Pharmacokinetics of Ceftriaxone in Humans

Transcription

1 ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Nov. 1981, p Vol. 20, No /81/ $02.00/0 Pharmacokinetics of Ceftriaxone in Humans I, H. PATEL,* S. CHEN,' M. PARSONNET,2 M. R. HACKMAN,' M. A. BROOKS,' J. KONIKOFF,2 AND S. A. KAPLAN' Department of Pharmacokinetics and Biopharmaceutics' and Department of Clinical Pharmacology,2 Hoffmann-La Roche Inc., Nutley, New Jersey Received 18 June 1981/Accepted 20 August 1981 Pharmacokinetics of the investigational cephalosporin ceftriaxone were studied after 30-min intravenous infusions of three ascending single doses of 0.5, 1, and 2 g crossed over in 12 normal subjects. Serially collected plasma and urine samples were analyzed for ceftriaxone by high-performance liquid chromatography. Plasma concentration-time profiles were characterized by a linear two-compartment open model with the following respective mean (+standard deviation) parameters at 0.5-, 1-, and 2-g dose levels: elimination half-life, , , and 5.9 ± 0.7 h; apparent volume of distribution, , , and 10.1 ± 1.0 liters; and plasma clearance, 929 ± 150, 1,007 ± 130, and 1,190 ± 150 ml/h. The respective renal excretion parameters were as follows: renal clearance, 373 ± 60, 399 ± 50, and ml/h; and percentage of dose excreted unchanged in the 48-h urine samples, 41 ± 8, 39 ± 5, and The 6-h elimination halflife of ceftriaxone was 2- to 10-fold longer than those reported for marketed and other known investigational cephalosporins. The small dose-related increases in the apparent volume of distribution and clearance parameters can be explained by the concentration-dependent plasma protein binding of ceftriaxone in humans. The impact of the small dose-dependent changes in the pharmacokinetics of ceftriaxone is anticipated to be of negligible clinical significance. In recent years, chemical modification of the side chain of 7-aminocephalosporanic acid has resulted in several newer parenteral cephalosporins such as cefotaxime (4), cefoperazone (10), moxalactam (12), ceftizoxime (7), and ceftriaxone (17). These cephalosporins exhibit expanded antibacterial spectra, increased potency against gram-positive and gram-negative bacteria, and increased stability against various types of fl-lactamases (2, 6, 15, 19, 20, 24, 25). Preliminary human pharmacokinetic studies have indicated the following. (i) Ceftriaxone is bound to human plasma proteins, and the binding is concentration dependent; e.g., the free fraction of ceftriaxone in plasma (f4) increases from 3.7 to 16.7% over a plasma concentration range of 0.5 to 300 j.g/ml (21). (ii) The elimination half-life of ceftriaxone (6.4 to 8.8 h) (16, 18, 21) is substantially longer than those reported for cefotaxime (0.9 to 1.5 h) (8, 9, 13, 22), cefoperazone (1.7 to 2.4 h) (1, 3, 8), moxalactam (2.7 to 2.85 h) (22, 23), ceftizoxime (1.4 h) (M. Nakashima, H. Hashimoto, K. Suzuki, and K. Nishijima, Abstr. Intersci. Conf. Antimicrob. Agents Chemother. 19th, Boston, abstr. no. 555, 1979) as well as the several marketed cephalosporins (0.6 to 1.8 h) (14, 15). (iii) The non-linearity observed for the single-dose pharmacokinetics of ceftriaxone can be explained by its concentration-dependent plasma protein binding (21). In the experiments described in this report, single-dose pharmacokinetics of ceftriaxone were further investigated after intravenous infusion (at a constant rate over 30 min) of three doses (0.5, 1, and 2 g) of the drug to 12 human volunteers. The findings of this study indicate that ceftriaxone exhibited dose-dependent pharmacokinetics, but the dose-dependent changes in the pharmacokinetic parameters (volume of 634 distribution and plasma clearance) were small (<30%) and are anticipated to have negligible clinical significance. MATERIALS AND METHODS Subjects. Included in this study were 12 normal volunteers (10 males and 2 females) ranging from 21 to 47 years in age (mean, 36 years) and from 53.1 to 94.8 kg in weight (mean, 74.1 kg). All volunteers provided written informed consent. They were in good general health as determined by history, physical examination, blood count, fasting blood sugar, blood urea nitrogen, creatinine, serum glutamic oxalacetic transaminase, serum glutamic pyruvic transaminase, alkaline phosphatase, bilirubin, VDRL, drug abuse screening, and urinalysis. A glucose-6-phosphate dehydrogenase screening test and hemoglobin electrophoresis were performed for new

2 VOL. 20, 1981 volunteers. Subjects over 40 years of age had an electrocardiogram before the study. All subjects had an electrocardiogram within the year of the study and a chest X ray within 2 years of the study. Study design. All subjects received three single intravenous doses of disodium ceftriaxone, equivalent to 0.5, 1, and 2 g of the free, anhydrous acid. Each dose was administered after an overnight fast, which was continued for an additional 4 h after drug administration. All subjects received 0.5 g as their first dose, 1 g as their second dose, and 2 g as their third dose. In each instance, the drug was dissolved in 100 ml of normal saline and was administered intravenously (antecubital vein) by means of an infusion pump (IMED no. 927) at a constant rate over a 30-min period. The successive doses were separated by a minimum of 1 week. Each higher dose was given only after we had determined that the previous dose had been well tolerated. Sample collection. Blood specimens were obtained at 0 (control), 10, 20, 30 (end of drug infusion), 35, 40, and 50 min, and at 1, 1.5, 2, 4, 6, 8, 10, 12, 16, and 24 h after initiation of the drug infusion. Blood was drawn into heparinized navy-blue Vacutainer tubes and centrifuged immediately. The plasma was separated and stored at -17 C. Urine samples were collected before we initiated the drug infusion (control) and then at the following time intervals: 0 to 2, 2 to 4, 4 to 8, 8 to 12, 12 to 24, and 24 to 48 h. A 15-ml sample of urine was removed from each collection and stored at -17 C. Analytical method. Plasma and urine samples were assayed for ceftriaxone by an automated, reversephase-ion pairing high-performance liquid chromatography method of Trautmann and Haefelfinger (K. H. Trautmann and P. Haefelfinger, J. High Resolut. Chromatogr. Chromatogr. Commun., in press) with the following modifications: (i) acetonitrile was substituted for ethanol to yield a clearer supernatant which was more compatible with the high-performance liquid chromatography mobile phase; (ii) a Chromegabond C-18 column (10-,Am particle, 30 cm by 4.6-mm internal diameter; E. S. Industries, Marlton, N.J.) was chosen in place of a hand-packed, Lichrosorb RP-18 column (5-,um particle, 15 cm by 3.2-mm internal diameter) for chromatography to avoid high back pressure associated with the latter; and (iii) N-i-ethyl analogs of nordiazepam and prazepam were selected to replace probenecid and p-nitrobenzoic acid as internal standards. The other components of the high-performance liquid chromatography system were a model 6000 A pump system (Waters Associates, Milford, Mass.), a model 440 dual-channel ultraviolet detector (Waters Associates), and a model 710 A automatic sample injector (Waters Associates). The ultraviolet detector was operated at 280 nm at 0.02 and 0.1 AUFS simultaneously, and the output responses were monitored with a dual-channel model 7132A chart recorder (Hewlett-Packard, Avondale, Penn.). Plasma assay. A 0.25-ml plasma sample was mixed with 0.75 ml of deionized water and 2 ml of acetonitrile containing 100 ug of nordiazepam. The mixture was shaken on a reciprocating shaker for 10 min and centrifuged at 2,500 rpm for 10 min at 10 C. Approximately 2 ml of the supernatant was transferred to a 4- PHARMACOKINETICS OF CEFTRIAXONE 635 ml screw cap autosampler vial with a Teflon septum, and a 50-pl portion was injected onto the column and eluted with a 2-ml/min flow rate of a mobile phase consisting of acetonitrile, hexadecyltrimethylammonium bromide (10 g/liter in water), 1 M phosphate buffer (ph 7), and deionized water (60:30:1:9). The retention times of ceftriaxone and nordiazepam were 3 and 5 min, respectively. Urine assay. A 0.25-ml sample of urine was diluted with 2 ml of acetonitrile containing 60,tg of prazepam, and the solution was transferred into a standard autosampler vial. A 50-pl portion was injected onto the column and eluted with a 2-ml/min flow rate of a solvent system consisting of acetonitrile, tetraoctylammonium bromide (10 g/liter in water), 1 M phosphate buffer (ph 7), and deionized water (44:35:1.2:19.8). The retention times of ceftriaxone and prazepam were 9 and 13 min, respectively. Linearity and precision. Both plasma and urine assays were linear (i.e., a plot of peak height ratio versus concentration was adequately described by an equation of the form, y = mx + b) over a 2- to 300-[g/ ml concentration range. The interday precision of the method was, on the average, 4% or better over the same concentration range, with an assay recovery of 97%. The assay was reproducible as judged by the slope of the line, which ranged from to with a mean (+standard deviation) of (±3%) for the plasma assay and ranged from to with a mean (±standard deviation) of (±6%) for the urine assay. Pharmacokinetic analysis. Plasma concentration-time curves were biphasic (see Fig. 1), and therefore a two-compartment open model with zero-order infusion and first-order elimination was selected to describe the pharmacokinetics of ceftriaxone. We fitted the plasma concentration-time data of individual subjects, using the NONLIN program (11), to the following equation (5), which describes plasma concentration at any time (t), during the infusion and postinfusion periods: Cp = [-A(1 - eat)e-"t - B(1 - e#t)e,t] (1) where Cp represents plasma concentration; A and B represent the coefficients of the biexponential equation; a and,b are the hybrid disposition rate constants representing the fast and slow disposition phases, respectively; and T varies with time, i.e., T = t while infusion is continuing, and when infusion ceases, T becomes a constant corresponding to the time infusion was stopped. The area under the plasma concentration-time curve from time zero to infinity (AUC) was calculated by using the conventional trapezoidal and extrapolation methods. The following apparent volume-of-distribution parameters were determined: Aa + 1B/3 Dose Vd =AU. where Ro represents the zero-order infusion rate, V, (2) (3)

3 636 PATEL ET AL. represents the volume of the central compartment, and Vd represents the volume of distribution in the phase. Systemic plasma and renal clearances (Cl, and Clr, respectively) of ceftriaxone were estimated from the following relationships: where Ae(t, Dose Clp = AU (4) C r= Ae(ti --e t2)5 Clr AUC t2) (5) excreted unchanged in the urine from time t1 to t2, and AUC (t, -* t2) is the area under the plasma concentration-time curve during the time interval ti to t2. Statistical analysis. Pharmacokinetic parameters were analyzed statistically by two-way analysis of variance to determine the influence of dose and to adjust for subject effects. The dose effects were then compared by employing the two-tailed paired t-test, which made use of the pooled variance estimate (treatment x subject interaction) obtained in the two-way analysis of variance test. Because the doses were not given in a random sequence, statistical conclusions were drawn with the assumption that there were no order or time effects. -e t2) represents the amount of drug RESULTS Plasma concentration-time data. Average plasma concentrations of ceftriaxone after 30- min, constant-rate intravenous infusion of 0.5-, 1-, and 2-g doses of the drug are presented in Table 1. As expected, maximum plasma concentrations were observed at the end of the 30-min infusion, with mean values of 82, 151, and 257,ug/ml after 0.5-, 1-, and 2-g doses, respectively. TABLE 1. ANTIMICROB. AGENTS CHEMOTHER. The increase in the mean maximum-plasmaconcentration value at the 2-g dose level was 15 to 20% less than that predicted from the 0.5- and 1-g dose data when linear pharmacokinetics were assumed. Twelve hours after drug administration, significant plasma concentrations were observed after all three doses, and mean concentrations resulting from the 0.5-, 1-, and 2-g doses were 15, 28, and 46,Lg/ml, respectively. Twentyfour hours after drug administration, mean plasma concentrations were 5, 9, and 15,tg/ml after the 0.5-, 1-, and 2-g doses, respectively. The pharmacokinetic parameters estimated from the plasma concentration data are listed in Table 2. The distribution half-life (t1/2a) of ceftriaxone was relatively short, ranging from 0.07 to 0.52 h, with an overall harmonic mean value of 0.17 h. The elimination half-lives (tl/2/) of 4.73 to 7.75 h ranged less than twofold among the 12 subjects, with harmonic mean values of 6.3 h for the 0.5-g dose, 6.1 h for the 1-g dose, and 5.o h for the 2-g dose. The mean volumes of the central compartment ranged from 4.5 to 4.9 liters. The mean apparent volumes of distribution were 8.46 liters for the 0.5-g dose, 9.00 liters for the 1- g dose, and liters for the 2-g dose. A small dose-related increase in mean plasma clearance was apparent; it increased from 0.93 liter/h at the 0.5-g dose to 1.01 liter/h at the 1-g dose to 1.19 liter/h at the 2-g dose. The two-way analysis of variance and paired t-test analyses of the data indicated statistically significant dose-related changes in all but one (volume of the central compartment) of the pharmacokinetic parameters (Table 2). Average plasma concentrations (pg/ml) of ceftriaxone after single-dose intravenous administration of 0.5-, 1-, and 2-g doses of ceftriaxone to 12 subjects Plasma concn (gg/ml) of ceftriaxone after: Time (h) after 0.5-g Dose 1-g Dose 2-g Dose administration Mean SDa Range Mean SD Range Mean SD Range 'SD, Standard deviation.

4 VOL. 20, 1981 PHARMACOKINETICS OF CEFTRIAXONE 637 TABLE 2. Pharmacokinetic parameters of ceftriaxone after single-dose intravenous administration of 0.5-, 1-, and 2-g doses of ceftriaxone to 12 subjects and statistical evaluation by two-way analysis of variance and two-tailed paired t-test Parameter' Parameter value' at indicated dose (g) ANOVA' Paired t-test of dose effect I vs0.5 2 vs0.5 2 vs 1 A (pg/ml) 37.1 ± ± ± 22.1 ( ) ( ) ( ) a (per h) 3.3 ± ± ± 2.5 P 0.01 NSd P 0.01 NS ( ) ( ) ( ) B (ug/ml) 1306 ± ± ± 387 ( ) ( ) ( ) f (per h) ± ± ± P < 0.01 NS P s 0.01 P c 0.01 ( ) ( ) ( ) ti/2a (h) 0.2le 0.17e 0.13e ( ) ( ) ( ) t112~(h) 6.30e 6.13e 5.82e ( ) ( ) ( ) AUC (pg.h/mi) 551 ± ± ± 203 ( ) ( ) ( ) V, (liter) 4.54 ± ± ± 1.14 NS NS NS NS ( ) ( ) ( ) Vd (liter) 8.46 ± ± ± 0.97 P < 0.01 P < 0.05 P _ 0.01 P < 0.01 ( ) ( ) ( ) Clp (litersa/h) ± ± ± 0.15 P < 0.01 P S 0.01 P s 0.01 P s 0.01 ( ) ( ) ( ) a Parameters are defined in the text. 'Mean ± standard deviation; ranges of values are indicated in parentheses. 'ANOVA, Two-way analysis of variance. d NS, Not significantly different at 5% level of significance. Harmonic mean values. Renal excretion. Average urinary concentrations of intact ceftriaxone after 0.5-, 1-, and 2-g doses are reported in Table 3. The mean urine concentrations in the 0- to 2-h urine samples were 526 ilg/ml after the 0.5-g dose, 995,ug/ml after the 1-g dose, and 2,692,ug/ml after the 2-g dose. In the 24- to 48-h urine samples, the respective mean concentrations were 15, 32, and 40 ilg/ml. The cumulative renal excretion profiles (Table 4) of ceftriaxone indicated that the renal excretion profiles were similar after the 0.5- and 1-g intravenous doses. However, a significantly higher fraction of the dose was excreted unchanged in the 0- to 2-h interval after the 2-g dose than that observed after the 0.5- or 1-g dose (Table 4). In 48 h, 41, 39, and 43% of the dose was excreted as intact ceftriaxone in the urine after 0.5-, 1-, and 2-g doses, respectively. The renal clearances of the total drug were calculated for each urine collection interval (Table 5). The mean renal clearance during each collection interval was plotted as a function of time (midpoint of the collection interval) in Fig. 1. After each intravenous dose, the renal clearance declined appreciably during the first 8 h and then remained relatively constant over the subsequent time period (8 to 24 h). The mean renal clearances in the 0- to 2-h interval were 439, 542, and 919 ml/h for the 0.5-, 1-, and 2-g doses, respectively. The respective clearances in the 12- to 24-h interval were 305, 351, and 340 ml/h. The decline in renal clearance from the 0- to 2-h interval to the 12- to 24-h interval was largest (63%) for the 2-g dose and moderate (31 to 35%) for the two lower doses. The renal clearances at each collection interval for the 0.5- and 1-g doses were reasonably similar. However, they were consistently and significantly lower than those observed for the 2-g dose during the

5 638 PATEL ET AL. 0 to 2, 2 to 4, and 4 to 8 h intervals (Table 5). DISCUSSION Intravenous pharmacokinetics of ceftriaxone were investigated in humans after infusion of TABLE 3. Average urinary concentrations of ceftriaxone after single-dose intravenous administration of 0.5-, 1-, and 2-g doses of ceftriaxone to 12 subjects Urine collection Urinary concn (jig/ml) at indicated dose (g)' interval (h) ± ± ± 1403 ( ) ( ) ( ) ± ± ± 1047 (80-753) ( ) ( ) ± ± ± 437 (34-224) (52-554) ( ) ± ± ±119 (41-152) (59-273) ( ) ± ± ±93 (41-117) (66-232) (74-306) ± 6 32 ± ± 24 (5-24) (5-54) (11-96) a Mean ± standard deviation; ranges of values are indicated in parentheses. ANTIMICROB. AGENTS CHEMOTHER. 0.5-, 1-, and 2-g doses at a constant rate over a 30-min period. The plasma concentration-time curves of ceftriaxone in the postinfusion phase were biphasic, with a relatively short distribution phase (overall mean distribution half-life, 0.17 h) followed by a slow elimination phase (overall mean elimination half-life, 6.1 h). Biexponential plasma concentration-time curves of ceftriaxone, with mean elimination half-lives ranging from 6.5 to 8.6 h, were previously reported (16, 18, 21). In the present study, a small but statistically significant decrease in the elimination rate constant was observed; it increased from a mean value of 0.110/h at the 0.5-g dose to 0.113/h (2.7%) at the 1-gm dose to 0.119/h (8.2%) at the 2-g dose (Table 2). However, in a previous study (21), such a statistically significant dose-dependent decrease in the elimination rate constant was not observed, even with a 10- fold change in the dose (0.15 g to 1.50 g). Significant dose-related increases were observed in the plasma clearance and volume of distribution; these findings are consistent with those of Stoeckel et al. (21). Stoeckel et al. observed that a threefold increase in the dose (0.5 to 1.5 g) resulted in a 27% increase in plasma clearance (from 10.2 to 13.0 ml/min) and a 28% increase in the volume of distribution (from 6.7 to 8.6 liters). In the present study, the observed increase in plasma clearance (28% from liter/h to liter/h) was comparable, whereas TABLE 4. Cumulative percentage of dose of ceftriaxone excreted unchanged in the urine after single-dose intravenous administration of 0.5-, 1-, and 2-g doses of ceftriaxone to 12 subjects and statistical evaluation by two-way analysis of variance and two-tailedpaired t-test Urine Cumulative % of indicated dose (g) in urinea ANOVAb of dose Paired t-test collection interval (h) effect 1 vs vs vs ±2 11±2 15c±6 PC0.05 NSd P'O.O1 PCO.O5 (7-13) (9-15) (1-23) ±4 18± 1 23c±8 P'0.01 NS P'0.01 P'0.01 (13-26) (15-20) (7-33) e ± 4 25 ± 3 32c ± 9 P 0.01 NS P 0.01 P 0.01 (19-34) (20-29) (15-43) e ± 6 30 ± 3 36c ± 9 NS NS NS NS (22-40) (24-34) (20-46) e ± 7 37 ± 5 42c ± 10 NS NS NS NS (24-48) (27-44) (25-53) e ± 8 39 ± 5 43C ± 10 NS NS NS P < 0.01 (27-52) (30-48) (26-56) a Mean ± standard deviation; ranges of values are indicated in parentheses. banova, Two-way analysis of variance. Cn = 10. d NS, Not significantly different at 5% level of significance. en = 11.

6 VOL. 20, 1981 PHARMACOKINETICS OF CEFTRIAXONE 639 TABLE 5. Renal clearance (ml/h) of ceftriaxone after single-dose intravenous administration of 0.5-, 1-, and 2-g doses of ceftriaxone to 12 subjects and statistical evaluation by two-way analysis of variance and twotailed paired t-test Urine Renal clearancea at indicated dose (g) ANOVAb of Paired t-test collection interval (h) dose effect 1 vs vs vs ± ± c ±235 P'0.01 NSd P'O.O1 P'O.O1 ( ) ( ) ( ) ± ± ± 199 P 0.01 NS P 0.01 P 0.01 ( ) ( ) ( ) e ± ± ± 120 P 0.01 NS P 0.01 P 0.01 ( ) ( ) ( ) ± ± ± 128 NS NS NS NS ( ) ( ) ( ) ± e ± ± 93 NS NS NS NS ( ) ( ) ( ) ± ± ± 128 PC 0.05 NS Pc 0.01 Ps0.01 ( ) ( ) ( ) a Mean ± standard deviation; ranges of values are indicated in parentheses. b ANOVA, Two-way analysis of variance. en = 10. d ND, Not significantly different at 5% level of significance. en= 11. the observed increase in the volume of distribution (18% from 8.78 to liter) was smaller than that determined by Stoeckel et al. (21). The renal clearance showed both dose- and time-related changes. It increased as the dose was increased during the first 8 h (Fig. 1). After each intravenous dose, the renal clearance declined at each time interval measured during the first 8 h and then remained relatively constant over the subsequent time period (Fig. 1). This decline in renal clearance from the 0- to 2-h interval to the 12- to 24-h interval was largest (63%) after administration of the 2-g dose and moderate (30 to 35%) after administration of the 0.5- and 1-g doses. These observations are consistent with the data of Stoeckel et al. (21). In both of these studies, increased renal clearance at the highest dose did not increase the fraction of the dose excreted unchanged in the urine at that dose because of a similar increase in the nonrenal clearance of ceftriaxone. In 48 h, 41, 39, and 43% of the dose was excreted unchanged in the urine after the 0.5-, 1-, and 2-g doses, respectively. These values are similar to those (33 to 44%) reported previously from our laboratories (16). The renal excretion data indicate that a substantial fraction of ceftriaxone may be eliminated from the body by nonrenal pathways. After intravenous administration of 150 mg of 14C-labeled ceftriaxone to two volunteers, 44% of the dose was recovered as microbiologically inactive material in the feces, indicating that biliary excretion plays a significant role in the elimination of ceftriaxone (H. Nottebrock, K. Stoeckel, H. W. Ziegler, and R. Heintz, unpublished data). The biliary excretion data for dogs in which 18 to 33% of the dose was recovered in the bile in 72 h support the role of biliary excretion in the overall elimination of ceftriaxone from the body (R. Heintz, H. Nottebrock, and E. Kovacs, unpublished data). Because of concentration-dependent plasma protein binding of ceftriaxone, the area under the total plasma concentration-time curve, as reported herein, is expected to show a less-thanproportional increase with an increase in the dose. However, area under the free (therapeutically active, unbound drug) plasma concentration-time curve is expected to be proportional to the dose. In a previous study (21), this was substantiated, because the free plasma concentration-time curve increased proportionately from 10.1 to 106,g.h/ml over a to 1.5-g dose range. Additionally, multiple dose studies (1 and 2 g every 12 h) (16) indicate that steadystate total plasma concentrations of ceftriaxone predicted from the single-dose data derived by assuming linear pharmacokinetics were overestimated by only 10 to 20%. Therefore, the impact of the nonlinear pharmacokinetics of ceftriaxone on its clinical usage is anticipated to be insignificant. In conclusion, intravenous single-dose phar-

7 C,Ao %-F-x PATEL ET AL ANTIMICROB. AGENTS CHEMOTHER. 0 CZ) -4 u cz c-j LJ<0 m z 0o - 0O TIME-MIDPOINT.HOURS FIG. 1. Time- and dose-dependent changes in the average renal clearance of ceftriaxone after constantrate, 30-min intravenous infusions of 0.5- (a), 1- (A), and 2-g (*) doses of the drug to 12 healthy subjects. macokinetics of ceftriaxone were investigated over a 0.5- to 2-g dose range. Ceftriaxone exhibited a relatively long elimination half-life (6.2 h) and a relatively small volume of distribution (9.1 liters) and plasma clearance (17.4 ml/min). Approximately 40% of the dose was excreted unchanged in the urine within 48 h after drug administration. The small dose-related changes in volume and clearance parameters were of negligible clinical significance. The 6-h elimination half-life of ceftriaxone suggests that a twicea-day or possibly once-a-day dosage regimen may be adequate for clinical use. ACKNOWLEDGMENTS The authors sincerely thank C. A. De George, R. Weinfeld, and S. Givens for contributions to this study. LITERATURE CITED 1. Allaz, A.-F., P. Dayer, J. Fabre, M. Rudhardt, and L. Balant Pharmacocinetique d'une nouvelle cephalosporine. La cefoperazone. Schweiz. Med. Wochenschr. 109: Angehrn, P., P. J. Probst, R. Reiner, and R. L. Then Ro , a long-acting broad-spectrum cephalosporin: in vitro and in vivo studies. Antimicrob. Agents Chemother. 18: Craig, W. A Single dose pharmacokinetics of cefoperazone following intravenous administration. Clin. Ther. 3: Fu, K. P., and H. C. Neu Beta-lactamase stability of HR 756, a novel cephalosporin, compared to that of cefuroxime and cefoxitin. Antimicrob. Agents Chemother. 14: Gibaldi, M., and D. Perrier Pharmacokinetics, p. 70. Marcell Dekker, Inc., New York. 6. Hinkle, A. M., and G. P. Bodey In vitro evaluation of Ro Antimicrob. Agents Chemother. 18: Kamimura, T., Y. Matsumoto, N. Okada, Y. Mine, M. Nishida, S. Goto, and S. Kuwahara Ceftizoxime (FK 749), a new parenteral cephalosporin: in vitro and in vivo antibacterial activities. Antimicrob. Agents Chemother. 16: Lode, H., B. Kemmerich, P. Koeppe, D. Belmega, and H. Jendroschek Comparative pharmacokinetics of cefoperazone and cefotaxime. Clin. Ther. 3: Luthy, R., R. Munch, J.Blaser, W. Bhend, and W. Siegenthaler Human pharmacology of cefotaxime (HR 756), a new cephalosporin. Antimicrob. Agents Chemother. 16: Matsubara, N., S. Minami, T. Muraoka, I. Saikawa, and S. Mitsuhashi In vitro antibacterial activity of cefoperazone (T-1551), a new semisynthetic cephalosporin. Antimicrob. Agents Chemother. 16: Metzler, C. M., G. L. Elfring, and A. J. McEwen A package of computer programs for pharmacokinetic modeling. Biometrics 30: Neu, H. C., N. Aswapokee, K. P. Fu, and P. Aswapokee Antibacterial activity of a new 1-oxa cephalosporin compared with that of other fl-lactam compounds. Antimicrob. Agents Chemother. 16: Neu, H. C., P. Aswapokee, K. P. Fu, I. Ho, and C. Matthijssen Cefotaxime kinetics after intravenous and intramuscular injection of single and multiple doses. Clin. Pharmacol. Ther. 27: Nightingale, C. H., D. S. Greene, and R. Quintiliani.

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