Apr 16, 1985 - Both clearance from plasma and elimination rate constant showed a linear ... elimination half-life remained relatively constant; however, as the ...
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, JUIY 1985, p. 46-50
Vol. 28, No. 1
0066-4804/85/070046-05$02.00/0 Copyright © 1985, American Society for Microbiology
Pharmacokinetics of Intravenous Amdinocillin in Healthy Subjects and Patients with Renal Insufficiency I.
H.
PATEL,'* L. D.
BORNEMANN,' V. M. BROCKS,2 L. S. T. FANG,3 N. E. TOLKOFF-RUBIN,3 AND R. H. RUBIN3
Departments of Pharmacokinetics, Biopharmaceutics and Drug Metabolism' and Chemotherapy,2 Hoffmann-La Roche Inc., Nutley, New Jersey 07110, and Medical Service of Massachusetts General Hospital and Department of Medicine, Harvard Medical School, Boston, Massachusetts 021143 Received 24 January 1985/Accepted 16 April 1985
Five healthy volunteers and 31 patients with various degrees of renal impairment received a 10-mg/kg intravenous dose of amdinocillin by infusion over 15 min to establish the disposition profile of the drug in plasma and urine. Both clearance from plasma and elimination rate constant showed a linear relationship with creatinine clearance. It was noted that in subjects with creatinine clearances of greater than 50 ml/min, the elimination half-life remained relatively constant; however, as the creatinine clearance decreased from 50 to 5 ml/min, there was a progressive rise in the elimination half-life. Despite the removal of the drug by hemodialysis (32 to 72% of the dose), concentrations of amdinocillin in plasma remained in the therapeutic range. In patients undergoing peritoneal dialysis, less than 4.0% of the infused dose was removed by dialysis during the hourly exchanges over a 14- to 18-h period. Although the clearance from plasma and the half-life of amdinocllin were altered up to fourfold in patients with creatinine clearances of less than 15 ml/min, the amdinocillin dosage per se may not need to be reduced for these patients if the frequency of dosing is reduced from six to three or four times daily. This is based on drug accumulation estimates of 56% from a regimen of 10 mg/kg every 8 h in these patients as compared with less than 10% from a regimen of 10 mg/kg every 4 h in subjects with normal renal function. In addition, supplemental doses may not be necessary during or at the end of hemodialysis for patients undergoing hemodialysis. informed consent was obtained from all volunteers. Before the study, a history of each subject was taken, and a physical examination and laboratory tests consisting of blood urea nitrogen, creatinine in serum, glutamic oxalacetic transaminase in serum, bilirubin in serum, alkaline phosphatase, leukocyte count (total and differential), hemoglobin, hematocrit, quantitative platelet count, creatinine clearance (CLcR), whenever possible, and urinalysis (biochemical and microscopic) were performed on all volunteers. The physical examination and laboratory tests were repeated at the conclusion of the study. Volunteers were divided into the following groups: five healthy subjects (CLCR, above 100 ml/min), five patients with mild renal impairment (CLCR, 51 to 100 ml/min), nine patients with moderate renal impairment (CLCR, 16 to 50 ml/min), nine patients (not maintained on dialysis procedures) with severe renal impairment (CLCR, 5 to 15 ml/min), and eight dialysis patients, five of whom were maintained on hemodialysis and three of whom were maintained on peritoneal dialysis. The ages of the subjects ranged from 25 to 64 years, and their body weights ranged from 43.0 to 113 kg. The demographic data and laboratory parameters are listed in Table 1. Experimental procedure. Amdinocillin was administered on a 10-mg/kg basis. The required amount of amdinocillin was dissolved in 50 ml of a 5% glucose solution and infused intravenously over 15 min. The dialysis patients received the drug on the day of the dialysis procedure. The hemodialysis patients were dialyzed for 4 h immediately after the end of drug infusion; the Travenol hemodialysis apparatus (Travenol Laboratories, Morton Grove, Ill.) with an EX25 membrane (thickness, 11 ,um; surface area, 1.0 mi2) was used. The flow rates were 250 ml/min for blood and 500 ml/min for dialysate. The peritoneal dialysis patients re-
Amdinocillin (also known as mecillinam) (recently approved by the Food and Drug Administration for clinical use and soon to be available under the trade name of Coactin) is an amdino penicillinate (6) which is active against a broad range of gram-negative bacteria and acts synergistically with other ,B-lactam antibiotics (2, 9, 12, 13). The pharmacokinetics of amdinocillin in healthy human volunteers have been defined by several investigators (3, 4, 7, 8, 10). According to these studies, amdinocillin has a relatively short elimination half-life (t1/20; 47 to 59 min), a small volume of distribution (V; 0.22 to 0.53 liter/kg), and a low clearance from plasma (CLp; 3.0 to 5.3 ml/min per kg). In addition, the fraction of a dose of amdinocillin excreted unchanged in urine (fe) is 50 to 70%, whereas biliary excretion and metabolism represent two minor pathways of elimination for amdinocillin in humans. Preliminary studies, which were limited to patients with severe-to-end-stage renal insufficiency, have shown that t1/2P of amdinocillin is prolonged in such patients (1, 11). The purpose of this investigation was (i) to define the pharmacokinetics of amdinocillin in healthy subjects and patients with a wide range of renal impairment; (ii) to compare the abilities of the peritoneal dialysis and hemodialysis procedures to remove amdinocillin from plasma; and (iii) to suggest appropriate modification of amdinocillin dosages or regimens for patients with various degrees of renal impairment, including those maintained on hemodialysis or peritoneal dialysis. MATERIALS AND METHODS A total of five healthy subjects with normal renal function and 31 patients with various degrees of renal impairment who were otherwise free of clinical illness were studied. Written *
Corresponding author. 46
VOL. 28, 1985
PHARMACOKINETICS OF INTRAVENOUS AMDINOCILLIN
47
TABLE 1. Characteristics and laboratory parameters of healthy subjects and patients with various degrees of renal impairmenta Laboratory parametersb: of No.je males/no. Age (yr) Body wt Bilirubin Creatinine CLcR Group AP BUN SGOT insruLnCeum (i/m (kg) subjects offmae In serum In serum of females (IU/liter) (mg/di) (Ulml) (ml/min) (lU/liter) (/mI) (mg/dl) (mg/dl) 0.5 ± 0.2 0.9 ± 0.2 138 ± 23 22 ± 3 13 ± 2 67 ± 7 19 ± 6 Healthy 5 2/3 29 4 Renal impairment 75 ± 21 87 ± 23 26 ± 13 31 ± 11 22 ± 10 0.5 ± 0.2 1.6 ± 0.8 Mild 5 3/2 36 6 45 ± 11 0.4 ± 0.2 3.4 ± 1.3 27 ± 6 50 10 75 ± 16 27 ± 10 17 ± 5 Moderate 9 6/3 94 ± 32 0.5 ± 0.2 8.7 ± 3.8 9.4 ± 3.3 Severe 46 11 78 ± 19 38 ± 24 16 ± 6 9 7/2 10± 1.8 Hemodialysis 5 2/3 43 12 66 ± 13 42 ± 29 19 ± 10 63 ± 12 0.4 ± 0.1
Healthy
Oand4h
4and8h
8and24h
573
22 + 26 (6.1-61)
1.7 + 0.7 (0.7-3.7)
200 + 239 (20-614) 176 ± 79 (82-333) 64 ± 28 (29-111)
15, 10
762
+
(59-1,719) Renal impairment Mild
Moderate
.01
TIME (hr) concentrations + SD of amdinocillin
in plasma in FIG. 5. Mean patients with severe renal impairment (D) and patients undergoing hemodialysis (x) or peritoneal dialysis (A).
Severe
812 ± 692
(96-2,232) 402 + 412 (43-1,579) 86 42 (24-146)
a Values are given as mean ± SD (range).
16 ± 10
(6.9-35) 10 ± 7.5 (2.7-27)
50
PATEL ET AL.
ANTIMICROB. AGENTS CHEMOTHER.
tion in plasma for patients with severe renal impairment would be 18.8 ,ug/ml and 56%, respectively, from a regimen of 10 mg/kg every 8 h. In summary, with increasing renal impairment the CLp of amdinocillin is decreased and its tl2.v is increased. Although the CLp and tl2p of amdinocillin were altered up to fourfold in patients with a CLCR of 0 to 15 ml/min, the amdinocillin dosage may not have to be reduced for these patients if the frequency of dosing is reduced from six to three or four times daily.
5. Lin, E. T., J. G. Gambertoglio, S. L. Barriere, R. K. L. Chen, J. E. Conte, Jr., and L. Z. Benet. 1981. High pressure liquid chromatographic determination of mecillinam in human plasma and urine. Anal. Lett. 14:1433-1447. 6. Lund, F., and L. Tybring. 1972. 6,B-amidinopenicillanic acidsa new group of antibiotics. Nature (London) 236:135-137. 7. Meyers, B. R., J. Jacobson, J. Masci, E. Srulevitch, and S. Z. Hirschman. 1983. Pharmacokinetics of amdinocillin in healthy adults. Antimicrob. Agents Chemother. 23:827-830. 8. Mitchard, M., J. Andrews, M. J. Kendall, and R. Wise. 1977. Mecillinam serum levels following intravenous injection: a comparison with pivmecillinam. J. Antimicrob. Chemother.
LITERATURE CITED 1. Bailey, K., H. B. Cruickshank, P. G. Bisson, and B. L. Radford. 1980. Mecillinam in patients on haemodialysis. Br. J. Clin. Pharmacol. 10:177-179. 2. Baltimore, R. S., J. 0. Klein, C. Wilcox, and M. Finland. 1976. Synergy of mecillinam (FL1060) with penicillins and cephalosporins against Proteus and Klebsiella, with observations on combinations with other antibiotics and against other bacterial species. Antimicrob. Agents Chemother. 9:701-705. 3. Barriere, S. L., J. G. Gambertogilo, E. T. Lin, and J. E. Conte, Jr. 1982. Multiple-dose pharmacokinetics of amdinocillin in healthy volunteers. Antimicrob. Agents Chemother. 21:54-57. 4. Gambertoglio, J. G., S. L. Barriere, E. T. Lin, and J. E. Conte, Jr. 1980. Pharmacokinetics of mecillinam in healthy subjects. Antimicrob. Agents Chemother. 18:952-956.
9. Neu, H. C. 1976. Mecillinam, a novel penicillanic acid derivative with unusual activity against gram-negative bacteria. Antimicrob. Agents Chemother. 9:793-799. 10. Roholt, K. 1979. Pharmacokinetic studies with mecillinam and pivmecillinam. J. Antimicrob. Chemother. 3(Suppl. B):71-81. 11. Svarva, P. L., and T. Wessel-aas. 1980. Serum levels of amdinocillin in patients with severely impaired renal function. Scand. J. Infect. Dis. 12:303-305. 12. Tybring, L. 1975. Mecillinam (FL 1060), a 6,-amidinopenicillanic acid derivative: in vitro evaluation. Antimicrob. Agents Chemother. 8:266-270. 13. Tybring, L., and N. H. Melchior. 1975. Mecillinam (FL 1060), a 63-amidinopenicillanic acid derivative: bactericidal action and synergy in vitro. Antimicrob. Agents Chemother. 8:271-276.
3(Suppl. B):83-88.