Sep 30, 1983 - MICHAEL D. REED,' ROBERT C. STERN,2 TOYOKO S. YAMASHITA,3 IRENE ACKERS,"4 CAROLYN M. MYERS,",4 AND JEFFREY L.
Vol. 25, No. 5
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, May 1984, p. 579-581
0066-48041841050579-03$02.00/0 Copyright © 1984, American Society for Microbiology
Single-Dose Pharmacokinetics of Cefsulodin in Patients with Cystic Fibrosis MICHAEL D. REED,' ROBERT C. STERN,2 TOYOKO S. YAMASHITA,3 IRENE ACKERS,"4 CAROLYN M. MYERS,",4 AND JEFFREY L. BLUMERl 4* Divisions of Pediatric Pharmacology and Critical Carel and Pulmonary Medicine,2 Department of Pediatrics, and Rainbow Babies and Childrens Hospital, Departments of Biometry3 and Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106 Received 30 September 1983/Accepted 22 February 1984
The single-dose pharmacokinetics of cefsulodin were evaluated in 12 patients with cystic fibrosis. Each patient received 3 g of cefsulodin intravenously over 30 min. Multiple plasma and urine samples were obtained during the 6-h study period for the determination of cefsulodin. Pharmacokinetic parameters were determined by model-independent methods. Mean values for t1/2, Vs,, and CLp were 1.53 h, 0.242 liters/kg, and 117.3 ml/min per 1.73 m2, respectively. Six-hour urine recovery revealed 73.2% of the administered dose with a corresponding cefsulodin urinary clearance of 75.1 ml/min. These pharmacokinetic data in patients with cystic fibrosis appear consistent with data reported for unaffected individuals.
Cefsulodin is a unique new 1-lactam antibiotic with activity virtually restricted to Pseudomonas aeruginosa (11, 13). Because of its narrow spectrum, this agent might be expected to be used in the management of acute pulmonary exacerbations in patients with cystic fibrosis. The pharmacokinetics of several ,-lactam antibiotics are altered in children with cystic fibrosis (J. S. Bertino, Jr., M. D. Reed, C. Myers, and J. L. Blumer, Abstr. Drug Intell. Clin. Pharm. 16:469, 1982) (7, 15). The single-dose pharmacokinetics of cefsulodin have been described in normal adults and in adult patients with various degrees of renal dysfunction (4, 6, 12). We report here the pharmacokinetics of cefsulodin in patients with cystic fibrosis. MATERIALS AND METHODS Patients .12 years of age with cystic fibrosis were eligible for enrollment in this study. The study protocol was approved by the Institutional Review Board for Human Subject Investigation of the University Hospitals of Cleveland. Written, informed consent was obtained from each patient or parent or both. Before drug administration, each patient underwent a complete physical examination and had a laboratory evaluation which included electrolyte analysis, tests of liver and renal function, urinalysis, complete blood count with differential, prothrombin and partial thromboplastin times, and Coomb's test. Each patient received a 3-g intravenous dose of sodium cefsulodin (Abbott Laboratories, North Chicago, Ill.; lot 37011AR) dissolved in 50 ml of 5% dextrose in water. This dose was chosen because it was the highest for which safety data were available at the time of the study. Blood samples (3 ml) were collected in heparinized tubes at 0, 0.5, 0.75, 1, 1.5, 2, 4, and 6 h after the initiation of a 30-min infusion. Blood samples were placed on ice immediately and centrifuged within 1 h of collection. An equal volume of 1 M potassium phosphate (pH 6.0) was added to each plasma sample to protect against hydrolysis (5). Patients were asked to void before drug administration, and all urine excreted during the 6-h study period was collected as 2-h aliquots in iced containers. Urine samples were measured, buffered, and immediately frozen. Plasma and urine samples were frozen at -70°C until analyzed. *
Under these conditions, plasma and urine cefsulodin standards were stable for at least 90 days. All samples were analyzed within 7 days of collection. Cefsulodin concentrations in plasma and urine were determined by high-pressure liquid chromatography. Our method is a modification of the technique described by Granneman and Sennello that was designed to accommodate small sample sizes (5). Briefly, 0.2 ml of buffered plasma is mixed with 0.2 ml of methanol at 0°C. This mixture is permitted to sit on ice for 5 min and is then centrifuged for 3 min in a microcentrifuge at 4°C. The supernatant (50 p.l) is then injected onto a Zorbax BP C-8 column maintained at 30°C with a heater block. The elution solvent, consisting of 95.5% of 0.035 M ammonium acetate, was adjusted to pH 5.2 with acetic acid and 4.5% acetonitrile. Column flow rates are maintained at 1.0 ml/min, and the eluate is monitored at 265 nm. Under these conditions, the peak area was linear with cefsulodin concentrations from 1 to 200 ,ug/ml. The withinday coefficient of variation was 1.3 and the between-day coefficient of variation was 4.4. Cefsulodin recovery from plasma and urine was >95%. Model-independent techniques were used to describe the biodisposition of cefsulodin (3, 14). Plasma cefsulodin concentrations for each patient were plotted against time on a semilogarithmic scale. The area under the plasma concentration time curve (AUC) was obtained by using the linear trapezoidal rule up to the final measured plasma concentration and extrapolated to infinity. The elimination half-life (tl/20) was determined by using the postdistributive terminal portion of the plasma concentration-time curve. Plasma clearance (CLp) was determined by the formula dose/ AUCo. The apparent steady state volume of distribution (Vss) was determined by the following equation: Vd,s = [dose (AUMC)/AUC 2] - (dose * D)/(AUC * 2) where AUMC is the area under the moment curve and T is the infusion duration. The renal clearance (CLR) of cefsulodin for each patient was calculated as CLR = Ac,J AUC0o, where A is the cumulative amount of drug excreted
(15). RESULTS Twelve patients ranging in age from 12 to 33 years were enrolled in the study (Table 1). None of the patients was in
Corresponding author. 579
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REED ET AL.
ANTIMICROB. AGENTS CHEMOTHER.
TABLE 1. Patient characteristics Patient
Age (yr)
Sex
no.no. Ag(
1 2 3 4 5 6 7 8 9 10 11 12
M M M F F F M F F M F M
12.8 28.4 22.7 17.8 29.8 18.4 30.0 22.4 22.3 13.1 12.0 32.7
Surface
Wt (kg)
(m2)
(lemi/me (ml/min 1.73 Mn2)2 ~~~~~~~per
(mHg
(in2)
1.34 1.55 1.60 1.27 1.45 1.54 1.49 1.39 1.63 1.22 1.11 1.88
106.4 108.7 126.1 126.9 157.4 80.7 132.9 122.3 63.6 101.0 105.3 117.0
29 37 33 32 29
area
)
39.8 47.8 53.5 38.4 45.4 53.8 48.0 39.7 59.5 35.5 30.2 71.3
Creatinine
(mmHg)
23 28 43 27 36 32 27
Abstr. Drug Intell. Clin. Pharm. 16:469, 1982) (7, 15). Cystic fibrosis patients appear to display a larger apparent volume of distribution and an increased total body clearance. These data and others (8, 9) support the increased antibiotic dosage requirements for treating acute pulmonary exacerbations in these patients. In the present investigation, the first-dose pharmacokinetics of cefsulodin were evaluated in patients with cystic fibrosis. Our results for tl2p and V are similar to those reported for unaffected adults with normal renal function (4, 6, 12). This is in contrast to reports describing the biodisposition of other antibiotics in patients with cystic fibrosis wherein the apparent volume of distribution was larger than in unaffected patients (8, 10, 15). Since the volume of distribution is generally employed to calculate clearance (CLp = ke V) (2, 3), it is possible that the reports of increased antibiotic clearance in patients with cystic fibrosis merely reflect the arithmetic influence of a larger V multiplied by an elimination rate constant which is basically no different from that found in unaffected patients. Cefsulodin, therefore, provides a unique opportunity to evaluate clearance in patients with cystic fibrosis under conditions where there is no difference in V between affected and unaffected patients. When our clearance data for patients with cystic fibrosis (Table 3) are compared with those reported for normal adults (1, 4, 6, 12), it can be seen that cefsulodin clearance is lower in our cystic fibrosis patients. This suggests that increased 1Blactam clearance may not be characteristic of patients with cystic fibrosis. More than 70% of the administered drug was excreted during the 6-h study period in our patients. Previous reports of urinary cefsulodin excretion in adults have revealed 50 to 61% of the dose recovered in 24 h (4, 6, 12). The difference in recovery most likely relates to differences in sample handling. We optimized urinary recovery by keeping our samples on ice and by adding the stabilizing buffer immediately after the urine was voided. Arvidsson et al. (1) have reported that the urinary clearance of cefsulodin in cystic fibrosis patients is comparable to that in normal controls, but that the actual renal elimination pathway(s) for cefsulodin is different in patients with cystic fibrosis. The exact mechanism for this difference is unclear, but it appears to result from reduced tubular secretion or increased reabsorption by the kidney or both. The latter may -
respiratory failure or had any evidence of serious renal insufficiency or compromised hepatic function. Blood and urine chemistries before and 24 h after cefsulodin administration were normal. Peak plasma concentrations occurred at the completion of the 30-min infusion and ranged from 230 to 470 pg/ml. Sixhour trough concentrations ranged from 5.5 to 31 p,g/ml (Table 2). Pharmacokinetic analyses of individual patient plasma concentration data are shown in Table 3. Patients received doses ranging from 50 to 99 mg of cefsulodin per kg. In patients with creatinine clearance values .80 ml/min per 1.73 m2, the AUC appeared dependent on dose (r = 0.69, P < 0.01) over the entire dosage range employed; however, the degree of scatter observed suggested that other patientspecific factors contributed. Urinary recovery data for cefsulodin are given in Table 2. The largest amount of the dose was excreted in the first 2-h collection period. Overall, 73.9 ± 10.3% of the dose was recovered in the urine during the 6-h study period. The renal clearance of cefsulodin averaged 75.1 ± 21.5 ml/min (Table 3). DISCUSSION The pharmacokinetics of several f-lactam antibiotics have been reported to be different in patients with cystic fibrosis when compared with those of unaffected individuals (J. S. Bertino, Jr., M. D. Reed, C. Myers, and J. L. Blumer,
TABLE 2. Time-dependent plasma concentration and urinary recovery of cefsulodin Patient no. 1
2 3 4 5
6 7 8 9 10 11 12 Mean
Cumulative % dose recovered
Plasma cefsulodin concn (Ipg/mi) at various times (h) after infusion 0.5 312.1
0.75 283.2 133.5
303.5 238.9 238.6 280.1 229.7 322.4 264.7 471.8 470.0 185.0
151.3 180.6 196.3 208.3 212.9 241.9 208.8 361.9 296.5 151.1
SD 301.5
±
92.9 218.9
1.0 213.8 113.3 112.5 136.4
167.3 163.3 200.8 176.0 308.3 225.8 112.9
67.3 175.4
1.5 148.3 83.0 75.8 98.3 159.7 104.1
2.0 97.8 66.2 55.9 61.0 118.9 72.7
96.6 138.0
101.7
115.0 176.0 179.8 74.6
59.8 120.8
±
38.2
126.8 129.6 55.4 88.6
4.0 23.2 26.0 16.3 16.8 49.5 28.9 24.8 37.8 56.2 35.2 23.7 26.4
29.8 30.4
±
6.0 13.3 11.1
8.2 5.5 27.3 11.8 12.0 18.9 31.0 14.2 17.4 12.4
12.3 15.3
±
in urine at various times (h) after infusion 2 4 6 29 40 61 2 62 70 44 73 43 60 44 42 52 57 36 49
7.4 44 + 18 62
78 92 63 80 67 79 82 82 76 57
51 91 52 76 55
61 74 77 47 54 ±
15 74
10
CEFSULODIN PHARMACOKINETICS IN CYSTIC FIBROSIS
VOL. 25, 1984
581
TABLE 3. Cefsulodin pharmacokinetic parameters for individual patients Patient no.
1 2 3 4 S 6 7 8 9 10 11 12 Mean
Dose (mg of cefsulodin per kg)
Vrs t(13(liters/kg)
75.4 62.8 56.1 78.1 65.9 55.7 62.5 75.6 50.5 84.5 99.3 42.1 ±
SD 67.4
±
15.9
1.0 1.5 1.4 1.1 1.8 1.4 2.1 1.6 2.1 1.3 1.3 1.7 1.53
±
0.272 0.368 0.216 0.239 0.225 0.201 0.287 0.218 0.197 0.170 0.203 0.303 0.35 0.242
±
0.06
C Corrected CLp ( CLp )(ml/mm (ml/min) per 1.73 M2) 117.98 161.39 144.84 160.35 78.19 111.61 114.18 98.34 78.86 97.59 107.27 136.71
91.22 144.44 133.83 117.82 65.93 99.46 98.25 78.70 74.10 69.0 68.55 148.56 99.16
±
30.31
117.28
account for the reduced plasma clearance observed in our
study. Our data suggest that the pharmacokinetics of cefsulodin are different from those of other P-lactam antibiotics in patients with cystic fibrosis. Cefsulodin may prove to be a valuable tool for probing renal drug excretory mechanisms in patients with cystic fibrosis. ACKNOWLEDGMENTS This work was supported in part by grants from Abbot Laboratories, the Pharmacology Toxicology Center grant from the Rainbow Babies and Childrens Hospital Board of Trustees, and by Public Health Service grant AM27651 from the National Institutes of Health. LITERATURE CITED 1. Arvidsson, A., G. Alvan, and B. Strandvik. 1983. Difference in renal handling of cefsulodin between patients with cystic fibrosis and normal controls. Acta Pediatr. Scand. 72:293-294. 2. Gibaldi, M., and J. R. Koup. 1981. Pharmacokinetic conceptsdrug binding, apparent volume of distribution, and clearance. Eur. J. Clin. Pharmacol. 20:299-305. 3. Gibaldi, M., and D. Perrier. 1982. Pharmacokinetics, 2nd ed. Marcel Dekker, Inc., New York. 4. Gibson, T. P., G. R. Granneman, J. E. Kallal, and L. T. Senneilo. 1982. Cefsulodin kinetics in renal impairment. Clin. Pharmacol. Ther. 31:602-608. 5. 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. 6. Granneman, G. R., L. T. Senneilo, R. C. Sonders, B. Wayne,
7. 8.
9. 10.
11.
12. 13.
14. 15.
±
28.34
AUCrCLRtCL AUC CLR CLr
(pLg * h/ml)
(ml/min)
(mi/mm 1.73 in2)per
548.12 346.16 373.61 424.38 758.37 502.73 508.90 635.34 674.73 725.11 729.42 336.63
55.5 115.2 73.6 111.9 46.4 82.8 76.9 59.9 68.6 60.7 61.3 88.7
71.7 128.6 79.6 152.4 55.4 93.0 89.3 74.6 72.8 86.1 95.5 81.6
546.96
±
155.77
75.1
±
21.5
90.1
±
26.4
and E. W. Thomas. 1982. Cefsulodin kinetics in healthy subjects after intramuscular and intravenous injection. Clin. Pharmacol. Ther. 31:95-103. Jusko, W. J., L. L. Mosovich, M. S. Gerbracht, M. E. Mattar, and S. J. Yaffe. 19875. Enhanced renal excretion of dicloxicillin in patients with cystic fibrosis. Pediatrics 56:1038-1044. Kearns, G. L., B. C. Hilman, and J. T. Wilson. 1982. Dosing implications of altered gentamicin disposition in patients with cystic fibrosis. J. Pediatr. 100:312-318. Kelley, J. B., R. Menendez, L. Fan, and S. Murphy. 1982. Pharmacokinetics of tobramycin in cystic fibrosis patients. J. Pediatr. 100:318-321. Kercsmar, C. M., R. C. Stern, M. D. Reed, C. M. Myers, D. Murdell, and J. L. Blumer. 1983. Ceftazidime in cystic fibrosis: pharmacokinetics and therapeutic response. J. Antimicrob. Chemother. 12(Suppl. A):289-296. Kondo, M., and K. Tsuchiya. 1978. Comparative in vitro activities of cefsulodin, sulbenicillin, and gentamicin against Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 14:151153. Matzke, G. R., and W. F. Keane. 1983. Cefsulodin pharmacokinetics in patients with various degress of renal function. Antimicrob. Agents Chemother. 23:369-373. Real, M. 1982. Clinical aspects of the use of new cephalosporins: celsulodin, p. 329-338. In H. C. Neu (ed.), New betalactam antibiotics: a review from chemistry to clinical efficacy of the new cephalosporins. Symposia on Frontiers of Pharmacology, vol. 1. F. C. Wood Institute, Philadelphia. Wagner, J. G. 1979. Fundamentals of clinical pharmacokinetics. Drug Intelligence Publications, Washington, D.C. Yaffe, S. J., L. M. Gerbracht, L. L. Mosovich, M. E. Mattar, M. Danish, and W. J. Jusko. 1977. Pharmacokinetics of methicillin in patients with cystic fibrosis. J. Infect. Dis. 135:828-831.
