Pharmacokinetics of amphotericin B lipid complex in critically ill patients undergoing continuous venovenous haemodiafiltration.

The objective of this study was to examine the effect of continuous venovenous haemodiafiltration (CVVHDF) on the pharmacokinetics of amphotericin B (AmB) in critically ill patients following administration of amphotericin B lipid complex (ABLC). Plasma and ultrafiltrate (UF) samples were collected from patients administered ABLC and either receiving or not receiving CVVHDF. Pharmacokinetic (PK) analysis was performed on eight profiles from patients receiving CVVHDF and six profiles from patients not receiving CVVHDF. For patients receiving CVVHDF, the following median PK data were calculated: area under the concentration-time curve (AUC) = 13.9 h·µg/mL, volume of distribution at steady state (V(ss)) = 1476L and drug clearance (CL) = 27.4 L/h; for patients not receiving CVVHDF, the corresponding median PK data were 11.5 h µg/mL, 2048 L and 43.7 L/h, respectively. The median half-lives calculated during the dosage interval (t(1/2int)) were 30.9 h and 32.5 h on and off CVVHDF, respectively, and the total range of t(1/2int) values was 15.6-180.4 h. Observed median peak concentrations on Day 1 were 0.563 µg/mL and 0.468 µg/mL in patients on and off CVVHDF, respectively. From AmB present in the UF, clearance via CVVHDF contributed<1% of total plasma clearance. The AmB concentration-time profiles for patients administered ABLC on and off CVVHDF were compared and no statistically significant differences in AUC, CL, t(1/2int) and V(ss) were observed. In conclusion, CVVHDF had no clinically significant effect on the pharmacokinetics of AmB following administration of ABLC.

An open prospective study of amikacin pharmacokinetics in critically ill patients during treatment with continuous venovenous haemodiafiltration.

BACKGROUND: The objectives of the current study were to determine amikacin pharmacokinetics in patients undergoing treatment with continuous venovenous haemodiafiltration (CVVHDF) in an Intensive Care Unit (ICU), and to determine whether peak and trough concentration data could be used to predict pharmacokinetic parameters. An open prospective study was undertaken, comprising five critically ill patients with sepsis requiring CVVHDF. METHODS: Peak and trough plasma concentrations and multiple serum levels in a dosage interval were measured and the latter fitted to both a one- and two-compartment model. Blood and ultrafiltrate samples were collected and assayed for amikacin to calculate the pharmacokinetic parameters; total body clearance (TBC), elimination rate constant (k) and volume of distribution (Vd). The concentration of amikacin in ultrafiltrate was used to determine the clearance via CVVHDF. CVVHDF was performed at prescribed dialysate rates of 1-2l h-1 and ultrafiltration rate of 2l h-1. Blood was pumped at 200ml/min using a Gambro blood pump and Hospal AN69HF haemofilter. Amikacin dosing was according to routine clinical practice in the Intensive Care Unit. RESULTS: The multi serum level study indicated that the one compartment model was adequate to characterize the pharmacokinetics in these patients suggesting that peak and trough plasma level data may be used to estimate individual patient pharmacokinetic parameters and to optimise individual patient dosing during treatment with CVVHDF. CVVHDF resulted in an amikacin k of 0.109+/-0.025 h, t1/2 of 6.74 +/- 1.69h, TBC of 3.39+/-0.817 h-1, and Vd of 31.4 +/- 3.27. The mean clearance due to CVVHDF of 2.86 l h-1 is similar to the creatinine clearance of 2.74 +/-0.4 lh-1. Amikacin was significantly cleared by CVVHDF, and its half life in patients on CVVHDF was approximately 2-3 times that reported in subjects without renal impairment and not undergoing haemodiafiltration for any reason. CONCLUSIONS: CVVHDF contributes significantly to total clearance of amikacin. The use of pharmacokinetic parameter estimates obtained from two steady state serum-drug concentrations (peak and trough) can be used to guide individualised dosing of critically ill patients treated with CVVHDF. This is considered a useful strategy in this patient cohort, particularly in avoiding the risk of underdosing.

An evaluation of ciprofloxacin pharmacokinetics in critically ill patients undergoing continuous veno-venous haemodiafiltration.

BACKGROUND: The study aimed to investigate the pharmacokinetics of intravenous ciprofloxacin and the adequacy of 400 mg every 12 hours in critically ill Intensive Care Unit (ICU) patients on continuous veno-venous haemodiafiltration (CVVHDF) with particular reference to the effect of achieved flow rates on drug clearance. METHODS: This was an open prospective study conducted in the intensive care unit and research unit of a university teaching hospital. The study population was seven critically ill patients with sepsis requiring CVVHDF. Blood and ultrafiltrate samples were collected and assayed for ciprofloxacin by High Performance Liquid Chromatography (HPLC) to calculate the model independent pharmacokinetic parameters; total body clearance (TBC), half-life (t1/2) and volume of distribution (Vd). CVVHDF was performed at prescribed dialysate rates of 1 or 2 L/hr and ultrafiltration rate of 2 L/hr. The blood flow rate was 200 ml/min, achieved using a Gambro blood pump and Hospal AN69HF haemofilter. RESULTS: Seventeen profiles were obtained. CVVHDF resulted in a median ciprofloxacin t1/2 of 13.8 (range 5.15-39.4) hr, median TBC of 9.90 (range 3.10-13.2) L/hr, a median Vdss of 125 (range 79.5-554) L, a CVVHDF clearance of 2.47+/-0.29 L/hr and a clearance of creatinine (Clcr) of 2.66+/-0.25 L/hr. Thus CVVHDF, at an average flow rate of ~3.5 L/hr, was responsible for removing 26% of ciprofloxacin cleared. At the dose rate of 400 mg every 12 hr, the median estimated Cpmax/MIC and AUC0-24/MIC ratios were 10.3 and 161 respectively (for a MIC of 0.5 mg/L) and exceed the proposed criteria of >10 for Cpmax/MIC and > 100 for AUC0-24/MIC. There was a suggestion towards increased ciprofloxacin clearance by CVVHDF with increasing effluent flow rate. CONCLUSIONS: Given the growing microbial resistance to ciprofloxacin our results suggest that a dose rate of 400 mg every 12 hr, may be necessary to achieve the desired pharmacokinetic-pharmacodynamic (PK-PD) goals in patients on CVVHDF, however an extended interval may be required if there is concomitant hepatic impairment. A correlation between ciprofloxacin clearance due to CVVHDF and creatinine clearance by the filter was observed (r2 = 0.76), providing a useful clinical surrogate marker for ciprofloxacin clearance within the range studied. TRIAL REGISTRATION: Current Controlled Trials ISRCTN52722850.