ANTImcRoBIAL AozNTs AND CHUMoTHURAPY, Dec. 1977, p. 730-732 Copyright 0 1977 American Society for Microbiology
Vol. 12, No. 6 Printed in U.S.A.
Pharmacokinetics of Cefaclor in Normal Subjects and Patients with Chronic Renal Failure RICHARD BLOCH,' JAMES J. SZWED,' REBECCA S. SLOAN,1 ,n FRIEDRICH C. LUFT*1 Renal Section, Department of Medicine, Indiana University Medical Center,' and Wishard Hospital,2 Indianapolis, Indiana 46202 Received for publication 9 August 1977
We studied the pharmacokinetics of cefaclor, a new cephalosporin antibiotic, in normal subjects and subjects with chronic renal failure. Cefaclor was largely, but not entirely, eliminated by the kidneys. The cefaclor half-life in normal subjects was 40 to 60 min; in subjects with essentially no renal function, it increased to 3 h. In normal subjects, 50 to 70% of a 250-mg dose was excreted in the urine within 8 h. The linear relationship between the elimination constant and creatinine clearance allowed the construction of a useful dosage modification nomogram.
Cefaclor, 3-chloro-7-D-(2-phenylglycinamido)3-cephem-4-carboxylic acid, is an orally absorbed, cephalosporin antibiotic that has a wide range of antibacterial activity against both gram-positive and gram-negative species (6). Pharmacokinetic data obtained from normal human volunteers indicate that cefaclor is rapidly absorbed when given orally (Cefaclor, Clinical Investigational Manual, Lilly Research Laboratories, Eli Lilly & Co., May 1976). The drug is eliminated from the plasma via the kidneys in 4 to 6 h and has a plasma halflife (Ti) of 40 to 45 min. The present study was performed to examine the pharmacokinetics of cefaclor in patients with diminished renal function. Guidelines for the use of cefaclor in patients with renal failure were formulated. MATERIALS AND METHODS Twenty-five subjects were selected for the study after informed consent was obtained. Sixteen had underlying chronic renal disease (creatinine clearance rate [Ccr], 0 to 59 ml/min). Three were older persons whose renal function (Ccr, 81 to 87 ml/min) was appropriate for their age. Six were young, healthy volunteers (Ccr, 93 to 125 ml/min). Five of the sixteen subjects with chronic renal disease required hemodialysis. The subjects' renal function is outlined in Table 1. After a single 250-mg oral dose, blood specimens for plasma concentrations were obtained at 0.5, 1, 2, 3, 4, 5, 6, 7 and 8 h. During that 8-h period, a urine specimen was collected from each of the nondialysis patients, which was analyzed for cefaclor concentration as well as Cer. Since cefaclor in plasma is unstable at room temperature (J. W. Lamb, M. A. Foglesong, Program Abstr. Intersci. Conf. Antimicrob. Agents Chemother. 16th, Chicago, Ill., Abstr. no. 355, 1976), the blood was drawn in previously refriger-
ated heparinized tubes, and the plasma was separated in a refrigerated centrifuge. The plasma specimens were plated immediately. The urine specimens were collected in containers stored on ice and assayed immediately at the end of the 8-h collection. Cefaclor was measured in plasma by cup-plate assay by using Bacillus subtilis as the marker organism (1). Urine samples were assayed by a turbidometric technique by using Staphylococcus aureus 9144 as the test organism. Assays of cefaclor in plasma and urine were performed at the Lilly Research Laboratories, Indianapolis, Ind. Measurements of creatinine in urine and serum were determined by the method of Martinez and Doolan (5). The Ti of cefaclor was determined by a computer-calculated regression curve plotted from the serum concentration data. The following formula was used to determine the rate constant of drug elimination (Kc) from the serum Ti data (4): Kc = (ln2/T1), where ln2 is the natural logarithm of 2. Statistical analysis was by parametric correlation coefficient, linear regression analysis, power curve fitting, and Student's t test where appropriate.
RESULTS Table 1 outlines the subject population, their renal function, and the drug elimination data. The Ti ranged from less than 1 h in normal subjects to 3 h in the subjects requiring intermittent hemodialysis. The relationship between the Ccr and the Ti was hyperbolic and best fit the expression: T1 = 4.88 Cer-0637. The plasma creatinine rate (Pcr) and Ti were directly correlated (r = 0.72, P < 0.05). By least squares regression, the line of best fit was defined by the expression: Ti = 0.224 Pcr + 0.821. The Ke and Ccr were directly correlated as well (r = 0.78, P < 0.05). A linear relationship was assumed, which was defined by the expression: Ke = 0.00717 Cc, + 0.24011 (Fig. 1). 730
VOL. 12, 1977
PHARMACOKINETICS OF CEFACLOR
731
TABLE 1. Renal function and drug elimination data ofpatient population
C., (ml/min)
Subject
1 125.00 2 122.3 117.64 3 4 95.23 5 95.23 6 93.0 7 86.95 8 86.3 9 81.3 58.9 10 11 55.5 12 51.2 13 51.0 14 28.5 15 20.5 16.9 16 17 12.6 9.3 18 19 8.4 6.4a 20 -a 21 22 23 24 25 a, Dialysis patients. CZFACLOR 1.
T,,2 (h)
KL (ln2/TU2)
Cefaclori(neg8
0.8 1.1 0.85 1.05 1.05 1.3 1.15 1.35 1.15 1.9 1.8 1.95 1.4 3.6 6.5 4.2 6.3 6.2 6.3 13.8
0.8 1.1 0.9 0.6 0.4 0.8 0.6 1.1 0.6 0.8 1.3 1.23 0.9 1.72 2.50 3.50 3.00 1.9 5.6 3.0 3.04 2.60 2.50 2.60 2.90
0.8664 0.63013 0.7701 1.1552 1.7328 0.8664 1.1552 0.63013 1.155 0.8664 0.5331 0.5635 0.7701 0.40299 0.27726 0.19804 0.2310 0.36481 0.12377 0.2310 0.22801 0.2660 0.2665 0.2660 0.2390
174 182 151 180 117 207 145 33 119 134 37 110 169 176 58 43 23 23 32 14
-
-
DOSAGE NOMOGRAM 0.
.
2
PI, (mg/ml)
I
.e-
I.
.2
* -*0
6
0
*
1.
0. 0.
.4-
0.
6
0.,
-2 I
I
0
10
I
I
60 90 100 70 80 30 40 50 CREATININE CLEARANCE (ml/min)
20
110
120
FIG. 1. Cefaclor dosage nomogram. The dose fraction appears on the right-hand side.
The relationship between the Ke and Pcr was hyperbolic and best fit the expression: Ke = 0.994 Pcr4m. The amount of cefaclor appearing in urine within the 8-h period of administration was correlated directly with the Ocr (r = 0.71, P < 0.05).
DISCUSSION The data indicate that in humans the elimination of cefaclor is primarily dependent on renal function. Such is also the case in mice and rats (6). Biliary excretion of cefaclor has
-
-
been observed in mice as well. In dogs however, cefaclor is labile to metabolism, and only a small amount is excreted unchanged in the urine (6). In our normal subjects, about 50 to 70% of cefaclor was recovered in the urine after 8 h. The linear relationship between the Ke of cefaclor and the 2cr allowed for construction of a useful nomogram for use of the compound in patients with diminished renal function (Fig. 1). The dosage modification was expressed as the dose fraction and appears on the righthand side of the graph. This expression stems from the relationship recently reviewed by Bryan and Stone (2) in which (patient dose/ normal dose) = (Ke at reduced excretion/K0 at normal excretion). In the individual with severely impaired renal function, about onequarter of the usual 24-h maintenance dose should be given during a 24-h period. At a Ctr of 40 ml/min, modification of the dose is probably unnecessary. ACKNOWLEDGMENTS This study was supported by a grant from the Eli Lilly Company. We appreciate the assistance of Helen Siegel, G. L. Brier, and J. D. Wolny, who conducted the cefaclor assay.
732
BLOCH ET AL. LITERATURE CITED
1. Brier, G. L., J. Wolny, and J. W. Smith. 1975. Serum bioassay for antimicrobial agents, p. 57-71. In Technical improvement service, no. 21. American Society of Clinical Pathologists, Chicago. 2. Bryan, C. S., and W. J. Stone. 1977. Antimicrobial doae in renal failure: a unifying nomogram. Clinical Nephrology 7:81-84. 3. Kammer, R. B., D. A. Preston, J. R. Turner, and L. C. Hawley. 1975. Rapid detection of ampicillin-resistant Haemophilus influenzae and their susceptibility to
ANTIMICROB. AGENTS CHEMOTHER. sixteen antibiotics. Antimicrob. Agents Chemother. 8:91-94. 4. Levy, G. 1977. Pharmacokinetics in renal dieas. Am. J. Med. 62:461-465. 5. Martinez, E., and P. D. Doolan. 1960. Determination of creatinine in small quantities of plasma. Clin. Chem. 6:233-242. 6. Sullivan, H. R., S. L. Due, D. L. K. Kau, J. F. Quay, and W. M. Miller. 1976. Metabolism of P"Clcefaclor, a cephalosporin antibiotic, in three species of laboratory animals. Antimicrob. Agents Chemother. 10:630-638.
Vol. 12, No. 6 Printed in U.S.A.
Pharmacokinetics of Cefaclor in Normal Subjects and Patients with Chronic Renal Failure RICHARD BLOCH,' JAMES J. SZWED,' REBECCA S. SLOAN,1 ,n FRIEDRICH C. LUFT*1 Renal Section, Department of Medicine, Indiana University Medical Center,' and Wishard Hospital,2 Indianapolis, Indiana 46202 Received for publication 9 August 1977
We studied the pharmacokinetics of cefaclor, a new cephalosporin antibiotic, in normal subjects and subjects with chronic renal failure. Cefaclor was largely, but not entirely, eliminated by the kidneys. The cefaclor half-life in normal subjects was 40 to 60 min; in subjects with essentially no renal function, it increased to 3 h. In normal subjects, 50 to 70% of a 250-mg dose was excreted in the urine within 8 h. The linear relationship between the elimination constant and creatinine clearance allowed the construction of a useful dosage modification nomogram.
Cefaclor, 3-chloro-7-D-(2-phenylglycinamido)3-cephem-4-carboxylic acid, is an orally absorbed, cephalosporin antibiotic that has a wide range of antibacterial activity against both gram-positive and gram-negative species (6). Pharmacokinetic data obtained from normal human volunteers indicate that cefaclor is rapidly absorbed when given orally (Cefaclor, Clinical Investigational Manual, Lilly Research Laboratories, Eli Lilly & Co., May 1976). The drug is eliminated from the plasma via the kidneys in 4 to 6 h and has a plasma halflife (Ti) of 40 to 45 min. The present study was performed to examine the pharmacokinetics of cefaclor in patients with diminished renal function. Guidelines for the use of cefaclor in patients with renal failure were formulated. MATERIALS AND METHODS Twenty-five subjects were selected for the study after informed consent was obtained. Sixteen had underlying chronic renal disease (creatinine clearance rate [Ccr], 0 to 59 ml/min). Three were older persons whose renal function (Ccr, 81 to 87 ml/min) was appropriate for their age. Six were young, healthy volunteers (Ccr, 93 to 125 ml/min). Five of the sixteen subjects with chronic renal disease required hemodialysis. The subjects' renal function is outlined in Table 1. After a single 250-mg oral dose, blood specimens for plasma concentrations were obtained at 0.5, 1, 2, 3, 4, 5, 6, 7 and 8 h. During that 8-h period, a urine specimen was collected from each of the nondialysis patients, which was analyzed for cefaclor concentration as well as Cer. Since cefaclor in plasma is unstable at room temperature (J. W. Lamb, M. A. Foglesong, Program Abstr. Intersci. Conf. Antimicrob. Agents Chemother. 16th, Chicago, Ill., Abstr. no. 355, 1976), the blood was drawn in previously refriger-
ated heparinized tubes, and the plasma was separated in a refrigerated centrifuge. The plasma specimens were plated immediately. The urine specimens were collected in containers stored on ice and assayed immediately at the end of the 8-h collection. Cefaclor was measured in plasma by cup-plate assay by using Bacillus subtilis as the marker organism (1). Urine samples were assayed by a turbidometric technique by using Staphylococcus aureus 9144 as the test organism. Assays of cefaclor in plasma and urine were performed at the Lilly Research Laboratories, Indianapolis, Ind. Measurements of creatinine in urine and serum were determined by the method of Martinez and Doolan (5). The Ti of cefaclor was determined by a computer-calculated regression curve plotted from the serum concentration data. The following formula was used to determine the rate constant of drug elimination (Kc) from the serum Ti data (4): Kc = (ln2/T1), where ln2 is the natural logarithm of 2. Statistical analysis was by parametric correlation coefficient, linear regression analysis, power curve fitting, and Student's t test where appropriate.
RESULTS Table 1 outlines the subject population, their renal function, and the drug elimination data. The Ti ranged from less than 1 h in normal subjects to 3 h in the subjects requiring intermittent hemodialysis. The relationship between the Ccr and the Ti was hyperbolic and best fit the expression: T1 = 4.88 Cer-0637. The plasma creatinine rate (Pcr) and Ti were directly correlated (r = 0.72, P < 0.05). By least squares regression, the line of best fit was defined by the expression: Ti = 0.224 Pcr + 0.821. The Ke and Ccr were directly correlated as well (r = 0.78, P < 0.05). A linear relationship was assumed, which was defined by the expression: Ke = 0.00717 Cc, + 0.24011 (Fig. 1). 730
VOL. 12, 1977
PHARMACOKINETICS OF CEFACLOR
731
TABLE 1. Renal function and drug elimination data ofpatient population
C., (ml/min)
Subject
1 125.00 2 122.3 117.64 3 4 95.23 5 95.23 6 93.0 7 86.95 8 86.3 9 81.3 58.9 10 11 55.5 12 51.2 13 51.0 14 28.5 15 20.5 16.9 16 17 12.6 9.3 18 19 8.4 6.4a 20 -a 21 22 23 24 25 a, Dialysis patients. CZFACLOR 1.
T,,2 (h)
KL (ln2/TU2)
Cefaclori(neg8
0.8 1.1 0.85 1.05 1.05 1.3 1.15 1.35 1.15 1.9 1.8 1.95 1.4 3.6 6.5 4.2 6.3 6.2 6.3 13.8
0.8 1.1 0.9 0.6 0.4 0.8 0.6 1.1 0.6 0.8 1.3 1.23 0.9 1.72 2.50 3.50 3.00 1.9 5.6 3.0 3.04 2.60 2.50 2.60 2.90
0.8664 0.63013 0.7701 1.1552 1.7328 0.8664 1.1552 0.63013 1.155 0.8664 0.5331 0.5635 0.7701 0.40299 0.27726 0.19804 0.2310 0.36481 0.12377 0.2310 0.22801 0.2660 0.2665 0.2660 0.2390
174 182 151 180 117 207 145 33 119 134 37 110 169 176 58 43 23 23 32 14
-
-
DOSAGE NOMOGRAM 0.
.
2
PI, (mg/ml)
I
.e-
I.
.2
* -*0
6
0
*
1.
0. 0.
.4-
0.
6
0.,
-2 I
I
0
10
I
I
60 90 100 70 80 30 40 50 CREATININE CLEARANCE (ml/min)
20
110
120
FIG. 1. Cefaclor dosage nomogram. The dose fraction appears on the right-hand side.
The relationship between the Ke and Pcr was hyperbolic and best fit the expression: Ke = 0.994 Pcr4m. The amount of cefaclor appearing in urine within the 8-h period of administration was correlated directly with the Ocr (r = 0.71, P < 0.05).
DISCUSSION The data indicate that in humans the elimination of cefaclor is primarily dependent on renal function. Such is also the case in mice and rats (6). Biliary excretion of cefaclor has
-
-
been observed in mice as well. In dogs however, cefaclor is labile to metabolism, and only a small amount is excreted unchanged in the urine (6). In our normal subjects, about 50 to 70% of cefaclor was recovered in the urine after 8 h. The linear relationship between the Ke of cefaclor and the 2cr allowed for construction of a useful nomogram for use of the compound in patients with diminished renal function (Fig. 1). The dosage modification was expressed as the dose fraction and appears on the righthand side of the graph. This expression stems from the relationship recently reviewed by Bryan and Stone (2) in which (patient dose/ normal dose) = (Ke at reduced excretion/K0 at normal excretion). In the individual with severely impaired renal function, about onequarter of the usual 24-h maintenance dose should be given during a 24-h period. At a Ctr of 40 ml/min, modification of the dose is probably unnecessary. ACKNOWLEDGMENTS This study was supported by a grant from the Eli Lilly Company. We appreciate the assistance of Helen Siegel, G. L. Brier, and J. D. Wolny, who conducted the cefaclor assay.
732
BLOCH ET AL. LITERATURE CITED
1. Brier, G. L., J. Wolny, and J. W. Smith. 1975. Serum bioassay for antimicrobial agents, p. 57-71. In Technical improvement service, no. 21. American Society of Clinical Pathologists, Chicago. 2. Bryan, C. S., and W. J. Stone. 1977. Antimicrobial doae in renal failure: a unifying nomogram. Clinical Nephrology 7:81-84. 3. Kammer, R. B., D. A. Preston, J. R. Turner, and L. C. Hawley. 1975. Rapid detection of ampicillin-resistant Haemophilus influenzae and their susceptibility to
ANTIMICROB. AGENTS CHEMOTHER. sixteen antibiotics. Antimicrob. Agents Chemother. 8:91-94. 4. Levy, G. 1977. Pharmacokinetics in renal dieas. Am. J. Med. 62:461-465. 5. Martinez, E., and P. D. Doolan. 1960. Determination of creatinine in small quantities of plasma. Clin. Chem. 6:233-242. 6. Sullivan, H. R., S. L. Due, D. L. K. Kau, J. F. Quay, and W. M. Miller. 1976. Metabolism of P"Clcefaclor, a cephalosporin antibiotic, in three species of laboratory animals. Antimicrob. Agents Chemother. 10:630-638.
