of ofloxacin tablets was greater than 98% compared to the solution. The other pharmacokinetic parameters were similar between the two dosage formulations. Ofloxacin tablets revealed an apparent volume of distribution of 1.5 Nkg, an elimination halflife of 5.6 hours, and a total clearance of 251 ml/min. In addition, a linear increase in plasma concentrations was observed when the dose of ofloxacin was increased. In summary, ofloxacin tablets was found to be reliably bioavailable and bioequivalent to the reference solution.
Key words: Ofloxacin - fluoroquinolones - bioavailability - pharmacokinetics
Introduction A new generation of 4-quinolone antibiotics has recently been introduced into 479
Curr Med Res Opin Downloaded from informahealthcare.com by University of California Irvine on 11/02/14 For personal use only.
Bioavailability and pharmacokinetics of oral ofloxacin formulations in normal subjects
clinical practice.8 These agents include norfloxacin, ciprofloxacin, pefloxacin and, most recently, ofloxacin.'* Ofloxacin differs structurally from other fluoroquinolones in that it contains a 1,4 benzooxacine ringg This ring structure increases the lipid solubility of this compound as well as expands its antimicrobial ~pectrum.~ Although the new fluoroquinolones are similar in structure and size, their bioavailability and pharmacokinetic profiles can vary significantly.6,10Both norfloxacin and ciprofloxacin are incompletely absorbed and exhibit significant hepatic metabolism. Ofloxacin, on the other hand, appears to be highly bioavailable and is predominantly eliminated by renal e x ~ r e t i o n . ~ , ' ~ The purpose of this study was to determine the relative bioavailability and pharmacokinetics of ofloxacin tablets after single-dose oral administration and compare these parameters to those of a reference solution of ofloxacin.
Subjects and methods Thirty-two healthy, non-obese male subjects (aged 18 to 37 years) with no known allergies to 4-quinolone derivatives participated in this investigation after informed written consent was obtained. Volunteers had no renal, hepatic, or haematological diseases. The mean body weight of the volunteers was 78 kg (range 59 to 99 kg). A complete blood count, chemistry profile, and urinalysis were performed on all subjects before drug administration. During the investigational period, the intake of other drugs, alcohol, and caffeine was prohibited. This study was conducted by Medical and Technical Research Associates (Jamaica Plain, MA). The protocol and informed consent document were approved by the local institutional review board. Study subjects were divided into four groups with 8 volunteers in each group. A randomized two-way crossover design was used to study the different dosage formulations of ofloxacin (Table I). After an overnight fast, subjects received a single 200 mg or 300 mg dose of ofloxacin (tablet or solution) with 8 ounces of water. Blood samples were obtained for assessment of plasma ofloxacin concentrations prior to and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, and 120 hours after the dose (Day 1). On Day 6, subjects were administered the same dose, but of the other formulation, and blood samples were collected in an identical manner. Table 1. Ofloxacin dosage scheme Group
I I1 I11 IV
No. objects
Day 1
Day 6
200 mg liquid 200 mg tablet 300 mg liquid 300 mg tablet
200 mg tablet 200 mg liquid 300 mg tablet 300 mg liquid
Plasma samples were immediately frozen and sent to Ortho Pharmaceutical Corporation for analysis. Samples were stored at -2OOC until assayed. N o 480
Curr Med Res Opin Downloaded from informahealthcare.com by University of California Irvine on 11/02/14 For personal use only.
Gary E. Stein, Marc LeBel, Soledad C. Flor and Miguel Zinny
detectable drug decomposition occurs under these condition^.'^ Ofloxacin and its metabolites were determined by high-pressure liquid chr~matography.~ The sensitivity limit of the assay was 0.01 pg/ml. Day-to-day and within-day coefficients of variation were less than 4.3%.Linear regression analysis of the standard calibration lines yielded a correlation greater than 0.999, indicating excellent linearity of the assay. Maximum ofloxacin concentrations (Cmax) as well as times of maximum conwere obtained from observed data. The areas under the plasma centrations (Tmax) versus time curves (AUC) from zero to infinity were calculated by the linear trapezoidal rule.The relative bioavailability was estimated by the formula: Relative F= AUCtabletx 100/AUC~,I,t,,,. Pharmacokinetic parameters were obtained by compartmental analysis using a non-linear extended least squares regression program (MK Model 3.13).5The single variance model is provided by the following equation: Var(Y) =SD2.(VO+YPWR), where: Var(Y) =predicted variance, Y =concentration predicted by a pharmacokinetic model, PWR = power parameter, VO =expected variance model when Y =0 and PWR =0, and SD =standard deviation. All disposition processes were assumed to be first order. After 48 hours, ofloxacin concentrations were below the limit of sensitivity of the assay (Figure 1). The individual plasma concentrations (C) of ofloxacin after tablets or liquid administration were best described by the equations chosen on the basis of visual inspection of the Schwartz ~ r i t e r i o n . ~ After tablet administration the following equation was chosen: C = Dose.Ka/ Vss.(Ka-CL/Vss) X (e-cL/vss (t-tl)-e-Ka (t-tl)). In this equation, CL and Vss are apparent values (CWF and Vss/Fj and F was omitted for clarity. Ka corresponds to absorption constant. A lag-time factor (tl) is subtracted from time (t) for each term. Since the absorption of ofloxacin solution was very fast and the absorption phase could not be described, these data sets were considered as intravenous administration. Thus, the following equation was chosen to describe the individual plasma concentrations of ofloxacin after solution administration: C =Dose x e(-CL/vss t,/Vss. In both equations, the total clearance was estimated by the following pharmacokinetic equation: CL= Dose/AUC and the volume of distribution was calculated from the following equation: Vss= [ Dose.AUMC/(AUC)z]-[Dose/(Ka.AUC)1, where AUC is the area under the plasma concentration-time curve estimated by logarithmic trapezoidal rule and AUMC the area under the first moment of concentration-time curve. The elimination rate constant can be derived from the following equation: Ke = CL/Vss. The comparison of the pharmacokinetic parameters of ofloxacin was performed by using a paired t-test. A p value G0.05 was considered statistically significant. All data are presented as meankstandard deviation.
Results Ofloxacin was rapidly absorbed after oral administration (Figure 1). The maximum plasma concentrations of ofloxacin were significantly (p
Current Medical Research and Opinion
Vol. 12, No. 8,1991
Bioavailability and pharmacokinetics of oral ofloxacin formulations in normal subjects
Gary E. Stein, Pharm.D., Marc LeBel,' Pharm.D., Soledad C. Flor,**Ph.D., and
Miguel Zinny,***M.D. Department of Medicine, Michigan State University, East Lansing. MI, US.A.,*Laboratoire de Pharmacocinetique Clinique, Ecole de Pharmacie, Universitg Laval, Quebgc, Canada, **DrugMetabolism Division, Robert Wood Johnson Pharmaceutical Research Unit, Raritan, N.J., U.S.A.. and ***Medicaland Technical Research Associates, Jamaica Plain, MA. U.S.A.
Curr. Med. Res. Opin., (1991), 12,479.
Received: 6th August 1991
Summary The relative bioavailability and pharmacokinetics of ofloxacin tablets and a reference oral solution of ofloxacin were compared in 32 normal male subjects using a randomized two-way crossover design. After an overnight fast, subjects were randomized to receive a single 200 mg or 300 mg dose of ofloxacin (tablet or solution) and blood samples were obtained prior to and 0.5, I , 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, and 120 hours after the dose. After a 5-day wash-out period, subjects were administered the same dose but of the other formulation, and blood samples were collected in an identical manner: Plasma concentrations of ofloxacin were determined by high-pressure liquid chromatography. The results showed that ofloxacin tablets were more slowly absorbed when compared to the solution and mean peak plasma concentrations were obtained in about 1.5 hours for the tablet preparation. Maximum plasma concentrations were higher after administration of the solution (Cma,=2.24 pglml, 200 mg; Cma,=3.25 pglml, 300 mg) compared to the tablet (C,,,= 1.74 &ml, 200 mg; 2.61 pg/ml, 300 mg). The bioavailability of ofloxacin tablets was greater than 98% compared to the solution. The other pharmacokinetic parameters were similar between the two dosage formulations. Ofloxacin tablets revealed an apparent volume of distribution of 1.5 Nkg, an elimination halflife of 5.6 hours, and a total clearance of 251 ml/min. In addition, a linear increase in plasma concentrations was observed when the dose of ofloxacin was increased. In summary, ofloxacin tablets was found to be reliably bioavailable and bioequivalent to the reference solution.
Key words: Ofloxacin - fluoroquinolones - bioavailability - pharmacokinetics
Introduction A new generation of 4-quinolone antibiotics has recently been introduced into 479
Curr Med Res Opin Downloaded from informahealthcare.com by University of California Irvine on 11/02/14 For personal use only.
Bioavailability and pharmacokinetics of oral ofloxacin formulations in normal subjects
clinical practice.8 These agents include norfloxacin, ciprofloxacin, pefloxacin and, most recently, ofloxacin.'* Ofloxacin differs structurally from other fluoroquinolones in that it contains a 1,4 benzooxacine ringg This ring structure increases the lipid solubility of this compound as well as expands its antimicrobial ~pectrum.~ Although the new fluoroquinolones are similar in structure and size, their bioavailability and pharmacokinetic profiles can vary significantly.6,10Both norfloxacin and ciprofloxacin are incompletely absorbed and exhibit significant hepatic metabolism. Ofloxacin, on the other hand, appears to be highly bioavailable and is predominantly eliminated by renal e x ~ r e t i o n . ~ , ' ~ The purpose of this study was to determine the relative bioavailability and pharmacokinetics of ofloxacin tablets after single-dose oral administration and compare these parameters to those of a reference solution of ofloxacin.
Subjects and methods Thirty-two healthy, non-obese male subjects (aged 18 to 37 years) with no known allergies to 4-quinolone derivatives participated in this investigation after informed written consent was obtained. Volunteers had no renal, hepatic, or haematological diseases. The mean body weight of the volunteers was 78 kg (range 59 to 99 kg). A complete blood count, chemistry profile, and urinalysis were performed on all subjects before drug administration. During the investigational period, the intake of other drugs, alcohol, and caffeine was prohibited. This study was conducted by Medical and Technical Research Associates (Jamaica Plain, MA). The protocol and informed consent document were approved by the local institutional review board. Study subjects were divided into four groups with 8 volunteers in each group. A randomized two-way crossover design was used to study the different dosage formulations of ofloxacin (Table I). After an overnight fast, subjects received a single 200 mg or 300 mg dose of ofloxacin (tablet or solution) with 8 ounces of water. Blood samples were obtained for assessment of plasma ofloxacin concentrations prior to and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 72, 96, and 120 hours after the dose (Day 1). On Day 6, subjects were administered the same dose, but of the other formulation, and blood samples were collected in an identical manner. Table 1. Ofloxacin dosage scheme Group
I I1 I11 IV
No. objects
Day 1
Day 6
200 mg liquid 200 mg tablet 300 mg liquid 300 mg tablet
200 mg tablet 200 mg liquid 300 mg tablet 300 mg liquid
Plasma samples were immediately frozen and sent to Ortho Pharmaceutical Corporation for analysis. Samples were stored at -2OOC until assayed. N o 480
Curr Med Res Opin Downloaded from informahealthcare.com by University of California Irvine on 11/02/14 For personal use only.
Gary E. Stein, Marc LeBel, Soledad C. Flor and Miguel Zinny
detectable drug decomposition occurs under these condition^.'^ Ofloxacin and its metabolites were determined by high-pressure liquid chr~matography.~ The sensitivity limit of the assay was 0.01 pg/ml. Day-to-day and within-day coefficients of variation were less than 4.3%.Linear regression analysis of the standard calibration lines yielded a correlation greater than 0.999, indicating excellent linearity of the assay. Maximum ofloxacin concentrations (Cmax) as well as times of maximum conwere obtained from observed data. The areas under the plasma centrations (Tmax) versus time curves (AUC) from zero to infinity were calculated by the linear trapezoidal rule.The relative bioavailability was estimated by the formula: Relative F= AUCtabletx 100/AUC~,I,t,,,. Pharmacokinetic parameters were obtained by compartmental analysis using a non-linear extended least squares regression program (MK Model 3.13).5The single variance model is provided by the following equation: Var(Y) =SD2.(VO+YPWR), where: Var(Y) =predicted variance, Y =concentration predicted by a pharmacokinetic model, PWR = power parameter, VO =expected variance model when Y =0 and PWR =0, and SD =standard deviation. All disposition processes were assumed to be first order. After 48 hours, ofloxacin concentrations were below the limit of sensitivity of the assay (Figure 1). The individual plasma concentrations (C) of ofloxacin after tablets or liquid administration were best described by the equations chosen on the basis of visual inspection of the Schwartz ~ r i t e r i o n . ~ After tablet administration the following equation was chosen: C = Dose.Ka/ Vss.(Ka-CL/Vss) X (e-cL/vss (t-tl)-e-Ka (t-tl)). In this equation, CL and Vss are apparent values (CWF and Vss/Fj and F was omitted for clarity. Ka corresponds to absorption constant. A lag-time factor (tl) is subtracted from time (t) for each term. Since the absorption of ofloxacin solution was very fast and the absorption phase could not be described, these data sets were considered as intravenous administration. Thus, the following equation was chosen to describe the individual plasma concentrations of ofloxacin after solution administration: C =Dose x e(-CL/vss t,/Vss. In both equations, the total clearance was estimated by the following pharmacokinetic equation: CL= Dose/AUC and the volume of distribution was calculated from the following equation: Vss= [ Dose.AUMC/(AUC)z]-[Dose/(Ka.AUC)1, where AUC is the area under the plasma concentration-time curve estimated by logarithmic trapezoidal rule and AUMC the area under the first moment of concentration-time curve. The elimination rate constant can be derived from the following equation: Ke = CL/Vss. The comparison of the pharmacokinetic parameters of ofloxacin was performed by using a paired t-test. A p value G0.05 was considered statistically significant. All data are presented as meankstandard deviation.
Results Ofloxacin was rapidly absorbed after oral administration (Figure 1). The maximum plasma concentrations of ofloxacin were significantly (p
