Pharmacokinetics of cefodizime: a review of the data on file
Jérôme Barré
Laboratoire Hospitalo-Universitaire de Pharmacologie,Centre Hospitalier Intercommunal de Créteil,40,avenue de Verdun, 94010 Creteil Cedex,France
Cefodizime is a new aminothiazolyl cephalosporin which may be administered iv or im.The absolute bioavailability im is almost 100%. The mean volume of distribu-tion is approximately 6·2-8·51. Protein binding of cefodizime is 73-89% over the plasma concentration range.Cefodizime penetrates into several tissues and body fluids such as lung, sputum, pleural and ascitic fluids, prostate, kidney, and urine to give concentrations often exceeding the MICs of susceptible pathogens.
Total body clearance is low (35-52 ml/min) and clearance is predominantly renal with up to 80% of an iv dose recovered unchanged in the urine. The pharmacokine-tics are linear within the range of doses studied (0-5-2g).The plasma concentration profile is best described by a triple exponential function.The ranges of half-lives reported are as follows: the distribution half-life is 0-2-0-5 h(accounting for 6-15% of the AUC), the β half-life is 1-5-2·1 h (accounting for 56-76% of the AUC), and the terminal (y) half-life is 3·9-7·9h (accounting for 18-43% of the AUC).
After 2g bd for five days in healthy volunteers,steady state was reached on the second administration, and no accumulation of the drug was noted.The total clearance is about 20% less in elderly subjects than in young adults, but no dosing adjustment is needed in the elderly. The pharmacokinetic profile is significantly altered in patients with a creatinine clearance less than 30 ml/min(three-to five-fold increase in half-life). Accordingly,the dose should be reduced to 50% of normal, at the same dosing interval. Hepatic cirrhosis does not appear to influence the pharmacokinetics of cefodizime.
Introduction
Cefodizime (Figure 1) is a ‘third generation’ amino-2-thiazolyl cephalosporin for parenteral use,resistant to β-lactamases, with a spectrum of activity similar in vitro to that of other third generation cephalosporins, and possessing immunomodulating properties. A bisubstituted thiothiazole group is attached at the 3 position of the cephem ring. This side chain confers a longer elimination half-life than that of cefotaxime in rodents as well as immunological properties.
The present report reviews pharmacokinetic data obtained in healthy volunteers and patients after iv or im administration. Cefodizime concentrations in plasma and body

Flgure 1.Structure of cefodizime.
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微1990 The British Society for Antimicrobial Chemotherapy 
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Table I.Mean(± S.D.) pharmacokinetic parameters of cefodizime after 0-5, 1, 1·5 and 2 g iv single dose administration as determined by HPLC
Doses
Parameters 0-5g 1g 1·5g 2g
C。(mg/l) 133-4±9-1 215-0±34·8 321·5±32·4 393-8±49-4
V(1) 6-3±0-4 7·8±0-9 7·8±0-8 8-5±1-0
AUC。-(b) 252·2±51-4 425·6±65-2 620-8±102·6 790-4±141-7
Cl(ml/min) 34·3±7-4 40±6 41·2±6-4 43·4±7·5
Cl,(ml/min) 31·8±5·4 31·9±4·8 32·4±5·2 33·9±5·8
Uo-48h(% dose) 93·8±5·7 80±8 79±12 78·5±13-6
‘One group of six healthy volunteers received 0-5g and another group of 12 healthy volunteers was administered 1, 1·5 and 2 g on separate occasions.
tissues or fluids have been determined using either a reversed-phase high performance liquid chromatographic technique (HPLC) with UV detection at 260 nm or microbiolo-gical assays.
Absorption and plasma concentrations
Intravenous bolus administration of cefodizime 1 and 2g to healthy adult subjects resulted in mean peak plasma concentrations of 215 and 394 mg/l. Following single 0·5, 1, 1·5 and 2 g iv bolus doses on separate occasions to healthy volunteers, peak serum concentrations and areas under the serum concentration-time curve increased approxi-mately linearly with dose (Table I). Mean peak serum concentrations after im injection occur at about 1h and are about one third to one half those after the same dose administered by the iv route.The mean AUC following intramuscular administration of cefodizime with and without 1% lignocaine chlorhydrate to healthy volunteers was almost identical to that following intravenous injection of the same dose,indicating a good absolute bioavailability with the intramuscular route(F = 98%). In general,the interindividual variability of cefodizime concentrations and of pharmacokinetic para-meters was found to be low.
Distribution
The apparent volume of distribution at steady-state of cefodizime in healthy adult caucasians has been reported to be 6·2 to 8·5 litres.These values are similar to those for other cephalosporins.Protein binding determined in vitro by equilibrium dialysis in healthy subjects ranged between 89% and 73% within the range of therapeutic concentrations (0-6-345 mg/l). A significant decrease in protein binding was noted at concentrations above 100mg/l cefodizime. Analysis of the protein binding data revealed that albumin is the binding protein for cefodizime.The number of binding sites per molecule of albumin (n= 1·6) as well as the affinity constant(K= 21,000 M-’)were found to be low. Binding to red blood cells was poor(≈7%).The volume of distribution did not vary significantly with dose (Table I) in spite of saturable binding protein and the reason for this was the very short time during which concentrations exceeded the saturating level (i.e. 100mg/l). 
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Table II. Concentrations of cefodizime in various tissues or body fluids
Concentration
Number Sampling (mg/l or mg/kg
Tissue or body fluid Doses of subjects time(h) for tissue)
Urine 1g iv 8 8-12 55-2±37-2
16-24 23·4±18·6
1g im 8 8-12 62·2±44·5
12-24 38-0±16-3
2giv 8 8-16 140-2±69-8
16-24 44·5±27-3
Prostate 4-6 g iv daily bd
or 7 1-4 69(37-419)
tid for 6 days 10-14 6-8(1·4-31)
Renal cortex 1-6g iv daily bd
or 18 2-4 203(17-420)
tid for 4-9 days 11-14 57(24-108)
Renal medulla 1-6g iv daily bd
or 18 2-4 164(13-523)
tid for 3-9 days 11-14 53(16-107)
Pleural fluid 1giv 14 12 15.6±1-6
Bronchial secretion 1g iv daily bd 1 4·8±1·3
for 2·5 days 6 1-4±0-3
Lung parenchyma 3 doses of 1 g iv 7 3 19-1±3·4
every 12 h 6 9-5±1-9
12 4·8±0-7
Ascitic fluid 1giv 10 12 5·1±1-0
24 3·5±0-8
“In repeat administration the sampling times mentioned are those performed after the last administration.
‘The results are expressed either as mean ±S.D.or as median with extreme values in parentheses.
Many studies have measured cefodizime concentrations in various tissues or body fluids after administration of single or repeated doses (Table II). After a single 1 g im dose of cefodizime to pregnant women, drug concentration in umbilical cord blood reached a peak of 5·8 mg/l about 2 h after administration to the mother (Berthelot et al.,1988).A maximum concentration of 9-9 mg/l was noted in amniotic fluid 11 h5 after injection.
In patients with lower respiratory tract disease, mean concentrations of cefodizime tered every 12 h. In bronchial secretions,it was shown that cefodizime levels were lower than those measured in plasma but always higher than MICs for susceptible pathogens during a 6-h period following multiple doses (1 g iv bd). Twelve hours after a single 1 g iv administration, the mean pleural fluid concentration was 15·6±1·6mg/l yielding a pleural fluid/plasma ratio of 2. Owing to the major role of the kidneys in cefodizime elimination (see below), urine levels far exceed the MICs for sensitive pathogens responsible for urinary tract infections at 8-12h and 16-24 h time intervals following single 1 and 2 g doses. The concentrations of cefodizime have been measured in samples of renal cortex or medulla of patients requiring kidney extirpation and perioperative treatment.All patients received a normal or very high dosage regimen i.e. 1 to 6g cefodizime doses for 3 to 9 days (bd or tid). The measurements were carried out either 2 or 14 h after the last presurgical dose and the tissue/plasma concentration ratios were 
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found to range from 1-4 to 4·5. When the dosing was high, the tolerance was good.In prostatic tissue after administration of 2giv bd and tid for some patients for 2·5 to 6 days,the median concentration was 6·8mg/kg from 10 to 14h after the last dose. Cefodizime also penetrates ascitic fluid as evidenced by the AUC ratio of ascitic fluid/ plasma （mean士S．D．： 0-43±0-15） obtained after a single 1g iv dose． Most of the reported observations confirm that the concentrations measured in various tissues or body fluids are in excess of the MICs for susceptible pathogens.
Elimination
The elimination of cefodizime has been studied in three healthy male volunteers after iv administration of a single dose of “C-labelled drug. The doses ranged from 8 to 12mg/kg. Over a period of 192 h, 68-90% of the dose was excreted in the urine and 11-30% in the faeces. The total radioactivity was eliminated with three half-lives:T0-1h, Tp2·4h,T, 26·4h.
Total serum clearance in patients and healthy volunteers was 34 to 56 ml/min. Since 70-80% of the iv dose was recovered unchanged in urine, the renal clearance accounted for the same percentage (70-80%) of the total clearance. In general, there was good agreement between HPLC and microbiological assays suggesting that no active meta-bolite was present in significant amounts in plasma. The AUCs increase proportionally with dose (0·5-2g) (TableI) indicating the clearance to be dose-independent in the range of the administered doses.
All the collected pharmacokinetic data were analysed by a uniform method i.e.the HOEREP program package(Wetzelberger,N.& Brockmeier,D.,1990,report on file, Hoechst AG, Frankfurt). The concentration-time profile, reflecting distribution and elimination of cefodizime from the body could be described by three exponential phases (Figure 2): a very short phase with a half-life (T+) ranging between 0·2 and 0·5 h and accounting for 6% to 15% of the total area under the curve; a second phase with a half-life (T;p) ranging between 1·5 and 2·1 h and accounting for most of the total area under the curve (56-76%); and a third phase characterized by a half-life(T)varying from 3-9 to 7·1 h related to 18-43% of the total area under the curve.

Tlme (h)
Figure 2.Plot of mean plasma cefodizime concentration vs time in healthy subjects after a l g iv dose. 
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For a drug such as cefodizime, the y phase may not be detectable if the time sampling is too short (especially if it does not exceed 24 h) and also if the detection limit of the assay is too high. The values of the decay phases remain constant over the range of the doses investigated (i.e. up to 2 g iv).
Multiple-dose pharmacokinetics
In a multiple dose study, twelve healthy male subjects (mean age ±S.D.: 24·9±0-9 years) received 2 g iv every 12 h for six days. Blood and urine samples were collected after the first injection (from 0 to 12h) and after the last one (from 0 to 72h). The results (Table III) show no accumulation and the pharmacokinetic parameters do not vary with time. In addition the mean pre-dose levels at 12, 36, 60, 84,96 and 108h ranged between 6-18 and 7·84 mg/l,exceeding the MICs for the susceptible pathogens.
Influence of age on pharmacokinetics
The pharmacokinetics of cefodizime have been studied in elderly subjects. One study was conducted in eight elderly patients with no major underlying disease, aged between 60 and 86 years, after administration of a single 2g iv cefodizime dose. The mean total clearance decreased significantly by 21% in comparison with that seen in young healthy adults.Over the age of 70,the decrease in clearance was pronounced (≈35%). The decrease in clearance accounts for the slight increase in terminal half-life(≈20%).
Another study reported the pharmacokinetics of cefodizime after 1g iv bd for five days. Twelve elderly patients (aged 64 to 88 years, mean: 74;mean Cl±S.D.: 79-9±27·3ml/min) requiring antimicrobial therapy took part in the study.These patients first received a single 1 g iv dose and the pharmacokinetic profile was measured over a period of 36h. Then they all received a 1-g iv dose twice a day for five days. Again,the pharmacokinetic parameters were determined over the last dosing interval. The pharmacokinetic parameters obtained during the first and the last dose were not statistically different and no accumulation was noted (Table IV). The mean trough concentrations ranged between 12·7 and 19mg/l over the period of the study.Total clearance was slightly lower (≈32 mi/min) than that of young adults (34-52 ml/min). The volume of distribution was not affected by age. As a result of this,the half-life was slightly increased in comparison with that in young healthy volunteers. Given the small increase in AUCs observed in the elderly group,no dosing adjustment seems necessary.
Table III.Pharmacokinetic parameters（mean 士 S.E.M.） of cefodizime in healthy volunteers during multiple intravenous administration of 2 g twice a day for sixdays (HPLC assays)
First dose Last dose ANOVA
V.(1) 12-28±0-85 11-61±0-71 NS
AUC(mg.l/h) 624±23 608±31 NS
Cl(ml/min) 54·16±1·83 56-33±2·66 NS
Cl,(ml/min) 36-00±1.66 39-30±3·33 NS
U12b”(% dose) 66-50±5-55 77-40±8·29 NS
·Amount of cefodizime excreted unchanged in urine(expressed in % of dose) over a period of 12 h following the first and the last administration. 
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Table IV.Pharmacokinetic parameters (mean±s.D.) of cefodizime in the elderly during multiple intravenous administration of 1 g twice a day for five days (HPLC assays)
First dose Last dose ANOVA
V.(1) 8·62±0-66 8-56±0-72 NS
AUC(mg.h/l) 557±43 494±38 NS
Cl1(ml/min) 32·17±2·83 36-67±3·83 NS
Cl(ml/min) 17-67±2-0 23·17±3·33 NS
U12b”(% dose) 56-90±5·70 62·40±5·0 NS
“Amount of cefodizime excreted unchanged in urine (expressed in % of dose) over a period of 12 h following the frst and the last administration.
Influence of disease on pharmacokinetics
Data obtained in patients with cirrhosis (grade B according to Child’s classification with ascites present in some patients) who received a single 1 g iv dose of cefodizime showed that volume of distribution, clearance and half life were not significantly different from those of volunteers with normal liver function.
The elimination rate of cefodizime, like most β-lactams,is proportional to renal function.When a 1-g single iv dose was administered to patients with different degrees of renal impairment,the results in Table V clearly show that when creatinine clearance was less then 30 ml/min, the areas under the curves of plasma concentrations vs time were increased up to fourfold in comparison with those in control groups (Table V). This increase was accounted for by a reduction in the total clearance which was decreased because of a rapid fall in renal clearance. As with other cephalosporins,renal impairment can thus lead to an increase in terminal half-life (up to 16h) proportional to the decrease in clearance.The relation between CIg and T, is shown in Figure 3. Accordingly,the dose should be reduced to 1-2g daily according to the severity of the infection in patients presenting with Cla values less than 30 ml/min. Single or divided doses may be given but 2 g per day should not be exceeded.
Single dose kinetics of cefodizime carried out in four patients on haemodialysis, showed that substantial levels of the antibiotic could be measured in dialysate.
Table V.Pharmacokinetic parameters of cefodizime (mean ± S.D.) in patients with different levels of renal function after administration of a single 2g intravenous dose (HPLC assays)
Cla AUC Cl Cl,
(ml/min) (mg.h/l) (ml/min) (ml/min)
Control group 100 773±139 44·5±8·1 >100
(n=12)
Group I 72-0±23-4 966±489 40-1±15-0 72-0±23-4
(n=4)
Group II 29-2±8-0 1561±449 23·9±10-8 29-2±8-0
(n=8)
Group III 12·7±2·7 2527±871 14·6±5·3 12·7±2·7
(n=5)
Group IV 6-8±2·3 2635±1899 17·1±8·5 6-8±2·3
(n=5)
 
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Flgure 3.Relationship between the half-life and the creatinine clearance in healthy subjects.
However no dosage recommendations could be given because the number of subjects was too small.
Conclusion
Cefodizime is a third generation cephalosporin mainly excreted unchanged by the renal route (70%). The remaining fraction (30%) is recovered in faeces. The iv pharmacoki-netics are linear within the dose range 0-5-2 g iv in spite of a slight saturation protein binding to albumin (85-70%). The tissue and body fluid penetration yields concentra-tions exceeding the MICs of most sensitive pathogens. The main pharmacokinetic feature distinguishing cefodizime from other cephalosporins (Balant, Dayer & Auckenthaler, 1985)is the triexponential decay.This profile accounts for the recovery in urine up to 36 h after single im or iv dose administration. Furthermore,trough concentrations at 24 h after single iv administration of 1 g and 2g are 0-48±0-14 and 0-92±0-60mg/l,respectively.With the exception of ceftriaxone,trough concentrations of third generation cephalosporins are usually not detectable after 16h. In repeat administration,steady-state is achieved very rapidly (as early as the second administra-tion) and trough concentrations are achieved which are above the MICs of most sensitive pathogens.Owing to the renal contribution in the elimination of the drug, dose adjustment is needed when the creatinine clearance is lower than 30 ml/min. The pharmacokinetic profile of cefodizime supports once or twice daily dosing in the treatment of respiratory tract infections. Further studies to evaluate once daily admin-istration in the treatment of hospital infections are in progress.
References
Balant, L., Dayer, P. & Auckenthaler, R. (1985). Clinical pharmacokinetics of the third generation cephalosporins. Clinical Pharmacokinetics 10, 101-43.
Berthelot,G.,Bornet,M.,Bergogne-Berezin, E. & Ravina, J. H. (1990). Etude du passage transplacentaire du cefodizime.Pathologie Biologie 36,699-701.