Ceftriaxone pharmacokinetic properties during continuous venovenous haemofiltration using an in vitro model

Introduction

During continuous venovenous haemofiltration (CVVH), drug clearance is dependent on the extracorporeal blood flow, ultrafiltration rate, albumin binding, molecular weight and the volume of distribution of the drug [1]. Doses are adjusted assuming reduced drug clearance by the renal system and CVVH. Variation in filtration practice, including predilution, high-volume haemofiltration and filters, greatly alters the removal of drugs. Assessing the adequacy of cephalosporin dosing during CVVH is complex; underdosing or overdosing may occur. We studied the pharmacokinetics properties of ceftriaxone during CVVH using an in vitro model.

Methods

Renoflow HF1200 filters were used to model a 50 kg patient. After completion of priming, each circuit and reservoir was then prepared with a known volume of Hartmann's solution, 4.5% albumin or whole blood using the Infomed 400. The blood pump speed and exchange rate for each of the circuit was 6 ml/kg/min and 30 ml/kg/hour, respectively. Haemasol BO was used as the replacement fluid, with 70% predilution. Following paired sampling from circuit (CS) and ultrafiltrate (UF) fluid, ceftriaxone (80 mg/kg) was injected into the postfilter port (time 0). Paired samples were taken at 5-minute, 10-minute, 15-minute, 30-minute, 60-minute, 90-minute, 120-minute, 240-minute, 480-minute, and 720-minute intervals. Ceftraxione concentrations were determined using HPLC.

Results

The maximum circuit concentration at 2 minutes for albumin, blood and Hartmann's solution was 4.8 ng/ml, 5.5 ng/ml and 3.6 mg/ml, respectively. The sieving coefficient (ratio of mean concentrations in the UF/CS) for albumin, blood and Hartmann's solution was 0.7 mg/ml, 0.96 mg/ml and 0.84 mg/ml, respectively. The mean residence time (average amount of time a molecule of the drug remains in the CS) and the half-life (calculated from the mean residence time) were 35 minutes and 24 minutes, respectively, for the blood circuit.

Conclusion

Estimates of a high sieving coefficient and short circuit half-life from this in vitro model suggest ceftriaxone is rapidly cleared during CVVH (almost entirely cleared by 240 min). This has important implications for dosing schedules during in vivo haemofiltration. Overall the albumin circuit had the lowest sieving coefficient and longest terminal half-life, reflecting protein binding of drug and suggesting ceftriaxone clearance may increase in hypoalbuminaemic patients. The maximum circuit concentration was lower in circuits primed with Hartmann's solution. This may reflect precipitation of the drug with calcium in this solution.