Vol. 36, No. 3
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Mar. 1992, p. 552-557
0066-4804/92/030552-06$02.00/0
Copyright © 1992, American Society for Microbiology
Pharmacokinetics of Cefepime after Single and Multiple Intravenous Administrations in Healthy Subjects RASHMI H. BARBHAIYA,l* S. THOMAS FORGUE,1 CAROL R. GLEASON,' CATHERINE A. KNUPP,1 KENNETH A. PITTMAN,' DONALD J. WEIDLER,2 HASSAN MOVAHHED,3 JAMES TENNEY,3 AND R. RUSSELL MARTIN3 Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4755, Syracuse, New York 13221-47551; Department of Medicine, Center for Advanced Therapeutics and Clinical Research, University of Miami School of Medicine, Miami, Florida 331013; and Department of Clinical Research, Infectious Diseases, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 064923 Received 16 August 1991/Accepted 23 December 1991
The pharmacokinetics of cefepime in 31 young, healthy volunteers were assessed after the administration of single and multiple 250-, 500-, 1,000-, or 2,000-mg intravenous doses. Each subject received a single dose of cefepime via a 30-min intravenous infusion on day 1 of the study. Starting from day 2, subjects received multiple doses of cefepime every 8 h for 9 days, and on the morning of day 11, they received the last dose. Serial blood and urine samples were collected after administration of the first dose and on days 1, 6, and 11. Cefepime concentrations in plasma and urine were assayed by using reverse-phase high-performance liquid chromatography with UV detection. Data were evaluated by noncompartmental methods to determine pharmacokinetic parameters. The mean half-life of cefepime was approximately 2 h and did not vary with the dose or duration of dosing. The regression analyses of peak levels (Cm.) in plasma at the end of the 30-min intravenous infusion and the area under the plasma concentration-versus-time curve (AUC>o.) showed a dose-proportional response. The steady-state volume of distribution (V,,) was approximately 18 liters and was independent of the administered dose. The multiple-dose pharmacokinetic data are suggestive of a lack of accumulation or change in clearance of cefepime on repeated dosing. Cefepime was excreted primarily unchanged in urine. The recovery of intact cefepime in urine was invariant with respect to the dose and accounted for over 80%o of the dose. The values for renal clearance ranged from 99 to 132 ml/min and were suggestive of glomerular filtration as the primary excretion mechanism. It is concluded that cefepime exhibits linear phannacokinetics in healthy subjects.
action of common 3-lactamases, and its low affinity for these enzymes are characteristics that make this a promising antibiotic. Cefepime is cleared primarily by urinary excretion in unchanged form in animals (2, 10, 11) and humans (1, 3-5). In the single-dose phase I evaluation, limited blood samples were obtained for the preliminary assessment of pharmacokinetics (1). The results of the single-dose phase I study indicated that cefepime is safe, is well tolerated, and obeys linear pharmacokinetics within the 62.5- to 2,000-mg dose range (1). The present phase I study was designed to investigate the safety, tolerance, and pharmacokinetics of cefepime after single and multiple doses in healthy male volunteers.
Cefepime, 7-[a-(2-aminothiozol-4-yl)-a-(7)-methoxyimuinoacetamido]-3-(1-methylpyrrolidinio)-methyl-3-cephem-4-carboxylate, is a new parenteral fourth-generation cephalosporin antibiotic with a broader spectrum of antimicrobial activity than other new cephalosporins and nontraditional P-lactam antibiotics (12, 17). The in vitro activities of cefepime have been reproduced in numerous in vivo infection models (19, 29). Compared with cefotaxime, cefepime has been shown to be five- to ninefold more active against Pseudomonas aeruginosa (17). In addition, cefepime has been found to be approximately fourfold more active than ceftazidime against gram-positive organisms (12, 17). Cefepime was also more active than ceftazidime, moxalactam, cefoperazone, cefpirome, and cefotaxime when tested against 326 members of the family Enterobacteraceae (12). Cefepime may be less affected by the nonhydrolytic barrier mechanism of bacterial resistance because it has a low affinity for major chromosomally mediated 13-lactamases (25). Cefepime may prove to be an effective therapy for bacterial infections that are resistant to other antibiotics. For example, in a recent study, cefepime resistance among ceftazidime- and cefotaximeresistant P. aeruginosa mutants was rare (13). The penetration of cefepime into cerebrospinal fluid is unusually good in experimental meningitis models (19, 29). As a result, cefepime has shown excellent efficacy in treating experimental bacteremia and meningitis caused by Escherichia coli, group B streptococci (19), and pneumococci (29). The excellent spectrum of cefepime, its resistance to the *
MATERIALS AND METHODS Study design. This was a parallel group study, designed to assess drug safety, tolerance, and pharmacokinetics after the administration of single and multiple intravenous (i.v.) doses of 250, 500, 1,000, and 2,000 mg to normal volunteers. Dose administration proceeded sequentially, with increasing doses given only after the safety and tolerance of the previous dose was determined. At each dose level, different groups of subjects participated in the study. Subjects. A total of 31 healthy male subjects, ages 20 to 44 years, participated in this single- and multiple-dose phase I study after having granted written informed consent. The weights of all individuals were within 15% of the range of desirable weights for their height (1983 Metropolitan Height and Weight Tables). The mean (standard deviation) weight
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(in kilograms) for each dose group was as follows: for the 250-mg group, 71.7 (8.6); for the 500-mg group, 70.6 (7.5), for the 1,000-mg group, 73.8 (10.0), and for the 2,000-mg group, 79.0 (12.7). The subject eligibility criteria included the absence of compromising drug allergies or intolerance, the absence of a drug or alcohol abuse history, and a normal test result for controlled substance screening conducted the evening preceding the dosing. The use of any medications within 1 week of the study or the use of alcohol within 24 h of induction into the study was not permitted. The use of any drug, including alcohol and caffeine, during the study was not allowed. Subjects were instructed to refrain from smoking during blood and urine sampling periods. Confinement to the test facility began the day before the subject received his first dose and continued until release from the study. To ensure adequate diuresis for urine sampling, subjects drank 200 ml of water or juice 1 h prior to the infusion and approximately 1, 2, and 3 h after the start of dosing. Drug formulation and administration. Cefepime (BMY28142) was supplied by the Pharmaceutical Product Development Department of Bristol-Myers Squibb Pharmaceutical Research Institute (Syracuse, N.Y.) as vials containing a lyophilized mixture with sodium chloride. The reconstitution of 500- or 1,000-mg vials with 1.9 or 3.8 ml of sterile water for injection, respectively, provided a 250-mg/ml solution of cefepime zwitterion. The reconstituted solution was diluted with sufficient sterile water to prepare cefepime infusion solutions of 5, 10, 20, and 40 mg/ml for doses of 250, 500, 1,000, and 2,000 mg, respectively. Subjects received i.v. doses of cefepime at a dose level of either 250 (n = 8), 500 (n = 9), 1,000 (n = 7), or 2,000 (n = 7) mg. Each subject received a total of 29 injections at a given dose level by a constant-rate i.v. infusion over 30 min. On day 1 of the study, only one dose was given and blood and urine samples were collected. On days 2 through 10 of the study, cefepime was administered every 8 h at the same dose level; a single dose was administered on day 11. Each cefepime dose was administered as a constant-rate infusion by means of a syringe infusion pump, calibrated to deliver 50 ml of infusion solution per 30-min interval. Drug administration was via a forearm vein contralateral to that used for blood sampling. Collection of blood and urine samples. Heparinized blood samples were obtained from every subject at the following time points after the first and last doses of the study: at the predose; at 10, 20, 30 (end of infusion), 33, 39, and 45 min; and at 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, and 16 h after the beginning of infusion. Serial blood and urine samples were also collected after the morning infusion on day 6. On day 6, the same serial blood sampling schedule was applied, ending with the 8-h sample, at which time the next dose was given. On treatment days 4, 6, and 8, blood samples were obtained at the end of the infusion of the morning dose and before the beginning of the afternoon dose to obtain steady-state peak and trough levels (Cmin) of cefepime. Blood samples were held on ice, and plasma was prepared by centrifugation within 1 h of collection. Plasma samples were stored at or below -20°C. The total urine output of each subject was collected prior to dosing (predose) and at 0 to 1, 1 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 16, and 16 to 24 h after the start of infusion of the first and last doses. On treatment day 6, sampling ended 8 h after the infusion, at which time the next infusion was given. Analysis of plasma and urine samples. Plasma and urine samples were analyzed for cefepime by a validated highperformance liquid chromatographic assay with UV detec-
PHARMACOKINETICS OF CEFEPIME
553
tion (2). The lower limits for quantitation of cefepime in plasma and urine were 0.5 and 2.0 ,ug/ml, respectively. The cefepime standard curves in plasma and urine were linear within the 0.5- to 50.0- and 2.0- to 1,000-,ug/ml ranges, respectively. Quality control samples containing known concentrations of cefepime were prepared prior to the initiation of drug administration at each dose level. These quality control samples were stored with the study samples. The between-day coefficients of variation for quality control sample concentrations of cefepime in plasma of 4.0 (n = 7) and 160 (n = 7) ,ug/ml were 4 and 3%, respectively, where n is the number of analytical sequences. The between-day coefficients of variation for quality control sample concentrations of cefepime in urine of 50 (n = 6) and 2,000 (n = 4) ,ug/ml were 2 and 2%, respectively. Excellent data for accuracy (deviation from nominal, less than 10%) and a coefficient of variation consistently less than 13% for the quality control samples suggest that the assays for cefepime in plasma and urine samples were accurate and precise, and cefepime was stable in the study samples during storage. Pharmacokinetic analysis. Plasma cefepime concentration, C, versus time, t, data were evaluated by noncompartmental methods (14, 27). The highest observed C, which occurred at the end of infusion, was defined as Cmax. The trough level (Cmin) was taken as the 8-h concentration in plasma after the commencement of an infusion. The elimination half-life (tj/2) was calculated as (ln 2)/b, where b was the absolute value of the slope of the least-squares regression line for n terminal datum points. These datum points (n > 3) were selected to minimize the mean-square error term for the regression. The area under the plasma drug concentration-time curve (AUC) and the area under the first moment of plasma concentrationtime curve (AUMC) were estimated by trapezoidal and log-trapezoidal methods. The values for the single-dose AUC and AUMC were extrapolated to infinity AUC O and AUMC O by using standard methods (14). For a single-dose administration, the mean residence time (MRT) in the body was estimated as MRT = AUMCOJAUCQO. For multiple dosings, MRT at a steady state (MRTSS) was estimated (6, 24) as MRTSS = [AUMCo, + T(C'/b)]/AUCo,, where AUCO, and AUMCO, correspond to AUC and AUMC for one dosing interval, T, and C' is the predicted concentration at time, T. The MRT equivalent for i.v. bolus administration, MRTIv, was calculated as MRTi.v = MRT - (T/2), where T is the infusion time, 0.50 h. Total body clearance (CLU) was calculated as CMr = dose/AUCO, and CLr = dose/AUCO_r after the first and the last doses, respectively. The steadystate volume of distribution was obtained as V, = MRTivV CLr (7). The accumulation ratios (R) after multiple dosings with cefepime were calculated by two different methods (9). The equations employed in these calculations are R, = 1/(1 e'3r) and R2 = AUC(OT)Ss/AUC O)1, where AUC(O_1), and AUC(O_r)ss correspond to the first dose (day 1) and the steady-state dose (day 6 or 11), respectively. Urinary recovery, X", was calculated as the product of C and the total volume of voided urine for a given interval. The percentage of the dose recovered in urine (% X") was calculated as X"/dose x 100. Renal clearance (CLR) values after the first and last doses were calculated as X,/AUCO, and X,(O_/AUC(O_), respectively. The Xi(O) value represents the urinary recovery of cefepime within one dosing interval. Statistical analysis. Repeated-measures analysis of variance (ANOVA) procedures were utilized to evaluate the noncompartmental parameters Cmax, AUC, t1/2, MRTi.,
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BARBHAIYA ET AL.
300
E 0)
30
0
0
0 co
E _o 3.0CL
0.30
4
8
12
0
4
8
12
Time (hr) * 250 MG --500 MG
-*- 1000 MG
El
2000 MG
FIG. 1. Mean concentration-time profiles of cefepime in plasma after 250-, 500-, 1,000-, and 2,000-mg i.v. doses.
with respect to the treatment day (day 1 to assess differ500, 1,000, and 2,000 mg). Dose-normalized C,ax and AUC values were used in this evaluation. The Tukey multiple-comparison procedure was utilized to compare mean parameter values with respect to dose differences. Linear regression procedures were utilized to determine whether Cmax and AUC values were proportional to the administered dose (250 to 2,000 mg). AUCO, and AUC., were the test parameters utilized for analysis on days 1 and 11, respectively. The slope and intercept estimates determined by weighted least-squares regression were tested for significance. Weights of the reciprocal of the variance at each dose level were applied in regression analyses to correct the observed heterogeneity of variance. A test of goodness-of-fit was carried out by adding quadratic and cubic terms to the linear model and testing for their significance. All hypotheses were tested at the 5% significance level.
CLr, CLR, and
V.,
or 11). One-way ANOVAs were performed ences with respect to the dose level (250,
RESULTS
Single-dose pharmacukinetics. The inspection of mean plasma concentration-time profiles for single i.v. infusions of 250, 500, 1,000, and 2,000 mg of cefepime to 31 healthy male
subjects indicated that cefepime concentrations decline at rates that are independent of the dose level (Fig. 1). The first dose in each treatment regimen was followed by a 24-h collection period to characterize the single-dose pharmacokinetics of cefepime. Key pharmacokinetic parameters are compiled in Table 1. Observed Cma values after a 30-min i.v. infusion were 17.9, 31.9, 65.1, and 126 p.g/ml for single doses of 250, 500, 1,000, and 2,000 mg, respectively. The levels of cefepime in plasma declined with an apparent elimination t112 of about 2 h at each dose level. The mean AUCO, values were 33.1, 56.6, 135, and 245 ,g. h/ml after 250-, 500-, 1,000-, and 2,000-mg doses, respectively. The mean values of CL, and CLR ranged from 126 to 152 and 100 to 138 ml/min, respectively. The Vs, was consistent among various doses and ranged from 16.6 to 19.3 liters. The urinary recovery of intact cefepime after the initial 250-, 500-, 1,000-, and 2,000-mg doses accounted for about 80% of the dose and was consistent within and among treatment groups. No significant differences as a function of administered doses were observed in ANOVAs of MRTiV,, t112, CLI, CLR, V., and the dose-normalized Cm,,. The ANOVA comparisons were complemented by analyses of the regression of Cm. (Fig. 2) and AUC0O, (Fig. 3) on dose. In the regression analyses of Cm. and AUC, intercept estimates
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555
TABLE 1. Pharmacokinetic parameters of cefepime after i.v. administrationa Mean (± SD) of the following parameter: CLq AUC t1/ (h) (pg. h/mlI' (ml/min)
CLR (mi/min)
V
/oX
128 (16)
107 (14)
16.6 (2.5)
83.6 (6.1)
124 (14)
101 (17)
17.0 (2.2)
88.8 (15.9)
152 (28)
138 (33)
18.3 (1.9)
91.0 (15.2)
144 (16)
117 (23)
18.2 (1.2)
85.7 (16.3)
126 (18)
100 (18)
18.3 (2.0)
79.6 (8.3)
125 (21)
99 (24)
18.2 (3.0)
86.8 (14.9)
245 (35) 138 (22) 110 (31) 238 (40) 2.16 (0.30) 2.32 (0.39) 239 (39) 143 (25) 132 (26) a Doses were administered every 8 h for 9 days. At each dose level, a single dose was administered on days 1 and 11. b AUCO, on day 1; AUCO, on days 6 and 11.
19.3 (3.4)
78.4 (12.7)
18.4 (3.8)
96.2 (7.8)
Day administered
Dose (mg)
250
500
1,000
2,000
Cm.
MRT.V (h)
1 6 11
(pg/ml) 17.9 (2.6) 18.4 (13.5) 17.5 (2.3)
Cmin
0.6 (0.2) 0.7 (0.2) 0.8 (0.2)
2.18 (0.21)
2.00 (0.38)
2.30 (0.34)
2.09 (0.32)
1 6 11
31.9 (6.0) 32.2 (4.5) 31.2 (2.6)
1.0 (0.3) 1.0 (0.3) 1.0 (0.3)
2.05 (0.31)
2.00 (0.64)
2.09 (0.29)
2.14 (0.28)
1 6 11
65.1 (7.0) 70.5 (8.5) 66.9 (12.4)
2.7 (0.8) 2.9 (1.0) 2.9 (1.0)
2.45 (0.31)
2.34 (0.24)
2.45 (0.33)
2.23 (0.35)
126 (21.7) 129 (27.1) 137 (30.7)
1 6 11
(6gml)
4.2 (1.3) 4.4 (1.6) 3.8 (1.3)
2.34 (0.37)
33.1 (4.3) 35.4 (6.0) 33.9 (4.3) 56.6 (11.4) 60.4 (8.6) 58.06 (6.6)
135 (23) 142 (21) 137 (24)
2.20 (0.31)
from both analyses were not significantly different from 0 (P > 0.20) and no deviation from linearity was observed. Multiple-dose pharmacokinetics. Cefepime concentrations were determined as a function of time after the commencement of infusion on treatment day 6 and on the final treatment day (day 11). These data are virtually superimposable on corresponding values for the very first dose (Fig. 1). Mean pharmacokinetic parameter values for repeated ad-
ministrations of 250, 500, 1,000, or 2,000 mg every 8 h are similarly indicative of the constancy of cefepime disposition over the duration of the study (Table 1). Parameter estimates for a given treatment group were compared by an ANOVA between study days. No significant differences as a function of the treatment day for MRTiV,, t42, CLR, CLr, and Vss within dose levels were observed. The parameter values for the final infusion (day 400-
300-
0
3
a
0
0
0
0
0 0
-
.
8 %-
0
500
DOSE (MG) FIG. 2. Regression of Cm. on cefepime dose. Weighted linear regression equation: Cma, = 2.17 + 0.06 x dose; r = 0.97.
DOSE (MG)
FIG. 3. Regression of AUCoO linear regression equation AUCO,.
cefepime dose. Weighted 1.94 + 0.12 x dose; r = 0.96.
on =
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11) were also compared with respect to dose levels in a manner analogous to that described above for the initial dose on day 1. The results for day 11 closely paralleled those noted above for day 1. No significant differences with respect to the dose in the analyses of tl2, MRT, CLr, CLR, VS., the dose-normalized Cm., and AUCO, were observed. Evaluations of the regression of Cm. and AUCO, on dose produced results similar to those on day 1. The urinary recovery of intact cefepime was reasonably consistent among the various dose levels during the course of treatment every 8 h. The urinary recovery of cefepime corresponding to doses of 250, 500, 1,000, and 2,000 mg every 8 h was evaluated by ANOVA methods, and the results indicated that there were no differences in the %X, among dose groups on day 11. No significant change in %X. was observed across study days; however, there was a significant trend toward elevated cefepime recoveries over the course of the 2,000-mg dosing every 8 h (P = 0.04). The degree of accumulation expected for cefepime was estimated from a theoretical factor, R1, which predicts that steady-state concentrations about 7% above single-dose levels will occur for a drug with a t1/2 of 2 h that is administered every 8 h. This calculation is based on an assumption of linear pharmacokinetic behavior. Estimates of an accumulation factor, R2, based on inspection of the AUC data are consistent with the R1 prediction. The group mean Cmin and Cmaxvalues (Table 1) as a function of treatment day were also suggestive of a lack of accumulation or change in clearance after multiple dosings. DISCUSSION In this report of the pharmacokinetics of cefepime after single and multiple i.v. doses, it was found that this novel fourth-generation cephalosporin is well tolerated at the clinically relevant dosage regimen of 250 to 2,000 mg every 8 h for 9 days. Mean trough levels of cefepime 8 h after the administration of 2,000-mg doses were 3.8 to 4.4 ,ug/ml. Most organisms of the Enterobactenaceae family have a minimal inhibitory concentration for 90% of the strains tested (MIC90) of about 0.25 ,ug/ml, and P. aeruginosa has a MIC90 of about 7.0 p.g/ml (17, 18). This study demonstrates that a dose of 2,000 mg every 8 h results in concentrations in plasma that are significantly higher than MIC90 for most gram-negative organisms for the entire dose interval. This observation is particularly relevant in light of the low protein binding (
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Mar. 1992, p. 552-557
0066-4804/92/030552-06$02.00/0
Copyright © 1992, American Society for Microbiology
Pharmacokinetics of Cefepime after Single and Multiple Intravenous Administrations in Healthy Subjects RASHMI H. BARBHAIYA,l* S. THOMAS FORGUE,1 CAROL R. GLEASON,' CATHERINE A. KNUPP,1 KENNETH A. PITTMAN,' DONALD J. WEIDLER,2 HASSAN MOVAHHED,3 JAMES TENNEY,3 AND R. RUSSELL MARTIN3 Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4755, Syracuse, New York 13221-47551; Department of Medicine, Center for Advanced Therapeutics and Clinical Research, University of Miami School of Medicine, Miami, Florida 331013; and Department of Clinical Research, Infectious Diseases, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 064923 Received 16 August 1991/Accepted 23 December 1991
The pharmacokinetics of cefepime in 31 young, healthy volunteers were assessed after the administration of single and multiple 250-, 500-, 1,000-, or 2,000-mg intravenous doses. Each subject received a single dose of cefepime via a 30-min intravenous infusion on day 1 of the study. Starting from day 2, subjects received multiple doses of cefepime every 8 h for 9 days, and on the morning of day 11, they received the last dose. Serial blood and urine samples were collected after administration of the first dose and on days 1, 6, and 11. Cefepime concentrations in plasma and urine were assayed by using reverse-phase high-performance liquid chromatography with UV detection. Data were evaluated by noncompartmental methods to determine pharmacokinetic parameters. The mean half-life of cefepime was approximately 2 h and did not vary with the dose or duration of dosing. The regression analyses of peak levels (Cm.) in plasma at the end of the 30-min intravenous infusion and the area under the plasma concentration-versus-time curve (AUC>o.) showed a dose-proportional response. The steady-state volume of distribution (V,,) was approximately 18 liters and was independent of the administered dose. The multiple-dose pharmacokinetic data are suggestive of a lack of accumulation or change in clearance of cefepime on repeated dosing. Cefepime was excreted primarily unchanged in urine. The recovery of intact cefepime in urine was invariant with respect to the dose and accounted for over 80%o of the dose. The values for renal clearance ranged from 99 to 132 ml/min and were suggestive of glomerular filtration as the primary excretion mechanism. It is concluded that cefepime exhibits linear phannacokinetics in healthy subjects.
action of common 3-lactamases, and its low affinity for these enzymes are characteristics that make this a promising antibiotic. Cefepime is cleared primarily by urinary excretion in unchanged form in animals (2, 10, 11) and humans (1, 3-5). In the single-dose phase I evaluation, limited blood samples were obtained for the preliminary assessment of pharmacokinetics (1). The results of the single-dose phase I study indicated that cefepime is safe, is well tolerated, and obeys linear pharmacokinetics within the 62.5- to 2,000-mg dose range (1). The present phase I study was designed to investigate the safety, tolerance, and pharmacokinetics of cefepime after single and multiple doses in healthy male volunteers.
Cefepime, 7-[a-(2-aminothiozol-4-yl)-a-(7)-methoxyimuinoacetamido]-3-(1-methylpyrrolidinio)-methyl-3-cephem-4-carboxylate, is a new parenteral fourth-generation cephalosporin antibiotic with a broader spectrum of antimicrobial activity than other new cephalosporins and nontraditional P-lactam antibiotics (12, 17). The in vitro activities of cefepime have been reproduced in numerous in vivo infection models (19, 29). Compared with cefotaxime, cefepime has been shown to be five- to ninefold more active against Pseudomonas aeruginosa (17). In addition, cefepime has been found to be approximately fourfold more active than ceftazidime against gram-positive organisms (12, 17). Cefepime was also more active than ceftazidime, moxalactam, cefoperazone, cefpirome, and cefotaxime when tested against 326 members of the family Enterobacteraceae (12). Cefepime may be less affected by the nonhydrolytic barrier mechanism of bacterial resistance because it has a low affinity for major chromosomally mediated 13-lactamases (25). Cefepime may prove to be an effective therapy for bacterial infections that are resistant to other antibiotics. For example, in a recent study, cefepime resistance among ceftazidime- and cefotaximeresistant P. aeruginosa mutants was rare (13). The penetration of cefepime into cerebrospinal fluid is unusually good in experimental meningitis models (19, 29). As a result, cefepime has shown excellent efficacy in treating experimental bacteremia and meningitis caused by Escherichia coli, group B streptococci (19), and pneumococci (29). The excellent spectrum of cefepime, its resistance to the *
MATERIALS AND METHODS Study design. This was a parallel group study, designed to assess drug safety, tolerance, and pharmacokinetics after the administration of single and multiple intravenous (i.v.) doses of 250, 500, 1,000, and 2,000 mg to normal volunteers. Dose administration proceeded sequentially, with increasing doses given only after the safety and tolerance of the previous dose was determined. At each dose level, different groups of subjects participated in the study. Subjects. A total of 31 healthy male subjects, ages 20 to 44 years, participated in this single- and multiple-dose phase I study after having granted written informed consent. The weights of all individuals were within 15% of the range of desirable weights for their height (1983 Metropolitan Height and Weight Tables). The mean (standard deviation) weight
Corresponding author. 552
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(in kilograms) for each dose group was as follows: for the 250-mg group, 71.7 (8.6); for the 500-mg group, 70.6 (7.5), for the 1,000-mg group, 73.8 (10.0), and for the 2,000-mg group, 79.0 (12.7). The subject eligibility criteria included the absence of compromising drug allergies or intolerance, the absence of a drug or alcohol abuse history, and a normal test result for controlled substance screening conducted the evening preceding the dosing. The use of any medications within 1 week of the study or the use of alcohol within 24 h of induction into the study was not permitted. The use of any drug, including alcohol and caffeine, during the study was not allowed. Subjects were instructed to refrain from smoking during blood and urine sampling periods. Confinement to the test facility began the day before the subject received his first dose and continued until release from the study. To ensure adequate diuresis for urine sampling, subjects drank 200 ml of water or juice 1 h prior to the infusion and approximately 1, 2, and 3 h after the start of dosing. Drug formulation and administration. Cefepime (BMY28142) was supplied by the Pharmaceutical Product Development Department of Bristol-Myers Squibb Pharmaceutical Research Institute (Syracuse, N.Y.) as vials containing a lyophilized mixture with sodium chloride. The reconstitution of 500- or 1,000-mg vials with 1.9 or 3.8 ml of sterile water for injection, respectively, provided a 250-mg/ml solution of cefepime zwitterion. The reconstituted solution was diluted with sufficient sterile water to prepare cefepime infusion solutions of 5, 10, 20, and 40 mg/ml for doses of 250, 500, 1,000, and 2,000 mg, respectively. Subjects received i.v. doses of cefepime at a dose level of either 250 (n = 8), 500 (n = 9), 1,000 (n = 7), or 2,000 (n = 7) mg. Each subject received a total of 29 injections at a given dose level by a constant-rate i.v. infusion over 30 min. On day 1 of the study, only one dose was given and blood and urine samples were collected. On days 2 through 10 of the study, cefepime was administered every 8 h at the same dose level; a single dose was administered on day 11. Each cefepime dose was administered as a constant-rate infusion by means of a syringe infusion pump, calibrated to deliver 50 ml of infusion solution per 30-min interval. Drug administration was via a forearm vein contralateral to that used for blood sampling. Collection of blood and urine samples. Heparinized blood samples were obtained from every subject at the following time points after the first and last doses of the study: at the predose; at 10, 20, 30 (end of infusion), 33, 39, and 45 min; and at 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, and 16 h after the beginning of infusion. Serial blood and urine samples were also collected after the morning infusion on day 6. On day 6, the same serial blood sampling schedule was applied, ending with the 8-h sample, at which time the next dose was given. On treatment days 4, 6, and 8, blood samples were obtained at the end of the infusion of the morning dose and before the beginning of the afternoon dose to obtain steady-state peak and trough levels (Cmin) of cefepime. Blood samples were held on ice, and plasma was prepared by centrifugation within 1 h of collection. Plasma samples were stored at or below -20°C. The total urine output of each subject was collected prior to dosing (predose) and at 0 to 1, 1 to 2, 2 to 4, 4 to 6, 6 to 8, 8 to 12, 12 to 16, and 16 to 24 h after the start of infusion of the first and last doses. On treatment day 6, sampling ended 8 h after the infusion, at which time the next infusion was given. Analysis of plasma and urine samples. Plasma and urine samples were analyzed for cefepime by a validated highperformance liquid chromatographic assay with UV detec-
PHARMACOKINETICS OF CEFEPIME
553
tion (2). The lower limits for quantitation of cefepime in plasma and urine were 0.5 and 2.0 ,ug/ml, respectively. The cefepime standard curves in plasma and urine were linear within the 0.5- to 50.0- and 2.0- to 1,000-,ug/ml ranges, respectively. Quality control samples containing known concentrations of cefepime were prepared prior to the initiation of drug administration at each dose level. These quality control samples were stored with the study samples. The between-day coefficients of variation for quality control sample concentrations of cefepime in plasma of 4.0 (n = 7) and 160 (n = 7) ,ug/ml were 4 and 3%, respectively, where n is the number of analytical sequences. The between-day coefficients of variation for quality control sample concentrations of cefepime in urine of 50 (n = 6) and 2,000 (n = 4) ,ug/ml were 2 and 2%, respectively. Excellent data for accuracy (deviation from nominal, less than 10%) and a coefficient of variation consistently less than 13% for the quality control samples suggest that the assays for cefepime in plasma and urine samples were accurate and precise, and cefepime was stable in the study samples during storage. Pharmacokinetic analysis. Plasma cefepime concentration, C, versus time, t, data were evaluated by noncompartmental methods (14, 27). The highest observed C, which occurred at the end of infusion, was defined as Cmax. The trough level (Cmin) was taken as the 8-h concentration in plasma after the commencement of an infusion. The elimination half-life (tj/2) was calculated as (ln 2)/b, where b was the absolute value of the slope of the least-squares regression line for n terminal datum points. These datum points (n > 3) were selected to minimize the mean-square error term for the regression. The area under the plasma drug concentration-time curve (AUC) and the area under the first moment of plasma concentrationtime curve (AUMC) were estimated by trapezoidal and log-trapezoidal methods. The values for the single-dose AUC and AUMC were extrapolated to infinity AUC O and AUMC O by using standard methods (14). For a single-dose administration, the mean residence time (MRT) in the body was estimated as MRT = AUMCOJAUCQO. For multiple dosings, MRT at a steady state (MRTSS) was estimated (6, 24) as MRTSS = [AUMCo, + T(C'/b)]/AUCo,, where AUCO, and AUMCO, correspond to AUC and AUMC for one dosing interval, T, and C' is the predicted concentration at time, T. The MRT equivalent for i.v. bolus administration, MRTIv, was calculated as MRTi.v = MRT - (T/2), where T is the infusion time, 0.50 h. Total body clearance (CLU) was calculated as CMr = dose/AUCO, and CLr = dose/AUCO_r after the first and the last doses, respectively. The steadystate volume of distribution was obtained as V, = MRTivV CLr (7). The accumulation ratios (R) after multiple dosings with cefepime were calculated by two different methods (9). The equations employed in these calculations are R, = 1/(1 e'3r) and R2 = AUC(OT)Ss/AUC O)1, where AUC(O_1), and AUC(O_r)ss correspond to the first dose (day 1) and the steady-state dose (day 6 or 11), respectively. Urinary recovery, X", was calculated as the product of C and the total volume of voided urine for a given interval. The percentage of the dose recovered in urine (% X") was calculated as X"/dose x 100. Renal clearance (CLR) values after the first and last doses were calculated as X,/AUCO, and X,(O_/AUC(O_), respectively. The Xi(O) value represents the urinary recovery of cefepime within one dosing interval. Statistical analysis. Repeated-measures analysis of variance (ANOVA) procedures were utilized to evaluate the noncompartmental parameters Cmax, AUC, t1/2, MRTi.,
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ANTIMICROB. AGENTS CHEMOTHER.
BARBHAIYA ET AL.
300
E 0)
30
0
0
0 co
E _o 3.0CL
0.30
4
8
12
0
4
8
12
Time (hr) * 250 MG --500 MG
-*- 1000 MG
El
2000 MG
FIG. 1. Mean concentration-time profiles of cefepime in plasma after 250-, 500-, 1,000-, and 2,000-mg i.v. doses.
with respect to the treatment day (day 1 to assess differ500, 1,000, and 2,000 mg). Dose-normalized C,ax and AUC values were used in this evaluation. The Tukey multiple-comparison procedure was utilized to compare mean parameter values with respect to dose differences. Linear regression procedures were utilized to determine whether Cmax and AUC values were proportional to the administered dose (250 to 2,000 mg). AUCO, and AUC., were the test parameters utilized for analysis on days 1 and 11, respectively. The slope and intercept estimates determined by weighted least-squares regression were tested for significance. Weights of the reciprocal of the variance at each dose level were applied in regression analyses to correct the observed heterogeneity of variance. A test of goodness-of-fit was carried out by adding quadratic and cubic terms to the linear model and testing for their significance. All hypotheses were tested at the 5% significance level.
CLr, CLR, and
V.,
or 11). One-way ANOVAs were performed ences with respect to the dose level (250,
RESULTS
Single-dose pharmacukinetics. The inspection of mean plasma concentration-time profiles for single i.v. infusions of 250, 500, 1,000, and 2,000 mg of cefepime to 31 healthy male
subjects indicated that cefepime concentrations decline at rates that are independent of the dose level (Fig. 1). The first dose in each treatment regimen was followed by a 24-h collection period to characterize the single-dose pharmacokinetics of cefepime. Key pharmacokinetic parameters are compiled in Table 1. Observed Cma values after a 30-min i.v. infusion were 17.9, 31.9, 65.1, and 126 p.g/ml for single doses of 250, 500, 1,000, and 2,000 mg, respectively. The levels of cefepime in plasma declined with an apparent elimination t112 of about 2 h at each dose level. The mean AUCO, values were 33.1, 56.6, 135, and 245 ,g. h/ml after 250-, 500-, 1,000-, and 2,000-mg doses, respectively. The mean values of CL, and CLR ranged from 126 to 152 and 100 to 138 ml/min, respectively. The Vs, was consistent among various doses and ranged from 16.6 to 19.3 liters. The urinary recovery of intact cefepime after the initial 250-, 500-, 1,000-, and 2,000-mg doses accounted for about 80% of the dose and was consistent within and among treatment groups. No significant differences as a function of administered doses were observed in ANOVAs of MRTiV,, t112, CLI, CLR, V., and the dose-normalized Cm,,. The ANOVA comparisons were complemented by analyses of the regression of Cm. (Fig. 2) and AUC0O, (Fig. 3) on dose. In the regression analyses of Cm. and AUC, intercept estimates
VOL. 36, 1992
PHARMACOKINETICS OF CEFEPIME
555
TABLE 1. Pharmacokinetic parameters of cefepime after i.v. administrationa Mean (± SD) of the following parameter: CLq AUC t1/ (h) (pg. h/mlI' (ml/min)
CLR (mi/min)
V
/oX
128 (16)
107 (14)
16.6 (2.5)
83.6 (6.1)
124 (14)
101 (17)
17.0 (2.2)
88.8 (15.9)
152 (28)
138 (33)
18.3 (1.9)
91.0 (15.2)
144 (16)
117 (23)
18.2 (1.2)
85.7 (16.3)
126 (18)
100 (18)
18.3 (2.0)
79.6 (8.3)
125 (21)
99 (24)
18.2 (3.0)
86.8 (14.9)
245 (35) 138 (22) 110 (31) 238 (40) 2.16 (0.30) 2.32 (0.39) 239 (39) 143 (25) 132 (26) a Doses were administered every 8 h for 9 days. At each dose level, a single dose was administered on days 1 and 11. b AUCO, on day 1; AUCO, on days 6 and 11.
19.3 (3.4)
78.4 (12.7)
18.4 (3.8)
96.2 (7.8)
Day administered
Dose (mg)
250
500
1,000
2,000
Cm.
MRT.V (h)
1 6 11
(pg/ml) 17.9 (2.6) 18.4 (13.5) 17.5 (2.3)
Cmin
0.6 (0.2) 0.7 (0.2) 0.8 (0.2)
2.18 (0.21)
2.00 (0.38)
2.30 (0.34)
2.09 (0.32)
1 6 11
31.9 (6.0) 32.2 (4.5) 31.2 (2.6)
1.0 (0.3) 1.0 (0.3) 1.0 (0.3)
2.05 (0.31)
2.00 (0.64)
2.09 (0.29)
2.14 (0.28)
1 6 11
65.1 (7.0) 70.5 (8.5) 66.9 (12.4)
2.7 (0.8) 2.9 (1.0) 2.9 (1.0)
2.45 (0.31)
2.34 (0.24)
2.45 (0.33)
2.23 (0.35)
126 (21.7) 129 (27.1) 137 (30.7)
1 6 11
(6gml)
4.2 (1.3) 4.4 (1.6) 3.8 (1.3)
2.34 (0.37)
33.1 (4.3) 35.4 (6.0) 33.9 (4.3) 56.6 (11.4) 60.4 (8.6) 58.06 (6.6)
135 (23) 142 (21) 137 (24)
2.20 (0.31)
from both analyses were not significantly different from 0 (P > 0.20) and no deviation from linearity was observed. Multiple-dose pharmacokinetics. Cefepime concentrations were determined as a function of time after the commencement of infusion on treatment day 6 and on the final treatment day (day 11). These data are virtually superimposable on corresponding values for the very first dose (Fig. 1). Mean pharmacokinetic parameter values for repeated ad-
ministrations of 250, 500, 1,000, or 2,000 mg every 8 h are similarly indicative of the constancy of cefepime disposition over the duration of the study (Table 1). Parameter estimates for a given treatment group were compared by an ANOVA between study days. No significant differences as a function of the treatment day for MRTiV,, t42, CLR, CLr, and Vss within dose levels were observed. The parameter values for the final infusion (day 400-
300-
0
3
a
0
0
0
0
0 0
-
.
8 %-
0
500
DOSE (MG) FIG. 2. Regression of Cm. on cefepime dose. Weighted linear regression equation: Cma, = 2.17 + 0.06 x dose; r = 0.97.
DOSE (MG)
FIG. 3. Regression of AUCoO linear regression equation AUCO,.
cefepime dose. Weighted 1.94 + 0.12 x dose; r = 0.96.
on =
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ANTIMICROB. AGENTS CHEMOTHER.
BARBHAIYA ET AL.
11) were also compared with respect to dose levels in a manner analogous to that described above for the initial dose on day 1. The results for day 11 closely paralleled those noted above for day 1. No significant differences with respect to the dose in the analyses of tl2, MRT, CLr, CLR, VS., the dose-normalized Cm., and AUCO, were observed. Evaluations of the regression of Cm. and AUCO, on dose produced results similar to those on day 1. The urinary recovery of intact cefepime was reasonably consistent among the various dose levels during the course of treatment every 8 h. The urinary recovery of cefepime corresponding to doses of 250, 500, 1,000, and 2,000 mg every 8 h was evaluated by ANOVA methods, and the results indicated that there were no differences in the %X, among dose groups on day 11. No significant change in %X. was observed across study days; however, there was a significant trend toward elevated cefepime recoveries over the course of the 2,000-mg dosing every 8 h (P = 0.04). The degree of accumulation expected for cefepime was estimated from a theoretical factor, R1, which predicts that steady-state concentrations about 7% above single-dose levels will occur for a drug with a t1/2 of 2 h that is administered every 8 h. This calculation is based on an assumption of linear pharmacokinetic behavior. Estimates of an accumulation factor, R2, based on inspection of the AUC data are consistent with the R1 prediction. The group mean Cmin and Cmaxvalues (Table 1) as a function of treatment day were also suggestive of a lack of accumulation or change in clearance after multiple dosings. DISCUSSION In this report of the pharmacokinetics of cefepime after single and multiple i.v. doses, it was found that this novel fourth-generation cephalosporin is well tolerated at the clinically relevant dosage regimen of 250 to 2,000 mg every 8 h for 9 days. Mean trough levels of cefepime 8 h after the administration of 2,000-mg doses were 3.8 to 4.4 ,ug/ml. Most organisms of the Enterobactenaceae family have a minimal inhibitory concentration for 90% of the strains tested (MIC90) of about 0.25 ,ug/ml, and P. aeruginosa has a MIC90 of about 7.0 p.g/ml (17, 18). This study demonstrates that a dose of 2,000 mg every 8 h results in concentrations in plasma that are significantly higher than MIC90 for most gram-negative organisms for the entire dose interval. This observation is particularly relevant in light of the low protein binding (
