Pharmacokinetics of Subcutaneous and Intravenous Ceftriaxone in an Older Population: The PhASAge Study

Abstract

Background: Ceftriaxone is frequently administered subcutaneously in France, especially in older patients, although this practice is currently off-label. This work aims to describe the pharmacokinetics (PK) and pharmacodynamics (PD) and tolerance of ceftriaxone administered by intravenous and subcutaneous routes in older patients.

Methods: Patients aged ≥65 years receiving intravenous or subcutaneous ceftriaxone 1 g every 24 hours were included. Steady-state plasma concentrations of ceftriaxone were measured. Based on intravenous and subcutaneous ceftriaxone concentrations and 24-hour area under the concentration-time curve (AUC), a population PK model was developed for probability of target attainment (PTA) analysis. Local and systemic adverse events (AEs) were collected.

Results: Data from 47 patients (24 in subcutaneous and 23 in intravenous groups) were analyzed. No between-group difference was observed in demographic and biological characteristics, ceftriaxone trough concentrations, or AUC. Bioavailability of subcutaneous ceftriaxone was estimated at 99% by population modeling. The PTA associated with subcutaneous administration were similar to or slightly better than that of the intravenous route. A dosing regimen of 1 or 2 g every 24 hours was associated with acceptable PTA and a low risk of overexposure in patients with normal or moderately altered renal function. Tolerance was assessed on 149 infusions (67 intravenous and 82 subcutaneous). One local AE (1.5%) was reported in the intravenous group versus 11 local AEs (mainly edema) in the subcutaneous group (13%), all transient and nonsevere.

Conclusions: Subcutaneous administration of ceftriaxone was associated with PK/PD and dosage requirements comparable to those of intravenous administration, supporting the use of subcutaneous ceftriaxone in older patients.

Keywords: ceftriaxone; older adults; pharmacokinetics; subcutaneous; tolerance.

Figure 1.

Pharmacokinetic profile (left panel) and area under the concentration-time curve (AUC) (right panel) for ceftriaxone (1 g), administered intravenously or subcutaneously. Left, Intravenous (purple) and subcutaneous (green) data are presented with means (points) and standard deviations (error bars). The concentrations at 24 hours are the trough concentrations measured just before administration of the next infusion. Right, Box plots show the median (bold horizontal lines) and interquartile range (horizontal edges of rectangles) of the ceftriaxone daily AUC for intravenous (purple) and subcutaneous (green) administration; dots represent outlier values.

Figure 2.

Probability of nontoxic trough concentration for fixed renal function values. Renal function was estimated using the Cockcroft-Gault formula, and probabilities are presented for intravenous (purple) and subcutaneous (green) routes. The tested dosing regimens were 1 g every 24 hours (squares), 2 g every 24 hours (circles), 1 g every 12 hours (triangles), and 2 g every 12 hours (diamonds).