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CARDIOVASCULAR ANESTHESIA

The Pharmacokinetics and Tolerability of an Intravenous Infusion of the New Hydroxyethyl Starch 130/0.4 (6%, 500 mL) in Mild-to-Severe Renal Impairment

Cornelius Jungheinrich, MD^*, Roland Scharpf, PhD^*, Manfred Wargenau, PhD, Frank Bepperling, PhD^*, and Jean-François Baron, MD PhD

*Clinical Research, Fresenius Kabi, Bad Homburg; M.A.R.C.O. Biostatistics Institute, Düsseldorf, Germany; and Medical Department, Fresenius Kabi France, formerly Anesthesia Department, Hôpital Pitié-Salpêtrière, Paris, France

Address correspondence and reprint requests to Cornelius Jungheinrich, MD, Clinical Research, Fresenius Kabi, 61346 Bad Homburg, Germany. Address e-mail to Cornelius.Jungheinrich@ fresenius-kabi.com.

Hydroxyethyl starches (HES) are almost exclusively excreted glomerularly, in part after hydrolysis by amylase. HES 130/0.4 (Voluven^®; Fresenius Kabi Deutschland GmbH, Bad Homburg, Germany) was developed to improve pharmacokinetics whereas preserving the efficacy of volume effect. We studied the dependency of pharmacokinetics of HES 130/0.4 on renal function. Nineteen volunteers with stable, non-anuric renal dysfunction, ranging from almost normal creatinine clearance (CL_cr) to severe renal impairment (mean CL_cr: 50.6 mL · min^-1 · 1.73 m^-2), were given a single infusion of 500 mL 6% HES 130/0.4 over 30 min. HES plasma concentrations were determined until 72 h, urinary excretion until 72–96 h. CL_cr had been obtained at least twice before and twice after dosing. Standard pharmacokinetic calculations and regression analysis were performed. Area under the time concentration curve (AUC_0–inf) clearly depended on renal function comparing subjects with CL_cr <50 with those with CL_cr 50 (ratio 1.73). Peak concentration (C_max, 4.34 mg/mL) as well as terminal half-life (16.1 h, model independent) were not affected by renal impairment. At CL_cr 30, 59% of the drug could be retrieved in urine, versus 51% at CL_cr 15–<30. The mean molecular weight of HES in plasma was 62,704 d at 30 min, showing lower values with increased renal impairment (P = 0.04). Pre-dose amylase concentrations inversely correlated with baseline CL_cr. Residual HES plasma concentrations after 24 h were small in all subjects (0.6 mg/mL). We conclude that HES 130/0.4 (500 mL 6%) can be safely administered to patients even with severe renal impairment, as long as urine flow is preserved, without plasma accumulation.

IMPLICATIONS: Dependency of the pharmacokinetics of hydroxyethyl starch 130/0.4 on renal function was studied. The area under the time concentration curve increased moderately with more severe renal dysfunction; however, small plasma concentrations were observed after 24 h. Terminal half-life and peak concentration remained unaffected by renal impairment.

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