Vol. 36, No. 5
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, May 1992, p. 993-996 0066-4804/92/050993-04$02.00/0 Copyright © 1992, American Society for Microbiology
Pharmacokinetic Profiles of Ciprofloxacin after Single Intravenous and Oral Doses JOHN T. LETTIERI,* MARK C. ROGGE,t LEE KAISER, ROGER M. ECHOLS, AND ALLEN H. HELLER Department of Clinical Pharmacology, Phannaceutical Division, Miles, Inc., West Haven, Connecticut 06516 Received 31 July 1991/Accepted 25 February 1992
Ciprofloxacin was administered to 12 healthy male volunteers at doses of 300 and 400 mg intravenously (i.v.) and 500 and 750 mg orally in a randomized, double-blind, single-dose, four-period crossover study. On each treatment day, each subject received both oral and i.v. formulations, one of which was a placebo. Blood and urine samples were obtained through 24 h postdose. By each dosing route, the pharmacokinetic profiles were dose proportional. The 400-mg i.v. dose was equivalent to the 500-mg oral dose with respect to the area under the concentration-time curve and was equivalent to the 750-mg oral dose with respect to the maximum concentration of ciprofloxacin in serum. The oral bioavailability was 78.0%o. The steady-state volume of distribution averaged 178 liters, and the terminal half-life in serum after i.v. dosing was approximately 4.3 h. Renal clearance accounted for approximately 60% of total body clearance. No significant adverse events were associated with either route of administration.
MATERIAL AND METHODS
Ciprofloxacin is a highly active fluoroquinolone anti-infective agent that is marketed in the United States as oral tablets of 250, 500, and 750 mg. Recently, an intravenous (i.v.) formulation of 200- and 400-mg doses was approved for marketing in the United States. Ciprofloxacin is effective in the treatment of urinary, lower respiratory tract, skin, bone, and joint infections caused by many gram-negative and some gram-positive organisms (2, 8, 9). Those gram-negative organisms with high levels of susceptibility to ciprofloxacin include Escherichia coli and Klebsiella, Enterobacter, Salmonella, Shigella, Proteus, Pseudomonas, Neisseria, and Haemophilus species (4, 13, 16). Gram-positive organisms with high levels of susceptibility include Staphylococcus species and some Streptococcus species. In general, MICs for fully susceptible organisms range from 0.008 to 1.0 ,ug/ml. Following oral administration of 500 mg of ciprofloxacin, the reported mean maximum concentrations in serum (Cm.) range from 1.5 to 2.8 ,ug/ml and are usually observed approximately 1.5 h postdose (5, 6). Following the absorption phase, concentrations in plasma fall, with a reported terminal half-life (t1/2) ranging from approximately 2.5 to 5.4 h. The volume of distribution following i.v. administration has been reported to be approximately 3 liters/kg. Binding to plasma proteins is approximately 30%. The purpose of this study was to establish the bioequivalence of the oral and i.v. dosing formulations of ciprofloxacin. Ciprofloxacin was administered to healthy volunteers at doses of 300 and 400 mg i.v. and 500 and 750 mg orally in a crossover fashion. The pharmacokinetic profile of ciprofloxacin was characterized following each dose; absolute oral bioavailability was determined and dose proportionality was assessed.
Twelve healthy male volunteers, who gave informed consent, entered the study, which was conducted at Medical and Technical Research Associates, Boston, Mass. In this randomized, double-blind, single-dose, four-period crossover study, each volunteer was assigned to one of four treatment sequences. The treatments consisted of ciprofloxacin at concentrations of 300 or 400 mg given i.v. and 500 or 750 mg given orally. On each treatment day, each subject received both an oral and an i.v. dose, one of which was a placebo. The i.v. doses were administered over 60 min in a volume of 200 ml; an infusion pump was used to administer the dose into a forearm vein. The oral doses were administered with 240 ml of tap water as 250-mg tablets or matching placebo. All treatments were administered following an overnight fast and were separated by a 7-day washout interval. Blood samples were obtained just prior to the administration of each dose and at the following times postdose: 0.50, 1.0, 1.25, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 20, and 24 h. The infusion was terminated at 1 h. Urine was collected quantitatively from 0 (predose) to 12 h and 12 to 24 h postdose. All blood samples were centrifuged immediately, and serum was frozen at -20°C until it was assayed. Serum samples were assayed for ciprofloxacin by a validated high-pressure liquid chromatographic method (11). The linear range in both serum and urine was 0.025 to 5.0 ,ug/ml. Within-day coefficients of variation for serum and urine assays across all concentrations averaged 3.6 and 3.1%, respectively. Between-day variability was less than 5%. At the lowest concentration, between-day accuracy was greater than 90% and overall accuracy was greater than 95%. Estimates of the area under the concentration-time curve from 0 to 24 h (AUCO-24), Cm., and renal clearance (CLR) were calculated by using standard noncompartmental methods. For AUC0_2 the log trapezoidal rule was applied (14). AUC extrapolated to infinity (AUC,O), t112, and the volume of distribution at steady-state (V.s) were derived by fitting the data to a two-compartment model by using the ADAPT package (7), in which concentrations of drug in serum were weighted by the reciprocal of the observed variance. All data
t Present address: R. W. Johnson Pharmaceutical Research In-
stitute, Raritan, NJ 08869-0602.
ANTIMICROB. AGENTS CHEMOTHER.
LETTIERI ET AL.
were also fit to a one-compartment model, with universally inferior results. Model discrimination was accomplished by application of the information criterion of Akaike (1). The model for the oral data included a lag time that averaged 0.35 h (500-mg dose) and 0.38 h (750-mg dose) followed by first-order absorption. Each set of data for a given subject and dose was fit independently. Total clearance (CL), was calculated as the i.v. dose divided by AUCG . CLR was calculated as the amount of drug recovered in urine through 24 h postdose (XUW24) divided by AUCO24. Vs, was calculated as V1[(kl2 + k21)/ k21, where V1 is the volume of the central compartment and k12 and k21 are the intercompartmental rate constants derived from fitting the i.v. data. The variables AUCOO, Cm,a, and XLW24 were analyzed for dose proportionality within the i.v. and oral routes and for equivalence between each i.v. and oral dose. The parameters t1/2 and CLR were analyzed for equivalence across all doses. The parameters CL and V., were analyzed for equivalence between the i.v. doses. The statistical analysis was conducted by analysis of variance that included terms for sequence, subject within sequence, period, and dose. AUC, Cm, and XL"24 values were normalized to the dose prior to analysis. The test for sequence effect was performed by comparing the mean square for sequence to the mean square for subject within sequence. Pairwise comparisons consisted of ratios of least-squares means with 90% two-sided confidence intervals calculated by Fieller's theorem (12). Bioavailability was calculated from the least-squares means as the mean dose-normalized AUCO, following oral administration divided by the mean dose-normalized AUCoO following i.v. administration. The safety of drug treatment was monitored by physical examination and periodic laboratory evaluations. Laboratory evaluations were carried out at the time of initial screening, prior to the administration of each dose, and 24 h after the administration of each dose. A complete physical examination was carried out at the time of initial screening and within 24 h after each dose. RESULTS
The mean (± standard deviation) age, height, and weight of the 12 subjects were 27.4 (4.3) years, 69.9 (1.8) in. (177.5 [4.6] cm), and 161.0 (14.7) lb (73.0 [6.7] kg), respectively. The ages ranged from 21 to 35 years. Reported adverse events were all classified as mild and were limited to gastrointestinal complaints in one subject (300-mg i.v. dose and 750-mg oral dose) and headache (300-mg i.v. dose) in two subjects. Mean serum ciprofloxacin concentration data for the i.v. and oral doses are presented in Fig. 1 and 2, respectively. Serum pharmacokinetic data are summarized in Table 1. Statistical results for equivalence and dose proportionality are presented in Table 2. Summary statistics on the concentration of drug in urine, the percentage of the dose recovered, and CLR are presented in Table 3. Twelve subjects completed the study. However, the serum ciprofloxacin concentration-time profile in subject 2 after the 300-mg i.v. dose was markedly greater than that after the 400-mg i.v. dose. To avoid inclusion of aberrant data into the pool of results, the pharmacokinetic data for subject 2 were removed from the final data analysis. A separate analysis (data not shown) was performed in which the results for subject 2 were included in the data pool.
C 3 0
9 l L 1 . _
8 10 12 14 16 18 20 22 24 Time (hr)
FIG. 1. Mean serum ciprofloxacin concentrations following single i.v. doses of 300 mg (-) and 400 mg (+). The duration of infusion was 1 h.
Inclusion of the data for subject 2 did not alter any of the conclusions reported here. Dose proportionality. To assess dose proportionality for each route of administration, dose-normalized AUCO, values were compared as a ratio for each route (Table 2). The ratio of the means (90% confidence interval) of the 400- and 300-mg i.v. doses was 0.985 (0.895 to 1.084), and the ratio of the means of the 750- and 500-mg oral doses was 1.036 (0.916 to 1.173). Ratios of mean dose-normalized AUCO24 values were similar. To assess dose proportionality with respect to Cma values, mean dose-normalized Cm. values for each route were compared as a ratio (Table 2). With respect to dose-normalized Cmax values, equivalence was observed following i.v. and oral dosing. The ratio of the means (90% confidence interval) of the 400- and 300-mg i.v. doses was 0.917 (0.839 to 1.001), and the ratio of the means of the 750- and 500-mg oral doses was 0.929 (0.782 to 1.102). With respect to the fraction of the dose recovered in urine, dose proportionality was suggested, although the 90% confidence intervals (which are given in parentheses) were wide. The ratio of the means of the 400- and 300-mg i.v. doses was 0.903 (0.677 to 1.194); the ratio of the means of the 750- and 500-mg oral doses was 0.986 (0.626 to 1.549).
C 3 0
9 L 1 0 0
8 10 12 14 16 18 20 22 24 Time (hr)
FIG. 2. Mean serum ciprofloxacin concentrations following single oral doses of 500 mg (*) and 750 mg ([1).
VOL. 36, 1992
TABLE 1. Pharmacokinetic parameters following i.v. and oral administrationa
Dose, route 300 mg, 400 mg, 500 mg, 750 mg,
i.v. i.v. oral oral
CM.a12x)Vs ltr (mg/liter) 178 ± 42 3.2 ± 0.7 4.3 ± 0.9 178 ± 37 4.0 ± 0.6 4.4 ± 6.8 NCb 2.7 ± 0.8 5.7 ± 1.2 6.4 ± 1.6 NC 3.8 ± 1.5
(mg h/liter) 8.6 + 1.5 11.4 ± 1.6 10.7 ± 2.6 16.8 ± 4.8
(ml/min) 603 ± 127
388 ± 180
597 ± 82 NC NC
358 ± 274 311 ± 143 280 ± 113
a Values are means + standard deviations. Statistical analyses were based on least-squares means derived from analysis of variance. b NC, not calculated.
The mean percentages of drug recovered in urine through 24 h postdose following the 300- and 400-mg i.v. doses were 61.8 and 55.8%, respectively. The mean percentages following the 500- and 750-mg oral doses were 37.9 and 37.3%, respectively. Dose equivalence. Equivalence was observed between the AUC.OO values following the 400-mg i.v. dose and the 500-mg oral dose. The ratio of the mean AUC,OO values for the i.v. and oral doses (90% confidence interval) was 1.042 (0.933 to 1.167). Similar results were obtained by using AUC-24 values: 1.043 (0.937 to 1.165). The AUC., values for each subject following the 400-mg i.v. and 500-mg oral doses are given in Table 4. At these doses, bioavailability ranged from 53 to 99%. The average bioavailability across all doses, which was determined by comparison of leastsquares means of AUC., values, was 78%, with a 90% confidence interval of 72 to 84%. With respect to Cma. values, the ratio of means (400-mg i.v. to 500-mg oral doses) was 1.431 (1.257 to 1.643 [90% confidence interval]). Equivalence, however, was established between the 400-mg i.v. dose and the 750-mg oral dose; the ratio of the means for these doses was 1.026 (0.896 to 1.189 [90% confidence interval]). The mean V,, was 178 liters for both the 300- and 400-mg i.v. doses. Thus, there was no statistically significant difference in VJs between doses. In all subjects, serum ciprofloxacin concentrations declined in a biexpotential manner. The mean t112 values of ciprofloxacin in serum following the 300-mg i.v., 400-mg i.v., TABLE 2. Statistical data for pharmacokinetic parameters in serum' Estimate of ratioc
oral oral oral oral
1.04 0.67 0.79 0.51
0.933-1.167 0.602-0.749 0.711-0.888
400 i.v./300 i.v. 750 oral/500 oral Bioavailability
0.99 1.04 0.78
400 i.v./500 oral 400 i.v./750 oral 300 i.v./500 oral 300 i.v./750 oral
1.431 1.026 1.171 0.840
1.257-1.643 0.896-1.189 1.032-1.342 0.735-0.971
400 i.v./500 400 i.v./750 300 i.v./500 300 i.v./750
400 i.v./300 i.v. 750 oral/500 oral
a Data are for 11 subjects. Numbers are doses (in milligrams). c Derived from least-squares mean data.
500-mg oral, and 750-mg oral doses were 4.3, 4.4, 5.7, and 6.4 h, respectively. The longer t1l2 values observed following the oral doses may reflect a deep tissue compartment from which the drug is eliminated more slowly than from the general circulation. Several investigators have reported ciprofloxacin t1l2 values that are somewhat longer than the usual 4- to 5-h range when samples were collected beyond 24 h (3, 10). The mean CL values following the 300- and 400-mg i.v. doses were 603 and 597 ml/min, respectively (P = 0.991). The mean CLR values following the 300-mg i.v., 400-mg i.v., 500-mg oral, and 750-mg oral doses were 388, 358, 311, and 280 ml/min, respectively. There were no significant differences between any pairs of values (P > 0.10). CLR accounted for 65 and 57% of CL following the 300- and 400-mg i.v. doses, respectively. DISCUSSION The results presented here are consistent with other reported data (3, 5, 6). However, this study directly compared the pharmacokinetic profile of ciprofloxacin across the oral and i.v. dose routes in clinically relevant dose ranges. The results demonstrate dose proportionality between the two i.v. doses and between the two oral doses. Furthermore, the 400-mg i.v. and 500-mg oral doses were equivalent with respect to serum AUC,O, values. As expected, the mean Cmax following the 400-mg i.v. dose was greater than that observed following the 500-mg oral dose. However, the mean Cm values for the 400-mg i.v. and 750-mg oral doses were equivalent. Hence, the Cmax observed following the 400-mg i.v. dose was similar to the Cma, observed following a 750-mg oral dose. The absolute oral bioavailability of 78% is also consistent with the bioavailability reported previously. The relatively narrow 90% confidence interval (72 to 84%) suggests that the average bioavailability is predictable and unlikely to vary significantly within a comparable patient population. In the current study, the overall mean V.,, following i.v.
TABLE 3. Mean urine ciprofloxacin concentration and pharmacokinetic data following i.v. and oral administration' Mean concn (mg/liter) during time interval (h) postdose
300 mg, i.V. 400 mg, i.V. 500 mg, oral 750 mg, oral
296 270 233 439
+ + ± +
98 132 103 360
% Dose recovered
28.4 30.1 35.1 56.9
± ± ± +
12.3 13.2 12.1 40.2
a Data are for 11 subjects. Values are means
62.5 57.0 38.8 35.5 +
+ ± ± +
25.6 36.1 17.7 12.1
CL (ml/min) (lmn
388 358 311 280
± ± ± ±
180 274 143 113
TABLE 4. Subject no.
1 3 4 5 6 7 8 9 10 11 12
ANTIMICROB. AGENTS CHEMOTHER.
LETTIERI ET AL.
AUCO,. values for individual subjects
AUCO, (,ug. h/ml) after administration of: 500 mg oral
400 mg i.v.
14.4 11.4 10.3 9.4 11.1 7.6 13.3 14.9 9.0 7.5 9.2
14.4 10.9 12.6 9.8 9.6 11.4 11.9 12.1 12.8 9.3 10.4
1.00 0.96 1.22 1.04 0.86 1.50 0.89 0.81 1.42 1.24 1.13
0.80 0.84 0.65 0.77 0.93 0.53 0.89 0.99 0.56 0.65 0.71
Mean + SD 10.74 ± 2.44 11.38 ± 1.50 1.10 ± 0.22 0.76 ± 0.14 a F, absolute bioavailability calculated as (AUCora,/AUCj.VJ) x (dosei.v./
administration was approximately 178 liters. This value far exceeds the 5-liter volume of the circulatory compartment (15). Given that ciprofloxacin is just 30% protein bound, these results suggest that greater than 98% of the drug resides in peripheral tissue. Previously published data (17) indicate that ciprofloxacin concentrations in peripheral tissue typically exceed concentrations in serum. The percentage of the ciprofloxacin dose recovered in urine was consistent within each dose route: approximately 60% following i.v. administration and 40% following oral administration. CLR values were also similar for each dose route. Although there was a general trend for CLR to decrease with increasing dose, these differences were not significant. CLR accounted for approximately 60% of CL following i.v. administration. This is consistent with previously published results and underscores the significance of both renal and nonrenal mechanisms in ciprofloxacin elimination (5, 6). The data presented here show that a 400-mg i.v. dose of ciprofloxacin is equivalent to a 500-mg oral dose with respect to AUC, while the peak concentration in serum achieved with the 400-mg i.v. dose administered over 1 h is equivalent to that achieved after a 750-mg oral dose. Ciprofloxacin exhibits a t1/2 in serum of approximately 4.3 h after i.v. dosing and approximately 6 h after oral dosing. The reason for this discrepancy is not clear, but it probably relates more to the vagaries of curve fitting than to any real difference in drug disposition. No significant adverse events were associated with either route of administration, and in general, ciprofloxacin given both i.v. and orally was well tolerated.
REFERENCES Akaike, H. 1979. A Bayesian extension of the minimum AIC procedure of autoregressive model fitting. Biometrika 66:237242. Arcieri, G., R. August, N. Becker, C. Doyle, E. Griffith, et al. 1986. Clinical experience with ciprofloxacin in the USA. Eur. J. Clin. Microbiol. 5:220-225. Aronoff, G., C. Kenner, R. Sloan, and S. Pottraz. 1984. Multiple dose ciprofloxacin kinetics in normal subjects. Clin. Pharmacol. Ther. 36:384-388. Bauernfeind, A., and C. Petermuller. 1983. In vitro activity of ciprofloxacin, norfloxacin and nalidixic acid. Eur. J. Clin. Microbiol. 2:111-115. Bergan, T., S. B. Thorsteinsson, I. M. Kolstad, and S. Johnsen. 1986. Pharmacokinetics of ciprofloxacin after intravenous and increasing oral doses. Eur. J. Clin. Microbiol. 5:187-192. Borner, K., G. Hoffken, H. Lode, P. Koeppe, C. Prinzing, P. Glatzel, R. Wiley, P. Olschewski, B. Sievers, and D. Reinitz. 1986. Pharmacokinetics of ciprofloxacin in healthy volunteers after oral and intravenous administration. Eur. J. Clin. Microbiol. 5:179-186. D'Argenio, D., and A. Schumitzky. 1990. ADAPT II users guide. Biomedical Simulations Resource, University of California, Los Angeles. Eron, L. J. 1987. Therapy of skin and skin structure infections with ciprofloxacin: an overview. Am. J. Med. 82(Suppl. 4A):
224-229. 9. Gleadhill, I. C., W. P. Ferguson, and R. C. Lowry. 1986. Efficacy and safety of ciprofloxacin in patients with respiratory infections in comparison with amoxicillin. J. Antimicrob. Chemother. 18(Suppl. D):133-138. 10. Guay, D., W. Awni, P. Peterson, S. Obaid, R. Breitenbacher, and G. Matzke. 1987. Pharmacokinetics of ciprofloxacin in acutely ill and convalescent patients. Am. J. Med. 82:124-129. 11. Krol, G. J., A. J. Noe, and D. Beermann. 1986. Liquid chromatographic analysis of ciprofloxacin and ciprofloxacin metabolites in body fluids. J. Liq. Chromatogr. 9:2897-2919. 12. Mandallay, D., and J. Mau. 1981. Comparison of different methods for decision making in bioequivalence assessment. Biometrics 37:213-222. 13. Reeves, D. S., M. J. Bywater, H. A. Holt, and L. 0. White. 1984. In-vitro studies with ciprofloxacin, a new 4-quinolone compound. J. Antimicrob. Chemother. 13:333-346. 14. Riegelman, S., and P. Collier. 1980. The application of statistical moment theory to the evaluation in vivo dissolution and absorption time. J. Pharmacokinet. Biopharm. 8:509-534. 15. Ritschel, W. A. (ed.). 1986. Handbook of basic pharmacokinetics ... including clinical applications, 3rd ed. Drug Intelligence Publications Inc., Hamilton, Ill. 16. Wise, R., J. M. Andrews, and L. J. Edwards. 1983. In vitro activity of Bay o 9867, a new quinolone derivative, compared with those of other antimicrobial agents. Antimicrob. Agents Chemother. 23:559-564. 17. Wise, R., and I. A. Donovan. 1987. Tissue penetration and metabolite of ciprofloxacin. Am. J. Med. 82(Suppl. 4A):103107.