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

Abstract

BackgroundThe 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.MethodsPeak 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.ResultsThe 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.ConclusionsCVVHDF 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.

Influence of Renal Replacement Modalities on Amikacin Population Pharmacokinetics in Critically Ill Patients on Continuous Renal Replacement Therapy

“…In previous studies with intensive care unit (ICU) patients undergoing CRRT, amikacin clearance varied from 0.53 to 5.34 liters/h, accounting for 40 to 89% of the total body clearance (10)(11)(12)(13)(14)(15). These studies also reported conflicting results on the correlation between drug clearance and CRRT settings (11,14).…”

“…Prefilter blood samples to determine plasma amikacin concentrations were taken at the baseline (predose), at the end of infusion (0.5 h), 30 min after the end of infusion (1 h), and 1.5, 2, 4, 8, 12, and 24 h after the start of infusion. Postfilter blood samples were taken up to 2,4,8,12, and 24 h after the start of infusion.…”

How can we ensure effective antibiotic dosing in critically ill patients receiving different types of renal replacement therapy?

“…Amikacin and gentamicin were significantly eliminated by continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodiafiltration (CVVHDF) (effluent flow rates 40-68 mL/min), with CRRT accounting for up to 80% of the total clearance (Akers et al, 2011;D'Arcy et al, 2012;Petejova et al, 2012a;Taccone et al, 2011). Both drugs had a sieving coefficient (Sc) of approximately 0.8, suggesting that they freely cross the semipermeable CRRT filter.…”

Implication of Haemodiafiltration Flow Rate on Amikacin Pharmacokinetic Parameters in Critically Ill Patients

“…Several authors have correlated the haemodiafiltration flow with both the plasma concentrations and the clarifications achieved by different types of antimicrobials [18, 22-25]. Regarding aminoglycosides, Moon et al [26], in a 6 patients’ study, concluded that the haemodiafiltration procedure could eliminate up to a 40% of the drug.…”

“…Both the dosage adjustment and the calculation of the pharmacokinetic parameters were performed by the Bayesian adjustment, using the PKS® software (Abbot Pharmacokinetics system). Pharmacokinetics parameters volume of distribution (Vd), elimination rate constant (Ke) and plasma clearance (Cl) were calculated through fitting of the concentration time data to a 1-compartment infusion model [18, 19]. …”