Journal of Antimicrobial Chemotherapy (1990) 26, Suppl. C, 71-75

Pharmacokinetics of cefodizime in the elderly following single and repeated intravenous administration of 1 g O. G. Nilsen", F. Rennemo', R. Rennemo" and B. Lenfanf

In an open, crossover study of 12 patients of mean age 74 (range 64-88) who required perioperative prophylactic antibiotic therapy, cefodizime was administered as a single iv infusion of 1 g, and repeated infusions of 1 g twice daily for 4-5 days. Serum and urine concentrations of cefodizime were determined by high performance liquid chromatography. The following pharmacokinetic indices were estimated after single and repeated (values in brackets) dosing: C,,,, 269 (285)mg/l; Cni 8-7 (8-5)mg/l; AUC 557 (494)mg.h/l; CT, 1-93 (2-20) 1/h; Va\. 8-62 (8-56)1; T,l2 4-06 (4-07) h; Uo.341,: 569 (624) mg; and Clr0.,lh 117 (1-39) 1/h. No statistically significant differences in these values were found between single and repeated dose treatments. These results demonstrate a lack of accumulation and no changes in the pharmacokinetic profile of cefodizime during repeated dosing in the elderly. No modification of the dosage regimen of cefodizime would appear to be necessary in the elderly as compared with young healthy subjects. Introduction Cefodizime is an aminothiazol methoxyimino cephalosporin characterized by a broad spectrum of activity against Gram-negative pathogens (Enterobacteriaceae, Haemophilus spp., Neisseria spp.) and Gram-positive organisms such as streptococci (except enterococci). In healthy subjects the single iv dose pharmacokinetics of cefodizime are linear in the range from 0-5 to 2 0 g. More than 70% of the administered dose is excreted unchanged in urine. The terminal elimination half-life ranges from about 4 to 8 h. No active metabolites have been detected either in serum or in urine. Cefodizime is bound mainly to serum albumin (80%). The high degree of renal excretion of unchanged drug indicates that the pharmacokinetics of cefodizime will be dependent upon renal function and age. The aim of this study was to evaluate the pharmacokinetics and accumulation potential of cefodizime in elderly patients after single and repeated iv dosing. Subjects and methods Subjects Twelve elderly patients (six males, six females) of age 64-88 years and weight 55-75 kg participated in the study. All patients were judged to be in need of perioperative 71 0305-7453/90/26C071 +05 $02.00/0

© 1990 The British Society for Antimicrobial Chemotherapy

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"Department of Pharmacology and Toxicology, Faculty of Medicine, University of Trondheim; hDepartment of Anaesthesiology, Gjevik Central Hospital, Norway; 'Medical Department, Roussel Uclaf Romainville, France

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O. G. NUsen et al.

prophylactic antibiotic therapy. Creatinine clearances were above 44 ml/min in all cases (mean 80 ml/min) and all participants had normal hepatic and renal function, with normal age-related haematological, clinical, chemical and urinary status. All volunteers gave informed consent and the study was approved by the regional ethics committee and regional drug control authority in Norway. Study design

Collection and handling of blood and urine Five ml of blood was collected from a vein in the opposite arm to that used for the infusion before administration of cefodizime and 0-15, 0-25, 0-5, 1, 2, 4, 8, 12, 24, 30, 36 h after the single and the last repeated dose. Trough concentrations of cefodizime were measured during repeated dosing just before the next infusion on day 1, (12 h), day 2 (36 h), day 3 (60 h), day 4 (84 h), day 5 (96 h) and day 6 (108 h). Blood was allowed to clot for 30min at room temperature then centrifuged at 1100 g for 15 min. Separated serum was stored at — 20°C. Urine was collected before dosing and up to 36 h after dosing. Subvolumes of urine were kept at 4°C during collection and a 5 ml mixed sample was frozen at — 20°C. All samples were protected from light. Assay method Serum (0-5 ml) was mixed with internal standard, (cefuroxime solution, 50 //I) and deproteinized 0-25 ml methanol:perchloric acid (50:50). Centrifugation was performed at room temperature for 10 min at 1100 g. Recovery exceeded 80%. Urine (0-25 ml) was mixed with internal standard (50 /d) and 1 ml of mobile phase. Assay of cefodizime was on OD-MP Spheri-5, C18 column (particle size 5/zm, dimensions 100x4-6 mm) (Brownlee Labs). The mobile phase consisted of 0-1 M phosphate buffer pH2-2: acetonitrile:methanol (79:19:2) pumped at 20ml/min. Detection was at 254 nm. Retention times for cefodizime and cefuroxime were 4-2 and 3-1 min, respectively. Linear response as a function of sample concentration was achieved in the range from 1 to 400 mg/1 in serum and 50 to 5000 mg/1 in urine. Detection limits were 0-3 and 10mg/l, respectively. The day to day variation was less than ± 5 % . Pharmacokinetics The serum concentration time curve was constructed from the sum of two exponential functions C = C,.c-1"

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The study was of an open crossover design. Dosage regimens were 1 g single dose and 1 g twice-daily for 4-5 days (a total of nine doses). A wash-out period of 48 h was used between treatments. Cefodizime was dissolved in 4 ml of sterile water for injection and was administered by an electric pump over a 5-min infusion period. The morning infusion was administered at 08.00 h after a standard hospital breakfast and evening infusion at 20.00 h after the evening meal.

Pharraacokinetks in tfae eWeriy

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where C is the serum concentration at time j . Statistics Comparison of pharmacokinetic parameters after single and repeated dosing, and changes in trough serum concentrations with time was performed by analysis of variance. All values are given as means (S.E.M.) P

Pharmacokinetics of cefodizime in the elderly following single and repeated intravenous administration of 1 g.

In an open, crossover study of 12 patients of mean age 74 (range 64-88) who required perioperative prophylactic antibiotic therapy, cefodizime was adm...
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