pharmacokinetics of ceftriaxone in humans

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Nov. 1981, p. 634-641 Vol. 20, No. 5

0066-4804/81/1 10634-08$02.00/0

Pharmacokinetics of Ceftriaxone in HumansI, 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 07110

Received 18 June 1981/Accepted 20 August 1981

Pharmacokinetics of the investigational cephalosporin ceftriaxone were studiedafter 30-min intravenous infusions of three ascending single doses of 0.5, 1, and 2g crossed over in 12 normal subjects. Serially collected plasma and urine sampleswere analyzed for ceftriaxone by high-performance liquid chromatography.Plasma concentration-time profiles were characterized by a linear two-compart-ment open model with the following respective mean (+standard deviation)parameters at 0.5-, 1-, and 2-g dose levels: elimination half-life, 6.5 + 0.7, 6.2 + 0.8,and 5.9 ± 0.7 h; apparent volume of distribution, 8.5 + 1.1, 9.0 + 1.1, 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 533 + 128 ml/h; and percentage of dose excreted unchangedin the 48-h urine samples, 41 ± 8, 39 ± 5, and 43 + 10. The 6-h elimination half-life of ceftriaxone was 2- to 10-fold longer than those reported for marketed andother known investigational cephalosporins. The small dose-related increases inthe apparent volume of distribution and clearance parameters can be explainedby the concentration-dependent plasma protein binding of ceftriaxone in humans.The impact of the small dose-dependent changes in the pharmacokinetics ofceftriaxone is anticipated to be of negligible clinical significance.

In recent years, chemical modification of theside chain of 7-aminocephalosporanic acid hasresulted in several newer parenteral cephalo-sporins such as cefotaxime (4), cefoperazone(10), moxalactam (12), ceftizoxime (7), and cef-triaxone (17). These cephalosporins exhibit ex-panded antibacterial spectra, increased potencyagainst gram-positive and gram-negative bacte-ria, and increased stability against various typesof fl-lactamases (2, 6, 15, 19, 20, 24, 25).

Preliminary human pharmacokinetic studieshave indicated the following. (i) Ceftriaxone isbound to human plasma proteins, and the bind-ing is concentration dependent; e.g., the freefraction of ceftriaxone in plasma (f4) increasesfrom 3.7 to 16.7% over a plasma concentrationrange of 0.5 to 300 j.g/ml (21). (ii) The elimina-tion half-life of ceftriaxone (6.4 to 8.8 h) (16, 18,21) is substantially longer than those reportedfor cefotaxime (0.9 to 1.5 h) (8, 9, 13, 22), cefop-erazone (1.7 to 2.4 h) (1, 3, 8), moxalactam (2.7to 2.85 h) (22, 23), ceftizoxime (1.4 h) (M. Na-kashima, H. Hashimoto, K. Suzuki, and K. Nish-ijima, Abstr. Intersci. Conf. Antimicrob. AgentsChemother. 19th, Boston, abstr. no. 555, 1979)as well as the several marketed cephalosporins(0.6 to 1.8 h) (14, 15). (iii) The non-linearityobserved for the single-dose pharmacokinetics

of ceftriaxone can be explained by its concentra-tion-dependent plasma protein binding (21).

In the experiments described in this report,single-dose pharmacokinetics of ceftriaxonewere further investigated after intravenous in-fusion (at a constant rate over 30 min) of threedoses (0.5, 1, and 2 g) of the drug to 12 humanvolunteers. The findings of this study indicatethat ceftriaxone exhibited dose-dependent phar-macokinetics, but the dose-dependent changesin the pharmacokinetic parameters (volume ofdistribution and plasma clearance) were small(<30%) and are anticipated to have negligibleclinical significance.

MATERIALS AND METHODS

Subjects. Included in this study were 12 normalvolunteers (10 males and 2 females) ranging from 21to 47 years in age (mean, 36 years) and from 53.1 to94.8 kg in weight (mean, 74.1 kg).

All volunteers provided written informed consent.They were in good general health as determined byhistory, physical examination, blood count, fastingblood sugar, blood urea nitrogen, creatinine, serumglutamic oxalacetic transaminase, serum glutamic py-ruvic transaminase, alkaline phosphatase, bilirubin,VDRL, drug abuse screening, and urinalysis. A glu-cose-6-phosphate dehydrogenase screening test andhemoglobin electrophoresis were performed for new

634

PHARMACOKINETICS OF CEFTRIAXONE 635

volunteers. Subjects over 40 years of age had an elec-trocardiogram before the study. All subjects had anelectrocardiogram within the year of the study and achest X ray within 2 years of the study.Study design. All subjects received three single

intravenous doses of disodium ceftriaxone, equivalentto 0.5, 1, and 2 g of the free, anhydrous acid. Each dosewas administered after an overnight fast, which wascontinued for an additional 4 h after drug administra-tion. All subjects received 0.5 g as their first dose, 1 gas their second dose, and 2 g as their third dose. Ineach instance, the drug was dissolved in 100 ml ofnormal saline and was administered intravenously (an-tecubital vein) by means of an infusion pump (IMEDno. 927) at a constant rate over a 30-min period. Thesuccessive doses were separated by a minimum of 1week. Each higher dose was given only after we haddetermined that the previous dose had been well tol-erated.Sample collection. Blood specimens were ob-

tained 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. Bloodwas drawn into heparinized navy-blue Vacutainertubes and centrifuged immediately. The plasma wasseparated and stored at -17°C. Urine samples werecollected before we initiated the drug infusion (con-trol) and then at the following time intervals: 0 to 2, 2to 4, 4 to 8, 8 to 12, 12 to 24, and 24 to 48 h. A 15-mlsample of urine was removed from each collection andstored at -17°C.

Analytical method. Plasma and urine sampleswere assayed for ceftriaxone by an automated, reverse-phase-ion pairing high-performance liquid chromatog-raphy method of Trautmann and Haefelfinger (K. H.Trautmann and P. Haefelfinger, J. High Resolut.Chromatogr. Chromatogr. Commun., in press) withthe following modifications: (i) acetonitrile was substi-tuted for ethanol to yield a clearer supernatant whichwas more compatible with the high-performance liquidchromatography mobile phase; (ii) a ChromegabondC-18 column (10-,Am particle, 30 cm by 4.6-mm internaldiameter; E. S. Industries, Marlton, N.J.) was chosenin place of a hand-packed, Lichrosorb RP-18 column(5-,um particle, 15 cm by 3.2-mm internal diameter) forchromatography to avoid high back pressure associ-ated with the latter; and (iii) N-i-ethyl analogs ofnordiazepam and prazepam were selected to replaceprobenecid and p-nitrobenzoic acid as internal stand-ards. The other components of the high-performanceliquid chromatography system were a model 6000 Apump system (Waters Associates, Milford, Mass.), amodel 440 dual-channel ultraviolet detector (WatersAssociates), and a model 710 A automatic sampleinjector (Waters Associates). The ultraviolet detectorwas operated at 280 nm at 0.02 and 0.1 AUFS simul-taneously, and the output responses were monitoredwith 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 acetonitrilecontaining 100 ug of nordiazepam. The mixture wasshaken on a reciprocating shaker for 10 min and cen-trifuged at 2,500 rpm for 10 min at 10°C. Approxi-mately 2 ml of the supernatant was transferred to a 4-

ml screw cap autosampler vial with a Teflon septum,and a 50-pl portion was injected onto the column andeluted with a 2-ml/min flow rate of a mobile phaseconsisting of acetonitrile, hexadecyltrimethylammon-ium bromide (10 g/liter in water), 1 M phosphatebuffer (pH 7), and deionized water (60:30:1:9). Theretention times of ceftriaxone and nordiazepam were3 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 au-tosampler vial. A 50-pl portion was injected onto thecolumn and eluted with a 2-ml/min flow rate of asolvent system consisting of acetonitrile, tetraoctylam-monium bromide (10 g/liter in water), 1 M phosphatebuffer (pH 7), and deionized water (44:35:1.2:19.8). Theretention times of ceftriaxone and prazepam were 9and 13 min, respectively.

Linearity and precision. Both plasma and urineassays were linear (i.e., a plot of peak height ratioversus concentration was adequately described by anequation of the form, y = mx + b) over a 2- to 300-[g/ml concentration range. The interday precision of themethod was, on the average, 4% or better over thesame concentration range, with an assay recovery of97%. The assay was reproducible as judged by theslope of the line, which ranged from 0.0128 to 0.0141with a mean (+standard deviation) of 0.0136 (±3%) forthe plasma assay and ranged from 0.0095 to 0.0114with a mean (±standard deviation) of 0.0102 (±6%) forthe urine assay.Pharmacokinetic analysis. Plasma concentra-

tion-time curves were biphasic (see Fig. 1), and there-fore a two-compartment open model with zero-orderinfusion and first-order elimination was selected todescribe the pharmacokinetics of ceftriaxone. We fit-ted the plasma concentration-time data of individualsubjects, using the NONLIN program (11), to thefollowing equation (5), which describes plasma concen-tration at any time (t), during the infusion and post-infusion periods:

Cp = [-A(1 - eaT)e-"t - B(1 - e#T)e,t] (1)

where Cp represents plasma concentration; A and Brepresent the coefficients of the biexponential equa-tion; a and ,B are the hybrid disposition rate constantsrepresenting the fast and slow disposition phases, re-spectively; and T varies with time, i.e., T = t whileinfusion is continuing, and when infusion ceases, Tbecomes a constant corresponding to the time infusionwas stopped.The area under the plasma concentration-time

curve from time zero to infinity (AUC) was calculatedby using the conventional trapezoidal and extrapola-tion methods.The following apparent volume-of-distribution pa-

rameters were determined:

Aa + 1B/3

DoseVd =AU .

(2)

(3)

where Ro represents the zero-order infusion rate, V,

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ANTIMICROB. AGENTS CHEMOTHER.

represents the volume of the central compartment,and Vd represents the volume of distribution in thephase.

Systemic plasma and renal clearances (Cl, and Clr,respectively) of ceftriaxone were estimated from thefollowing relationships:

Dose

Clp = AU (4)

Cr=

Ae(ti --et2)5

Clr AUC t2) (5)

where Ae(t, -e t2) represents the amount of drug

excreted unchanged in the urine from time t1 to t2, andAUC (t, -* t2) is the area under the plasma concentra-

tion-time curve during the time interval ti to t2.Statistical analysis. Pharmacokinetic parameters

were analyzed statistically by two-way analysis of var-

iance to determine the influence of dose and to adjustfor subject effects. The dose effects were then com-

pared by employing the two-tailed paired t-test, whichmade use of the pooled variance estimate (treatmentx subject interaction) obtained in the two-way anal-ysis of variance test. Because the doses were not givenin a random sequence, statistical conclusions were

drawn with the assumption that there were no orderor time effects.

RESULTS

Plasma concentration-time data. Averageplasma concentrations of ceftriaxone after 30-min, constant-rate intravenous infusion of 0.5-,1-, and 2-g doses of the drug are presented inTable 1. As expected, maximum plasma concen-trations were observed at the end of the 30-mininfusion, with mean values of 82, 151, and 257,ug/ml after 0.5-, 1-, and 2-g doses, respectively.

The increase in the mean maximum-plasma-concentration value at the 2-g dose level was 15to 20% less than that predicted from the 0.5- and1-g dose data when linear pharmacokineticswere assumed. Twelve hours after drug admin-istration, significant plasma concentrations wereobserved after all three doses, and mean concen-

trations resulting from the 0.5-, 1-, and 2-g doseswere 15, 28, and 46,Lg/ml, respectively. Twenty-four hours after drug administration, mean

plasma concentrations were 5, 9, and 15 ,tg/mlafter the 0.5-, 1-, and 2-g doses, respectively.The pharmacokinetic parameters estimated

from the plasma concentration data are listed inTable 2. The distribution half-life (t1/2a) of cef-triaxone was relatively short, ranging from 0.07to 0.52 h, with an overall harmonic mean valueof 0.17 h. The elimination half-lives (tl/2/) of 4.73to 7.75 h ranged less than twofold among the 12subjects, with harmonic mean values of 6.3 h forthe 0.5-g dose, 6.1 h for the 1-g dose, and 5.o hfor the 2-g dose. The mean volumes of the cen-tral compartment ranged from 4.5 to 4.9 liters.The mean apparent volumes of distribution were8.46 liters for the 0.5-g dose, 9.00 liters for the 1-g dose, and 10.05 liters for the 2-g dose. A smalldose-related increase in mean plasma clearancewas apparent; it increased from 0.93 liter/h atthe 0.5-g dose to 1.01 liter/h at the 1-g dose to1.19 liter/h at the 2-g dose. The two-way analysisof variance and paired t-test analyses of the dataindicated statistically significant dose-relatedchanges in all but one (volume of the centralcompartment) of the pharmacokinetic parame-ters (Table 2).

TABLE 1. Average plasma concentrations (pg/ml) of ceftriaxone after single-dose intravenousadministration 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 Doseadministration

Mean SDa Range Mean SD Range Mean SD Range0.167 34.6 6.8 27-47 69.2 14.6 49-104 124.2 16.8 101-1610.333 60.6 8.2 47-74 115.3 14.6 96-140 201.7 21.8 165-2400.5 82.0 10.4 69-102 150.7 14.0 129-175 256.9 16.8 223-2760.583 74.2 9.6 63-93 138.5 11.6 120-159 236.5 18.7 209-2570.667 69.4 8.7 58-84 128.5 11.9 111-152 219.7 16.5 193-2430.883 63.1 7.5 55-79 118.1 10.8 104-138 204.7 15.1 175-2251 58.9 7.3 51-74 111.0 9.8 98-129 192.0 14.1 166-2091.5 52.0 6.7 45-66 98.3 8.9 84-114 169.7 14.0 148-1912 47.9 6.6 41-60 88.2 8.5 76-105 154.3 12.6 135-1734 36.8 6.0 30-50 67.3 7.3 55-80 117.3 11.9 99-1356 28.6 4.8 22-39 52.5 5.1 44-62 89.3 10.2 75-1048 23.3 3.5 18-30 42.7 4.7 34-52 73.7 8.8 59-8710 19.2 2.9 14-24 35.2 4.4 27-44 59.0 8.3 45-7212 15.3 3.1 10-21 28.1 3.9 19-34 46.0 6.9 32-5816 10.3 2.4 7-14 18.4 3.2 12-23 30.8 5.4 19-4024 5.3 1.4 3-8 9.3 2.4 5-14 15.1 3.9 7-22

'SD, Standard deviation.

636 PATEL ET AL.


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-testParameter value' at indicated dose (g) ANOVA' Paired t-test

Parameter' of dose0.5 1.0 2.0 effect I vs0.5 2 vs0.5 2 vs 1

A (pg/ml) 37.1 ± 5.5 68.1 ± 14.6 101.3 ± 22.1(26.2-46.9) (53.9-97.8) (74.0-77.8)

a (per h) 3.3 ± 1.2 4.1 ± 2.4 5.2 ± 2.5 P 0.01 NSd P 0.01 NS(1.6-5.9) (1.3-10.0) (2.2-9.7)

B (ug/ml) 1306 ± 174 1894 ± 219 3213 ± 387(779-1381) (1446-2317) (2489-3872)

f (per h) 0.110 ± 0.013 0.113 ± 0.014 0.119 ± 0.015 P < 0.01 NS P s 0.01 P c 0.01(0.089-0.124) (0.096-0.139) (0.101-0.147)

ti/2a (h) 0.2le 0.17e 0.13e(0.12-0.39) (0.07-0.52) (0.07-0.31)

t112~(h) 6.30e 6.13e 5.82e(5.45-7.75) (5.00-7.24) (4.73-6.84)

AUC (pg.h/mi) 551 ± 91 1006 ± 118 1703 ± 203(462-737) (764-1238) (1308-2055)

V, (liter) 4.54 ± 0.96 4.56 ± 1.14 4.86 ± 1.14 NS NS NS NS(3.27-5.97) (2.29-6.47) (2.86-6.60)

Vd (liter) 8.46 ± 1.11 9.00 ± 1.07 10.05 ± 0.97 P < 0.01 P < 0.05 P _ 0.01 P < 0.01(6.40-9.73) (7.21-10.58) (8.87-11.85)

Clp (litersa/h) 0.929 ± 0.150 1.007 ± 0.13 1.190 ± 0.15 P < 0.01 P S 0.01 P s 0.01 P s 0.01(0.678-1.190) (0.808-1.309) (0.973-1.529)

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 concentra-tions of intact ceftriaxone after 0.5-, 1-, and 2-gdoses are reported in Table 3. The mean urineconcentrations in the 0- to 2-h urine sampleswere 526 iLg/ml after the 0.5-g dose, 995 ,ug/mlafter the 1-g dose, and 2,692 ,ug/ml after the 2-gdose. In the 24- to 48-h urine samples, the re-spective mean concentrations were 15, 32, and40 iLg/ml. The cumulative renal excretion pro-files (Table 4) of ceftriaxone indicated that therenal excretion profiles were similar after the0.5- and 1-g intravenous doses. However, a sig-nificantly higher fraction of the dose was ex-creted unchanged in the 0- to 2-h interval afterthe 2-g dose than that observed after the 0.5- or1-g dose (Table 4). In 48 h, 41, 39, and 43% ofthe dose was excreted as intact ceftriaxone inthe urine after 0.5-, 1-, and 2-g doses, respec-tively.The renal clearances of the total drug were

calculated for each urine collection interval (Ta-ble 5). The mean renal clearance during eachcollection interval was plotted as a function oftime (midpoint of the collection interval) in Fig.1. After each intravenous dose, the renal clear-ance declined appreciably during the first 8 hand then remained relatively constant over thesubsequent time period (8 to 24 h). The meanrenal clearances in the 0- to 2-h interval were439, 542, and 919 ml/h for the 0.5-, 1-, and 2-gdoses, respectively. The respective clearances inthe 12- to 24-h interval were 305, 351, and 340ml/h. The decline in renal clearance from the 0-to 2-h interval to the 12- to 24-h interval waslargest (63%) for the 2-g dose and moderate (31to 35%) for the two lower doses. The renal clear-ances at each collection interval for the 0.5- and1-g doses were reasonably similar. However,they were consistently and significantly lowerthan those observed for the 2-g dose during the

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0 to 2, 2 to 4, and 4 to 8 h intervals (Table 5).

DISCUSSIONIntravenous pharmacokinetics of ceftriaxone

were investigated in humans after infusion ofTABLE 3. Average urinary concentrations of

ceftriaxone after single-dose intravenousadministration of 0.5-, 1-, and 2-g doses of

ceftriaxone to 12 subjectsUrine

collection Urinary concn (jig/ml) at indicated dose (g)'interval

(h) 0.5 1.0 2.0

0-2 526 ± 302 995 ± 734 2692 ± 1403(148-1088) (223-2491) (988-4568)

2-4 366 ± 203 855 ± 615 1976 ± 1047(80-753) (180-2234) (523-3913)

4-8 142 ± 63 293 ± 163 757 ± 437(34-224) (52-554) (117-1329)

8-12 87 ± 45 147 ± 66 274±119(41-152) (59-273) (101-505)

12-24 70 ± 25 132 ± 47 198±93(41-117) (66-232) (74-306)

24-48 15 ± 6 32 ± 16 40 ± 24(5-24) (5-54) (11-96)

a Mean ± standard deviation; ranges of values areindicated in parentheses.

0.5-, 1-, and 2-g doses at a constant rate over a

30-min period. The plasma concentration-timecurves of ceftriaxone in the postinfusion phasewere biphasic, with a relatively short distribu-tion phase (overall mean distribution half-life,0.17 h) followed by a slow elimination phase(overall mean elimination half-life, 6.1 h). Biex-ponential plasma concentration-time curves ofceftriaxone, with mean elimination half-livesranging from 6.5 to 8.6 h, were previously re-ported (16, 18, 21). In the present study, a small

but statistically significant decrease in the elim-

ination rate constant was observed; it increasedfrom a mean value of 0.110/h at the 0.5-g doseto 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 aprevious study (21), such a statistically signifi-cant dose-dependent decrease in the eliminationrate 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 ob-served in the plasma clearance and volume ofdistribution; these findings are consistent withthose 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 plasmaclearance (from 10.2 to 13.0 ml/min) and a 28%increase in the volume of distribution (from 6.7to 8.6 liters). In the present study, the observedincrease in plasma clearance (28% from 0.929liter/h to 1.190 liter/h) was comparable, whereas

TABLE 4. Cumulative percentage of dose of ceftriaxone excreted unchanged in the urine after single-doseintravenous 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-testUrine Cumulative % of indicated dose (g) in urinea ANOVAb of dose Paired t-test

collectioninterval (h) 0.5 1.0 2.0 effect 1 vs 0.5 2 vs 0.5 2 vs 1

0-2 10±2 11±2 15c±6 PC0.05 NSd P'O.O1 PCO.O5(7-13) (9-15) (1-23)

2-4 17±4 18± 1 23c±8 P'0.01 NS P'0.01 P'0.01(13-26) (15-20) (7-33)

4-8 25e ± 4 25 ± 3 32c ± 9 P 0.01 NS P 0.01 P 0.01(19-34) (20-29) (15-43)

8-12 31e ± 6 30 ± 3 36c± 9 NS NS NS NS(22-40) (24-34) (20-46)

12-24 38e ± 7 37 ± 5 42c± 10 NS NS NS NS(24-48) (27-44) (25-53)

24-48 41e ± 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.

638 PATEL ET AL.


TABLE 5. Renal clearance (ml/h) of ceftriaxone after single-dose intravenous administration of 0.5-, 1-, and2-g doses of ceftriaxone to 12 subjects and statistical evaluation by two-way analysis of variance and two-

tailed paired t-testUrine Renal clearancea at indicated dose (g) ANOVAb of Paired t-test

collectioninterval (h) 0.5 1.0 2.0 dose effect 1 vs 0.5 2 vs 0.5 2 vs 1

0-2 439 ±80 542 ± 100 919c ±235 P'0.01 NSd P'O.O1 P'O.O1(358-656) (378-791) (571-1378)

2-4 413 ± 113 454 ± 68 613 ± 199 P 0.01 NS P 0.01 P 0.01(291-694) (322-556) (404-1085)

4-8 367e ± 85 342 ± 94 461 ± 120 P 0.01 NS P 0.01 P 0.01(233-486) (139-437) (235-688)

8-12 363 ± 84 331 ± 61 397 ± 128 NS NS NS NS(192-472) (242-430) (204-578)

12-24 305 ± 77 351e ± 67 340 ± 93 NS NS NS NS(146-392) (272-508) (226-530)

0-24 373 ± 60 399 ± 50 533 ± 128 PC 0.05 NS Pc 0.01 Ps0.01(292-494) (308-503) (323-800)

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 distri-bution (18% from 8.78 to 10.33 liter) was smallerthan that determined by Stoeckel et al. (21).The renal clearance showed both dose- and

time-related changes. It increased as the dosewas increased during the first 8 h (Fig. 1). Aftereach intravenous dose, the renal clearance de-clined at each time interval measured during thefirst 8 h and then remained relatively constantover the subsequent time period (Fig. 1). Thisdecline in renal clearance from the 0- to 2-hinterval to the 12- to 24-h interval was largest(63%) after administration of the 2-g dose andmoderate (30 to 35%) after administration of the0.5- and 1-g doses. These observations are con-sistent with the data of Stoeckel et al. (21). Inboth of these studies, increased renal clearanceat the highest dose did not increase the fractionof the dose excreted unchanged in the urine atthat dose because of a similar increase in thenonrenal clearance of ceftriaxone. In 48 h, 41, 39,and 43% of the dose was excreted unchanged inthe urine after the 0.5-, 1-, and 2-g doses, respec-tively. These values are similar to those (33 to44%) reported previously from our laboratories(16).The renal excretion data indicate that a sub-

stantial fraction of ceftriaxone may be elimi-nated from the body by nonrenal pathways.After intravenous administration of 150 mg of14C-labeled ceftriaxone to two volunteers, 44% ofthe dose was recovered as microbiologically in-

active material in the feces, indicating that bili-ary excretion plays a significant role in the elim-ination of ceftriaxone (H. Nottebrock, K.Stoeckel, H. W. Ziegler, and R. Heintz, unpub-lished data). The biliary excretion data for dogsin which 18 to 33% of the dose was recovered inthe bile in 72 h support the role of biliary excre-tion in the overall elimination of ceftriaxonefrom the body (R. Heintz, H. Nottebrock, andE. Kovacs, unpublished data).Because of concentration-dependent plasma

protein binding of ceftriaxone, the area underthe total plasma concentration-time curve, asreported herein, is expected to show a less-than-proportional increase with an increase in thedose. However, area under the free (therapeuti-cally active, unbound drug) plasma concentra-tion-time curve is expected to be proportional tothe dose. In a previous study (21), this wassubstantiated, because the free plasma concen-tration-time curve increased proportionatelyfrom 10.1 to 106 ,g.h/ml over a 0.15- to 1.5-gdose range. Additionally, multiple dose studies(1 and 2 g every 12 h) (16) indicate that steady-state total plasma concentrations of ceftriaxonepredicted from the single-dose data derived byassuming linear pharmacokinetics were overes-timated by only 10 to 20%. Therefore, the impactof the nonlinear pharmacokinetics of ceftriaxoneon its clinical usage is anticipated to be insignif-icant.

In conclusion, intravenous single-dose phar-

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000-

00

CZ)

-4

0o -

<0

c-Ju

cz

LJm

z

0O

4.00 8.00 12.00 16.00 20.00TIME-MIDPOINT .HOURS

FIG. 1. Time- and dose-dependent changes in the average renal clearance of ceftriaxone after constant-rate, 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 investigatedover a 0.5- to 2-g dose range. Ceftriaxone ex-hibited a relatively long elimination half-life (6.2h) and a relatively small volume of distribution(9.1 liters) and plasma clearance (17.4 ml/min).Approximately 40% of the dose was excretedunchanged in the urine within 48 h after drugadministration. The small dose-related changesin volume and clearance parameters were ofnegligible clinical significance. The 6-h elimina-tion half-life of ceftriaxone suggests that a twice-a-day or possibly once-a-day dosage regimenmay be adequate for clinical use.

ACKNOWLEDGMENTSThe authors sincerely thank C. A. De George, R. Weinfeld,

and S. Givens for contributions to this study.

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VOL. 20, 1981

pharmacokinetics of ceftriaxone in humans

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