Dose linearity and other pharmacokinetics of cefodizime after single-dose intravenous administration

Pharmacokinetics of cefodizime, a broad-spectrum cephalosporin antibiotic, were determined after intravenous (IV) administration of single doses of 1.0, 1.5, and 2.0 gm to 12 healthy male volunteers in an open study. In a separate pilot study, data were obtained after IV administration of 0.5 gm of cefodizime to six healthy male volunteers. Determinations of cefodizime in serum and urine using a microbiological assay agreed with determinations using high-pressure liquid chromatography (HPLC), which specifically measures the unchanged drug. Active metabolites of cefodizime were not detected. After IV administration of 1.0, 1.5, and 2.0 gm of cefodizime, initial mean serum concentrations were 215, 322, and 394 mg/L, respectively (HPLC determinations). A linear response to dosage was shown (coefficient of correlation r = .89), as was the case for area under the serum concentration-time curve to infinity, AUC infinity (r = .82), and 48-hour urinary recovery of cefodizime (r = .94). In all cases, the corresponding values obtained after the 0.5-gm dose showed that the linearity extended to this dose. The kinetics of single-dose administration of cefodizime corresponded to a two-compartment open model with an apparent steady-state volume of distribution of about 40 L. Volume of distribution, terminal elimination half-life, serum and renal clearance, and percent urinary recovery were not dose dependent. Cefodizime combined a long terminal elimination half-life (mean, 2.5 hours) with a high urinary recovery (80%). After IV administration of cefodizime, urinary concentrations of the unchanged drug remained above 5 micrograms/ml for at least 24 hours after drug administration and were dose dependent. Mean values for the 1.0-gm and 2.0-gm doses were, respectively, approximately 12 mg/L and 30 mg/L, several times the minimal inhibitory concentrations (MIC90) for most clinically relevant bacteria. These results suggest that once- or twice-daily IV dosing with cefodizime (depending on the dose regimen) would be suitable for clinical use. The drug was safe and well tolerated.