Journal of Antimicrobial Chemotherapy (1990) 26, Suppl. C, 65-70

Phannacokinetics of cefodizime administered intravenously as a singledose (10 and 2 0 g) to healthy adult volunteers A. Brvskler", T. Procyk', D. Tremblay", B. Lenfanf and J. B. Fomtfflan* -Institut Roussel-Uclaf, 102, route de Noisy, 93230 Romainville; b CEMAF, Poitiers, France

Introduction Cefodizime is a 2-aminothiazolyl cephalosporin for parenteral use (Durckheimer, Fischer & Latrell, 1989). While retaining the 2-aminothiazolyl side chain of cefotaxime, with a .sy/j-methoxyimino group in the 7-position, cefodizime contains a mercaptothiazolyl moiety instead of the 3-acetoxy group of cefotaxime. This change has led to an improved pharmacokinetic profile in laboratory animals and enhanced tissue diffusion (Klesel et al., 1984a); compared with a range of other cephalosporins, cefodizime displayed a greater in-vivo activity in experimental infections than might have been expected from in-vitro data (Klesel et al., 19846). Cefodizime shows a high level of in-vitro activity against the Enterobacteriaceae, and moderate activity against Staphylococcus aureus, whilst streptococci are highly susceptible (Scully, Jules & Neu, 1983; Le Noc, Bryskier & Le Noc, 1985). Cefodizime also displays synergistic activity with components of the host defence system (Labro et al., 1987; Labro, 1990). This report describes a study carried out to evaluate the pharmacokinetic behaviour of cefodizime after 10 and 2 0 g given as single iv doses. Materials and methods Subjects and study design The study enrolled eight healthy volunteers (four men and four women) aged 20-28 years (mean 24 ± 1) with a mean height of 1-72 ±0-03 m and a weight from 42 to 76 kg 0305-7453/90/26C065 + 06 $02.00/0

65 © 1990 The British Society for Antimicrobial Chemotherapy

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Cefodizime is a new third generation cephalosporin for parenteral use. The purpose of this study was to define the pharmacokinetic profile of cefodizime after intravenous dosing with 1-0 and 20 g in healthy adult volunteers. Concentrations in plasma were determined over a period of 34 h and in urine over 48 h, using high-pressure liquid chromatographic procedures. Cefodizime displays a long elimination half-life (3-5-3-7 h). Mean total clearance was 2-63±0-191/h and mean renal clearance was l-37±O-151/h. Areas under the curve were 422±43mg.h/l and 757±39mg.h/l for 1-0 and 2.0 g respectively. The apparent volumes of distribution were 12-8 ± 1-81 and 14-3 ±1.11. After 1-Og administration the residual concentrations were 3-94 ±0-79 mg/1 and O-38±0-10mg/l at 12 and 24 h, respectively; after 2-0 g administration the residual concentrations were 6-80 ±1-40 mg/1 and 0-65 ±0-18 mg/1, at 12 h and 24 h. Cefodizime is mainly eliminated via the kidneys. This profile supports once-daily administration of cefodizime, when indicated in non-life-threatening infections.

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(mean, 58 ± 4). Subjects participated in this study after giving informed written consent and ethics committee approval had been granted. Before starting, a history, physical examination, vital signs, and the following laboratory tests were performed: complete blood count and differential; platelet count, prothrombin time and standard biochemical tests. The results of these renal, hepatic, and haematological tests were normal. Laboratory tests were repeated at the conclusion of the study. None had a history of allergy to /Mactam antibiotics. In a cross-over design, following an overnight fast of 10 h the volunteers received a 1 or 2 g of cefodizime by iv route. There was a one week wash-out period between administrations.

Blood samples were collected in heparinized tubes before cefodizime was administered and at 10, 15, 20, 30, 40min, and 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 24, 26, 28, 30, 32, 34 h after the end of the 3-min iv infusion. These samples were centrifuged immediately and the plasma was stored at — 80°C until assayed. Total urine voided was collected at the following intervals: Oh (control), 0-4, 4-8, 8-16, 16-24, 24-32, 32-40, 40-48 h. Urine obtained during each collection interval was refrigerated at 4°C until the end of the collection interval. The total volume was recorded and a 10 ml aliquot stored at — 80°C until assay. Drug

Cefodizime (HR 221) was supplied by Roussel-Uclaf, France, as 10 g vials for clinical use, the active substance for assay being supplied as disodium salt (batch CL 20509-53). Assay method Assays were performed by high pressure liquid chromatography (HPLC) on a liquid chromatograph (model 6000A, Waters Associates) equipped with a fixed wavelength (280 nm) UV detector, and automatic sample processor (WIPS710B, Waters Associates). A stock solution of cefodizime (1-6 mg/100 ml) was prepared in double-distilled water. Appropriate dilutions in double-distilled water were added to blank plasma to give standards at concentrations ranging from 0-49 to 800mg/l. Plasma samples (1-ml) were mixed with 0-5 ml amounts of 0-5 N hydrochloric acid. The mixture was mechanically shaken for 10 sec and again after supplementation with 7-5 ml of a solution of chloroform/1-pentanol (60/20v/v). The mixture was again shaken for lOmin and further centrifuged for lOmin. The organic phase was transferred to a 10-ml glassstoppered centrifuge tube and supplemented with buffer pH 7 and shaken for lOmin. After centrifugation for 10 min, 5—100 /il of the upper aqueous phase was injected into the chromatographic system. The reverse-phase column was /xBondapack C)8 10^m (Waters Associates). A mixture of methanol and ammonium acetate was used as the mobile phase. The flow rate was l-5ml/min. The retention time of cefodizime was 70min. Cefodizime was quantified by comparing peak height for the unknown with that of a standard curve. The linearity of the method was determined for concentrations ranging from 0 to 400 mg/1 (plasma) and 0-50 mg/1 (urine). The precision of the

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Specimen collection

Phannacoldnetics of single-dose (1 g, 2 g)

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Table I. Mean plasma concentrations of cefodizime measured at various time intervals after dosing Dosage 10 giv 20giv

10 min

30 min

Mean plasma concentration (mg/l)±s.E.M. 1 h 12 h 16 h 24 h

199O±19 132± 12 339-616-7 24O-2±7-6

98± 11 173±9-8

30 h

3-94±0-79 1-53±0-33 0-38±0-10 O09±0O4 6-8±l-4 2-68±O62 0-65±0-18 0-20±0O8

Data analysis By conventional least-squares non-linear regression analysis (IGPHARM program), plasma concentration-time data after iv doses were fitted individually to triexponential equations which described the standard three-compartment open model. The area under the plasma concentration-time curve ( A U Q was calculated by the trapezoidal rule and determined from zero to infinity. Remits Mean plasma concentrations of cefodizime after iv doses of 10 and 20 g are shown in Table I. After 10 g iv the concentrations decreased from a mean initial value (10 min) of 1990±19 to 3-94±0-79mg/1 after 12h, 1-53 ±0-33 mg/1 after 16h, 0-38±010mg/1 after 24 h and 0-09 ± 0-04 mg/1 at 30 h. After 2-0 g iv the concentrations decreased from a mean initial value (lOmin) of 339-6±6-7mg/1 to 6-8±l-40 after 12h, 2-68±0-62mg/1 after 16h, 0-65 ± 0-18 mg/1 after 24 h and 0-20 ± 0-08 mg/1 at 30 h. The decline in drug levels in plasma was described by a three-compartment open model. The mean pharmacokinetic parameters are presented in Table II. The drug was eliminated with a mean elimination half-life (7^) of about 3^ h which resulted in a high

Table n. Pharmacokinetic data (mean value

-00

V^Q) C/^O/h) C/r(l/h)

(mg.h/1)

±S.E.M.)

10 g iv

2O g iv

3-48±O15 422±43 12-8 ±1-8 2-57 ±0-29 1-31 ±0-18

3-72±0-15 757±39 14-3 ±1.1 2-69 ±0-13 l-43±0O8

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method was studied by multiple assays (five to ten for each concentration) performed on plasma samples containing 200, 100, 50, 25, 3125, 0-39, 0-049 mg of cefodizime per litre. The coefficients of variation for the study were 1-2, 0-4, 3-6, 3 1 . 6 1 . 3-4, 16-9%, respectively. Urine samples were directly injected in the chromatographic system after dilution in double-distilled water. The signal for the theoretical limit of quantification calculated from the repeatability test on ten plasma samples (blanks) was significantly lower than 50 ng/ml. The assay sensitivity limit was 50 ng/ml for plasma and urine.

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Table m . Total amount of cefodizime excreted in ( U ( J J measured at various time intervals after dosing

Dosage

4h

8h

Mean U , , ^ (mg) (cumulative) 16 h 24 h

1-0 g iv 2-0 g iv

364 804

464 982

501 1053

505 1164

32 h

40 h

48 h

% Dose excreted after 48 h

507 1167

509 1167

510 1167

51±3 53-4 ±2-6

Discussion The pharmacokinetic parameters of cefodizime found in our study are in agreement with those reported by Dagrosa et al. (1987). They have shown that after 10 and 2-0 g iv the mean initial plasma values were 215 ± 3 5 mg/1 and 394±49mg/l, the AUC were 426 ± 6 5 mg.h/1 and 790 ± 142 mg.h/1, and renal and total clearances are similar to that found in our study. Our results differ in the half-life determination, owing to the low sensitivity of their HPLC method (sensitivity limit of 400 ng/ml instead of 50 ng/ml with our method). It should be noted also that sampling was carried out over a longer period of time (0-36 h compared with 0-8 h). Cefodizime is bound in serum solely to plasma albumin (72%-90%) in a saturable fashion to a limited number of sites with a weak affinity (Barre, 1990). The total elimination of cefodizime is low (34-52 ml/min), with renal clearance representing approximately 70% to 80% of the total clearance. Cefodizime belongs to the so-called long-acting cephalosporins, like ceftriaxone. In Table IV, we have reported the pharmacokinetic parameters determined and calculated for other 2-aminothiazolyl cephalosporins, such as cefotiam (Brisson et al., 1984), cefotaxime (Carmine et al., 1983), cefmenoxime (Fourtillan el al., 1984), ceftazidime (Leroy et al., 1984), cefoperazone (Fourtillan, Brisson & Becq-Giraudon, 1982), latamoxef (Fourtillan & Brisson, 1983), and ceftriaxone (Patel et al., 1981). Like ceftriaxone, cefodizime shows favourable pharmacokinetic properties such as high and prolonged blood levels, long elimination half-life and large areas under the concentration-time curves. According to in-vitro studies, the MICs for 90% of Escherichia coli, Klebsiella pneumoniae, Serratia marcescens and Haemophilus influenzae strains tested are often less than < 0-5 mg/1 (Scully, Jules & Neu, 1983). Shah (1986) has demonstrated that cefodizime is rapidly bactericidal and this activity continues for a mean period of 10 h against Esch. coli and for as long as 4 h against Enterobacter and Citrobacter spp. The bacteria require a long time to recover from the effect of the drug. Concentrations in plasma at 12 h would be adequate for the majority of serious infections caused by Gram-negative micro-organisms, with some exceptions such as those caused by Enterobacter spp. However, plasma concentrations remained above the MICX and for most Enterobacteriaceae and some Gram-positive cocci for up to 16-24 h

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AUC of 422±43mg.h/l and755±39mg.h/l for 10 and 2 0 g respectively. Systemic clearance was 2-63±O191/h and renal clearance l-37±0151/h. Nearly 5 1 % to 53% of the drug could be detected in urine within 48 h after the administration (Table III). The apparent volumes of distribution (AVD) were calculated to be 12-8 ±1-81 and 14-3±1.11 for 10 and 2 0 g , respectively. Metabolites were not detected.

ND, Not detectable.

Cefodizime Cefotaxime Cefmenoxime Cefotiam Ceftazidime Cefoperazone Latamoxef Ceftriaxone 1-0 1-0 1-0 1-0 1-0 1-0 1-0 1-0

Dose(g) 3-5 1-2 1-5 1-2 1-57 2-5 2-7 6-13

r,(h) 3-9 01 01 01 01 1-02 2-2 35-2

04 ND ND ND ND ND ND 9-3

Plasma concentrations (mg/1) 24 h 12 h AUQ^, (mg.h/1) 422 704 90 38-5 144-150 248 275 1006

C = 1 mg/1 (h) 16-24 4-6 6 . 4 10 12 12 >24

This study Carmine et al. (1983) Fourtillan et al. (1984) Brisson et al. (1984) Leroy et al. (1984) Fourtillan et al. (1982) Fourtillan & Brisson (1983) Patel et al. (1981)

References

Table IV. Comparative phannacokinetics of cefodizime and other extended spectrum cephalosponns

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after administration, supporting once or twice daily administration in non life-threatening infections. References

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Barre, J. (1990). Pbarmacokinetics of ccfodizime: a review of the data on file. Journal of Antimicrobial Chemotherapy 26, Suppl. C. 95-101. Brisson, A. M., Bryskier, A., Millerioux, L. & Fourtillan, J. B. (1984). Pharmacokinetics of cefotiam administered intravenously and intramuscularly to healthy adults. Antimicrobial Agents and Chemotherapy 26, 513-8. Carmine, A. A., Brogden, R. N., Heel, R. C, Speight, T. M. & Avery, G. S. (1983). Cefotaxime: a review of its antibacterial activity, pharmacological properties and therapeutic use. Drugs 25, 223-89. Dagrosa, E. E., Hajdu, P., Malerczyk, V., de Looze, S., Seeger, K. & Grotsch, H. (1987). Dose linearity and other pharmacokinetics of ccfodizime after single-dose intravenous administration. Clinical Therapeutics 10, 18-31. Durckheimer, W., Fischer, G. & Latrell, R. (1989). New developments in the synthesis and SAR of several series of 2-aminothiazolyl ccphalosporins. In Recent Advances in the Chemistry of P-Lactam Antibiotics (Bentley, P. H. & Southgate, R., Eds), pp. 49-76. Royal Society of Chemistry. Fourtillan, J. B. & Brisson, A. M. (1983). Pharmacocinetique comparee de moxalactam et d'autres cephalosporines. Semaine des Hopitaux de Paris 59, 1968—71. Fourtillan, J. B., Brisson, A. M. & Becq-Giraudon, B. (1982). Etude pharmacocinetique de la cefoperazone (T-1551) chez rhomme, apres administration intraveineuse de doses de 1 g et 2g. Dosages effectues par chromatographie liquide haute performance. Midecine et Maladies Infectieuses 12, Suppl., 21-6. Fourtillan, J. B., Bryskier, A., Mignot, A., Borsa, F. & Humbert, G. (1984). Pharmacokinetic study of cefmendxime (SdE 1365-CMX) in healthy adults. American Journal of Medicine 77, Suppl. 6A, 28-31. Klesel, N., Limbert, M., Seibert, G., Winkler, I. & Schrinner, E. (1984a). Cefodizime, an aminothiazolylcephalosporin. HI. Therapeutic activity against experimentally induced pneumonia in mice. Journal of Antibiotics 37, 1712-8. Klesel, N., Limbert, M., Seeger, K., Seibert, G., Winkler, I. & Schrinner, E. (19846). Cefodizime, an aminothiazolylcephalosporin. II. Comparative studies on the pharmacokinetic behavior in laboratory animals. Journal of Antibiotics 37, 901-9. Labro, M. T. (1990). Cefodizime as a biological response modifier a review of its in-vivo, exvivo, and in-vitro immunomodulatory properties. Journal of Antimicrobial Chemotherapy 26, Suppl. C, 11-41. Labro, M. T., Amit, N., Babin-Chevaye, C. & Hakim, J. (1987). Cefodizime (HR221): potentiation of human neutrophil oxygen-independent bactericidal activity. Journal of Antimicrobial Chemotherapy 19, 331-41. Le Noc, P., Bryskier, A. & Le Noc, D. (1985). Activite antibacterienne in vitro du cefodizime (HR221) sur 323 souches hospitalieres de bacilles a Gram negatif. Comparaison avec le cefotiam, la cefoperazone, le cefotetan et le cefotaxime. Pathologie et Biologie 33, 399-403. Leroy, A., Leguy, F., Borsa, F., Spencer, G. R., Fillastre, J. P. & Humbert, G. (1984). Pharmacokinetics of ceftazidime in normal and uremic subjects. Antimicrobial Agents and Chemotherapy 25, 638-42. Patel, H. I., Chen, S., Parsonnet, M., Hackman, M. R., Brooks, M. A., Konikoff, J. & Kaplan, S. A. (1981). Pharmacokinetics of ceftriaxone in humans. Antimicrobial Agents and Chemotherapy 20, 634-41. Scully, B. E., Jules, K. & Neu, H. C. (1983). In vitro activity and /I-lactamase stability of cefodizime, an aminothiazolyl iminomethoxy cephalosporin. Antimicrobial Agents and Chemotherapy 23, 907-13. Shah, P. (1986). Bactericidal activity of cefodizime under conditions simulating serum pharmacokinetic parameters. In Recent Advances in Chemotherapy (Ishigami, J., Ed.), pp. 935-6. University Tokyo Press, Tokyo.