Multiple Intravenous Dose Pharmacokinetics of Ceftriaxone in Man

Abstract

Multiple-dose pharmacokinetics of ceftriaxone were investigated following 1 g every 12 h (1GMQ12H) and 2 g every 12 h (2GMQ12H) intravenous dosage regimens. In each dosage regimen, seven successive doses were infused at a constant rate over 30 min to 12 normal subjects. Plasma and urine samples were collected after the first and last dose and assayed for ceftriaxone by HPLC. After the first and last dose, the respective mean values of maximum plasma concentrations were 145 and 168 μ g/ml for the 1GMQ12H and 255 and 280 μ g/ml for the 2GMQ12H dosage regimen. Pharmacokinetic analyses of the data indicated the following: (i) the elimination half-life (6.6 h) and fraction of dose excreted unchanged in the urine (0.37) remained constant with dose and were not affected by the subchronic administration; (ii) steady-state ceftriaxone concentrations in plasma after the last dose indicated a 20% accumulation for both dosage regimens; (iii) the plasma clearance (Cl_p) and apparent volume of distribution (V_d) increased with dose; and (iv) V_d and Cl_p also increased within a dosage regimen (first dose vs. last dose comparison) by a factor of 14% at the 1GMQ12H and 19% at the 2GMQ12H dosage regimen. Utilizing the first dose data of each dosage regimen and assuming linear pharmacokinetics, respective steady-state plasma concentrations were predicted. The predicted concentrations were higher than the observed concentrations by 10% at the 1GMQ12H and by 15% at the 2GMQ12H dosage regimen. The observed increases in V_d and Cl_p as well as the prediction errors may be explained by the concentration-dependent plasma protein binding of ceftriaxone in man. The clinical significance of the increases observed in V_d and Cl_p is probably negligible since the increase in either V_d or Cl_p was not more than 20% even after a two-fold change in the dose. Therefore, linear pharmacokinetics can be reasonably assumed for ceftriaxone under clinical situations.