ANTIMICROBIAL AGENTS AND CHEMOTHERPY, Mar. 1983, p. 369-373 0066-4804/83/030369-05$02.

00/0 Copyright 1983, American Society for Microbiology

Vol. 23, No. 3

Cefsulodin Pharmacokinetics in Patients with Various Degrees of Renal Function

GARY R. MATZKE .2* AND WILLIAM F. KEANE1'3 Drug Evaluation Unit, Department of Medicine, Hennepin County Medical Center,1 and College of Pharmacy2* and School of Medicine,3 University of Minnesota, Minneapolis, Minnesota 55415 Received 18 October 1982/Accepted 3 January 1983

The pharmacokinetics of cefsulodin were characterized in 19 patients with different degrees of renal function after a single 500-mg, 30-min intravenous infusion. Six subjects had a creatinine clearance (Clcr) of >100 ml min-1 (group I), eight had a Clcr of between 12 and 42 ml min-' (group II), and five had a Clcr of <10 ml min-' (group III). Nine plasma and four urine samples were collected in the first 36 h. The plasma concentration-time data were fitted to a twocompartment open model. The mean P-phase half-life was 1.77, 6.37, and 10.12 h in groups I, II, and III, respectively. A significant decline in plasma clearance (Clp) was also noted between the three groups: 136 to 49.6 to 27.2 ml min-' in groups I, II, and III, respectively. Steady-state volume of distribution was 0.26 liter kg-1, regardless of renal function. The observed linear relationship between Clp and Clcr (Clp = 24.09 + 0.765 Clcr; r = 0.9566) can be utilized to revise dosage schedules for patients with any degree of renal impairment. The nonrenal clearance of cefsulodin was also noted to be significantly lower in groups II and III than in group I. Further investigations will be necessary to elucidate the mechanism(s) responsible for the decrease in the nonrenal clearance of cefsulodin.

The pharmacokinetic characteristics of cefsu- neapolis, Minn. Written informed consent was granted lodin after the administration of single intrave- by each subject. Before participating in the study, all nous doses to individuals with normal renal patients underwent a complete medical history, physifunction have been described previously (5). cal examination, chest radiograph, electrocardiogram, The kinetic behavior of cefsulodin in these pa- and series of laboratory screening procedures (a comblood chemistry profile, 24-h creatinine tients is similar to that of cephalothin in that puterized [ClCr], and a complete blood count with clearance approximately 60%o of each drug is eliminated differential). Patients with major disorders of the hepaunchanged in the urine. However, the terminal tobiliary, cardiovascular, central nervous, or respirahalf-life of cefsulodin is considerably longer than tory systems were excluded from the study. No pathat reported for cephalothin (5, 6). Since cefsu- tients received concurrent antibiotic therapy. Procedures. Patients were divided into three groups lodin is primarily eliminated by urinary excretion, it would be expected that renal failure on the basis of 24-h Clcr measurements. Groups I, II, to 42, would prolong its elimination. Furthermore, and III had Cl,rs of >100, 12subjectsand <10 mlamin-1, received single 1). All since the metabolism of cephalothin has been respectively (Table dose of cefsulodin-free acid as the 500-mg intravenous reported to be decreased in patients with renal sodium salt (lot 92-758-AL [ST3]; Abbott Laboraimpairment, a further prolongation of the elimi- tories, North Chicago, Ill.) dissolved in 50 ml of 5% nation of cefsulodin in uremic patients might be dextrose in water. The drug was infused into a forearm expected (7). Available data on the kinetics of vein over a 30-min period beginning at approximately 8 cefsulodin in patients with renal impairment are a.m. All subjects fasted from midnight until 2 h after limited (3). Therefore, this study was initiated to the drug infusion was started. Blood samples were collected in heparinized tubes characterize the pharmacokinetics of cefsulodin in 19 patients with different levels of renal func- from a forearm vein in the arm other than that used for drug administration at 0, 0.5, 1, 2, 4, 6, 8, 12, 24, and tion. 36 h after the drug infusion was started. The heparinMATERIALS AND METHODS Subjects. Nineteen subjects who had no known hypersensitivity to penicillins or cephalosporins participated in this study. The study protocol and consent form were approved by the Research Advisory Committee of the Hennepin County Medical Center, Min369

ized samples were immediately cooled in an ice-water bath and centrifuged within 1 h. An equal volume of 1.0 M phosphate buffer (pH 6) was added to the plasma to protect against hydrolysis. Urine was collected as four 6-h fractions (0 to 6, 6 to 12, 12 to 18, and 18 to 24) relative to the start of the infusion. The volume of urine of each fraction was recorded, and a

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ANTIMICROB. AGENTS CHEMOTHER.

TABLE 1. Clinical characteristicsa

Group (n)
Sex (M/F)

(mgDkg-)

Age (yr)

Ht (cm)

Wt (kg)

CLr (ml min-')

I (6) 6/0 7/1 II (8) 5/0 III (5) a Numbers in parentheses

27.7 (3.2) 7.02 (1.45) 52.1 (15.3) 7.18 (1.91) 49.0 (16.8) 6.45 (1.16) represent standard deviations.

165.5 (7.8) 172.8 (10.0) 175.0 (7.3)

73.5 (14.3) 73.9 (18.6) 79.6 (14.7)

148.7 (26.6) 31.0 (12.1) 5.0 (3.2)

10-ml sample was withdrawn and frozen. Plasma and urine samples were stored at -20C until assayed. Concentrations of cefsulodin in plasma were determined by high-pressure liquid chromatography (4). The inter- and intra-assay coefficients of variation of the procedure are less than 4 and 2%, respectively. The limit of quantification is 0.2 Fig/ml. Cefsulodin is stable (>98% recovery) for 81 days when buffered and frozen at approximately -17C (4). Cefsulodin concentration in urine was measured by a microbiological assay in which Pseudomonas aeruginosa ATCC 27853 was used as the test organism. All assays were performed by the Drug Metabolism Department of Abbott Laboratories. Data analysis. The decline in cefsulodin concentration in the plasma of each patient was clearly biexponential; therefore, the data were analyzed in terms of the following equation:

h period. Nonrenal clearance (Clnr) was calculated as the difference between Clp and Cl, The pharmacokinetic parameters obtained were evaluated by analysis of variance. Differences between groups were subsequently analyzed by the unpaired Student t test. The relationships between these parameters and renal function were assessed by orthogonal regression analysis. The 0.05 level was chosen as the level of statistical significance.

C = A e-' + B e-'
where C is the concentration in plasma at time t. A and B are the intercepts, and a and a are the disposition rates obtained from the first and second phases, respectively, of the plot of log cefsulodin concentration in plasma versus time. Initial estimates of the parameters in the above equation were obtained by standard curve-stripping procedures. Final estimates were obtained by nonlinear regression analysis with the program KINA on a Control Data digital computer (University Computing Center, University of Minnesota, Minneapolis). All cefsulodin concentrations were weighted according to their reciprocal-squared concentrations during the computer fitting procedure. Since the cefsulodin doses were infused over a period of 30 min, the results of the computer analysis were analyzed with the appropriate equations for the biphasic decay of log concentration versus time after the termination of an intravenous infusion (9). The volume of distribution of the central compartment (Vdl), the steady-state volume of distribution (Vd35), the half-life of the a- and 3-phases (t0/2a and t'/2p, respectively), and the plasma clearance (Clp) were calculated by standard techniques (1). The area under the plasma concentration versus time curve to infinite time (AUCX) was calculated for each subject by the trapezoidal method. The renal clearance (Clr) of each subject was calculated as:
Clr
=

RESULTS cefsulodin concentration in plasmaThe mean time profiles of the three groups are shown in Fig. 1. The biexponential decay of cefsulodin concentrations in plasma is evident in each case. Considerable differences in the rate at which cefsulodin disappeared from plasma in the three groups were noted; these differences correlated with the decline in renal function. The 24-h cumulative urinary excretion of cefsulodin averaged 61.53% of the dose in subjects with normal renal function. This fraction declined to 33.5% in group II subjects and to less than 7% of the dose in subjects with severe renal impairment. The pharmacokinetic parameters obtained from the three groups are shown in Table 2. The effect of renal function impairment on the rate of cefsulodin clearance from the body is indicated by the significant changes in the values of 3, t1/2f, and Clp. The mean t0/2 of cefsulodin in
100

t hr.3 10.12

hr
l

E 10E
0

010

30

Hours After Infusion

R/AUCO24

where R is the amount of drug excreted during the 24-h sampling period and AUCO,24 is the area under the plasma concentration versus time curve during the 24-

FIG. 1. Mean plasma concentration-time curve of cefsulodin for subjects in groups I (..... ), II (-), and III (-.-.) receiving single 500-mg intravenous doses of cefsulodin. Bars represent the mean 1 standard deviation for each group.

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TABLE 2. Pharmacokinetic parameters of cefsulodin in 19 patients with various degrees of renal function
Groupa

CMb (a.g/ml)
50.2 43.2 51.4 47.8 42.7 33.3

tYzcc
(h)

t/P
(h)

(liters kg-)

Vdl

VdSS (liters kg1-)

0.236 0.233 0.279 0.194 0.214 0.195 0.225

(~lg ml-) 83.3 58.8 54.5 65.5 56.0 57.1 62.5 (10.9)

AUCO-

CIP (ml min-')

100.0 141.8 153.0 127.2 148.8 145.9 136.1 (19.8)

(ml min-1)
65.0 90.9 93.6 74.1 85.8 91.9 83.6 (11.5)

Cir

Clnr (ml min-')

35.0 50.9 59.4 53.1 63.1 54.0 52.6 (8.9)

(ml min-1)
125 179 182 143 144 119

Cl,r

1 2 3 4 5 6

0.919 0.547 0.085 0.222 0.269 0.705

2.53 1.78 1.47 1.46 1.49 1.90

1.77 (0.42)

0.190 0.170 0.141 0.137 0.147 0.157

Mean (SD)

44.8
(6.7)

0.458 (0.320)

0.157 (0.020)

(0.032)

148.7 (26.6)

II
7 8 9 10 11 12 13 14

26.1 45.8 28.5 31.8 58.3 42.6 52.5 43.4

41.1 (11.5)

1.700 0.371 1.164 1.277 0.489 0.910 0.345 0.638

5.28 3.46 7.85 7.35 2.71 6.35 10.38 7.57

6.37

0.198 0.146 0.203 0.237 0.151 0.120 0.147 0.246

0.181

0.268 0.229 0.343 0.345 0.224 0.189 0.308 0.390

0.287

92.2 134.6 162.8 208.0 133.2 220.2 359.4 282.1

199.1 (88.1)

90.4 61.9 51.2 40.1 62.6 37.8 23.2 29.6

49.6 (21.8)

28.7 29.7 12.2 16.0 28.9 9.5 17.5 9.4 17.5 (10.1)

61.7 32.2 39.0 24.0 33.6 28.3 18.0 20.2 32.1 (13.9)

42 41 38 38 38 23 16 12

Mean (SD)

0.862 (0.488)

(2.50)

(0.047)
0.165 0.122 0.098 0.154 0.225

(0.071)

31.0 (12.1)

III 15 16 17 18 19 Mean (SD)

45.6 46.7 51.0 49.9 28.0

0.323 0.163 0.248 0.441 3.700

8.40 12.28 9.73 7.73 12.44

0.279 0.405 0.233 0.258 0.259

316.9 241.4 289.9 318.7

410.0

26.3 34.5 28.8 26.1 20.3

7.0 0.0 0.2 1.1 0.0

19.3 34.5 28.6 25.0 20.3

7 8 4 6 0

44.2 (9.3)

Patients in groups function, respectively. b Cm, Maximum observed concentration of cefsulodin in plasma.

25.5 5.0 27.2 1.7 315.4 0.287 0.153 10.12 0.975 (6.3) (3.0) (5.1) (61.4) (1.527) (2.17) (0.048) (0.068) (3.2) I, II, and III had normal, mildly to moderately impaired, and severely impaired renal

groups

plasma increased from 1.77 to 6.37 to 10.12 h in to estimate the expected values of these parameters given values of Clcr. Parameters associated I, II, and III, respectively, whereas ClIp decreased from 136.1 to 49.6 to 27.2 ml min-' in with cefsulodin elimination such as 1B and Clp groups I, II, and III, respectively. There were no correlated well with Clcr (Fig. 3 and 4). Howevsignificant differences in Vdl and Vdss among the er, no significant relationship was observed between Vdl or VdSS and Clcr three groups. The Clr of cefsulodin was significantly reduced in group II as compared with group I, and DISCUSSION a further significant reduction was observed in This study shows that the pharmacokinetic group III as compared with group II. The Clnr of cefsulodin also decreased as renal function de- behavior of cefsulodin differs from those of clined (Fig. 2). Although the Cl,s of cefsulodin many other cephalosporins (6). After intravein groups II and III were statistically indistin- nous dosage, it distributes initially into an apparguishable (32.1 and 25.5 ml min-1, respectively), ent fluid volume equal to approximately 16% of it was significantly reduced in both of these total body weight and subsequently into a volume equal to approximately 26% of total body groups as compared with group I. Based on the observed correlations between weight. After distribution is complete, the plassome pharmacokinetic parameters and CLr, re- ma concentrations decline monoexponentially, gression analysis was used to obtain equations with a half-life of approximately 1.77 h in sub-

372

MATZKE AND KEANE

60
0
-

ANTIMICROB. AGENTS CHEMOTHER.

-i

50

o _

40

z7

C.) -I

30 7
0
0

-2w
0

w
0

2C

ic3

GROUP I GROUP 11 GROUP III of cefsulodin in subjects in groups I, FIG. 2. Cl,,, II, and HI. The Clr was significantly lower in subjects in groups II and III than in subjects in group I. However, there was no statistical difference between subjects in groups II and III. Bars represent the mean + 1 standard deviation for each group.

jects with normal renal function. However, the Clp and Clr of cefsulodin are considerably smaller than those of most currently available cephalosporins. Furthermore, the ratio of Clr to ClCr was less than 1 in all subjects. Although sufficient data were not obtained to define the site(s) or mechanism(s) involved, this observation suggests that cefsulodin undergoes tubular reabsorption, since the protein binding of cefsulodin

is approximately 15%. This finding contrasts with the glomerular filtration of free drug and active secretion of total drug characteristic of the Clr of other cephalosporins (6). Only 61.53% of the cefsulodin dose was recovered unchanged in the urine of subjects with normal renal function. This finding is comparable to the value of 60.4% reported by Granneman et al. (5) and suggests that cefsulodin is extensively metabolized, subject to biliary excretion, or unstable in biological fluids. Because its Clnr appeared to be considerable, only a moderate reduction in cefsulodin Clp was expected with declining renal function (10). However, a significant reduction in Clp as well as a prolongation of the terminal half-life was noted (Table 2). The pharmacokinetic parameters of cefsulodin in subjects with normal renal function are similar to those reported by Granneman et al. (5). The Vdl and Vd,, were not significantly different among patient groups, and the mean values were similar to those reported in normal subjects (5). The observed decrease in Clp and Cl, in these patients with renal impairment were similar to those reported by Gibson et al. (3). The degree of decline in Clnr was similar in the two study populations with mild to moderate renal impairment. However, the decline was markedly less in our patients with severely impaired renal function. The reason for this difference is not readily discernible. The mean Cl., of cefsulodin was 51.2% lower in the patients with severely impaired renal function than in those with normal renal function. This finding suggests that the metabolism or biiary excretion of cefsulodin is decreased or the stability of cefsulodin in biological fluids is increased in uremia. It is also possible that this decrease may be related to the advanced ages of the subjects in group III. Sufficient data were not obtained in this study or available in the literature to define the potential

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150 200 100 50 Clearance (ml/mm) Creatinine FIG. 3. Correlation of cefsulodin, disposition rate with CL.r, n = 19; r = 0.9434; 3 = 0.0023 Clcr 0.060;

P < 0.001.

150 100 Creatinine Clearance (ml/min) FIG. 4. Correlation of cefsulodin Clp with Cl, n = 19; r = 0.9566; ClP 0.765 Clcr + 24.09; P < 0.001. 50

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CEFSULODIN PHARMACOKINETICS

373

site(s) or mechanism(s) which contribute to the decrease in the Clnr of cefsulodin. Although the impact of declining renal function on the elimination of cefsulodin is not as marked as has been reported with some of the cephalosporins, dosage adjustment may be required. There are several approaches to modify the drug dosage schedules in patients with impaired renal function (2, 8). Because of its simplicity and the combined benefits of less frequent drug administration and the assurance of attaining high peak drug concentrations, the prolongation of the maintenance dosing interval (-y) may be preferred. Regardless of which method is utilized, since Vd33 is not affected by renal failure, the loading dose in renal failure patients will be identical to that in normal subjects. The degree of alteration of y may then be calculated by utilizing the relationship between Clp and Clcr (Fig. 4). From this relationship, a Clp of 116 ml min-' can be calculated for a "normal" Clcr of 120 ml min-. The new dosing interval, utilizing the standard dose, can then be estimated from the following equation:
'Yfailurc
=

vestigation will be necessary to determine the mechanism(s) responsible for this decrease.
ACKNOWLEDGMENTS
This work was supported in part by a grant from Abbott Laboratories, North Chicago, Ill. We wish to thank Tom Chin and Robert McGory for their valuable technical assistance, G. R. Granneman and L. T. Sennello for their analytical expertise, J. E. Kallel for his continued support, and Kim Podany for preparation of the

manuscript.
LITERATURE CITED
1. Gibaldi, M., and D. Perrier. 1975. Pharmacokinetics. Marcel Dekker, New York. 2. Gibson, T. P. 1980. Influence of renal disease on pharmacokinetics, p. 32-56. In W. E. Evans, J. J. Schentag, and W. J. Jusko (ed.), Applied pharmacokinetics: principles of therapeutic drug monitoring. Applied Therapeutics, Inc., San Francisco. 3. Gibson, T. P., G. R. Granneman, J. E. Kalial, and L. T. SenneHo. 1982. Cefsulodin kinetics in renal impairment. Clin. Pharmacol. Ther. 31:602-608. 4. Granneman, G. R., and L. T. Sennello. 1982. Precise highperformance liquid chromatographic procedure for the determination of cefsulodin, a new antipseudomonal cephalosporin antibiotic in plasma. J. Pharm. Sci. 71:1112-1115. 5. Granneman, G. R., L. T. SenneOo, R. C. Sonders, B. Wynne, and E. W. Thomas. 1982. Cefsulodin kinetics in healthy subjects after intramuscular and intravenous injection. Clin. Pharmacol. Ther. 31:95-103. 6. Nightingale, C. H., M. A. Frencb, and R. Quintlliani. 1980. Cephalosporins, p. 240-275. In W. E. Evans, J. J. Schentag, and W. J. Jusko (ed.), Applied pharmacokinetics: principles of therapeutic drug monitoring. Applied Therapeutics, Inc., San Francisco. 7. Reidenberg, M. M. 1977. The biotransformation of drugs in renal failure. Am. J. Med. 62:482-485. 8. Tozer, T. N. 1974. Nomogram for modification of dosage regimens in patients with chronic renal function impairment. J. Pharmacokinet. Biopharm. 2:13-28. 9. Wagner, J. G. 1975. Fundamentals of clinical pharmacokinetics, p. 82-101. Drug Intelligence Publications, Inc.,

'Ynormal (116 ml

24.09 ml

min-')

minI1/0.765 Clcr +

This yields a yfailure of approximately 1.9, 2.5, and 3.7 times the normal value for patients with Clcrs of 50, 30, and 10 ml min-1, respectively. Our data demonstrate that the pharmacokinetic parameters of cefsulodin are markedly altered in patients with renal impairment. The Clp and Clr were significantly reduced in the patients with severe renal impairment, and the decline was linearly related to Clcr. The significant relationship between Clp and Clcr may be used to revise dosage schedules for patients with any degree of renal function impairment. The Clnr was also significantly lower in the patients with decreased renal function. However, further in-

Hamilton, Ill.

10.

Welling, P. G., W. A. Craig, and C. M. Kunin. 1975. Prediction of drug dosage in patients with renal failure using data derived from normal subjects. Clin. Pharmacol. Ther. 18:45-52.