Pharmacokinetics and safety of 6 % hydroxyethyl starch 130/0.4 in healthy male volunteers of Japanese ethnicity after single infusion of 500 ml solution.

PURPOSE: This phase I study was performed in volunteers of Japanese ethnicity to compare pharmacokinetic data after infusion of 6 % hydroxyethyl starch (HES) 130/0.4 with historical data of Caucasians. METHODS: In an open-label, uncontrolled, single-center study, 12 healthy male Japanese volunteers received single intravenous infusions of 500 ml 6 % HES 130/0.4 (Voluven 6 %; Fresenius Kabi Deutschland, Bad Homburg, Germany) over 30 min. RESULTS: Plasma concentration of 6 % HES 130/0.4 was highest at end of infusion (5.53 ± 0.55 mg/ml) and decreased following a biphasic manner. Total plasma clearance and rapid and slow elimination half-lives obtained by a two-compartment model were 1.14 ± 0.16 l/h, 1.12 ± 0.26 h, and 9.98 ± 2.38 h, respectively, and the volume of distribution was 4.76 ± 0.64 l. Mean area under the concentration-time curve was 26.7 ± 3.75 mg/ml h. The total amount of HES excreted into urine was 59.4 % of the applied dose. Hemodilution was observed in all 12 subjects as indicated by a decrease of hemoglobin from 15.5 ± 0.4 g/dl at baseline to 13.8 ± 0.4 g/dl after the end of infusion. Adverse events in this study refer to changes of laboratory parameters and were assessed as not clinically relevant. CONCLUSION: Single administration of a 500 ml solution of 6 % HES 130/0.4 was confirmed to be safe and tolerable in healthy male Japanese subjects. A rapid renal excretion was observed within 24 h after drug administration, accounting for 96 % of the total amount excreted. A comparison with pharmacokinetic data derived from Caucasians did not reveal significant differences to Japanese and confirmed the good tolerability in both ethnic groups.

Volume replacement therapy during major orthopedic surgery using Voluven (hydroxyethyl starch 130/0.4) or hetastarch.

BACKGROUND: The purpose of this study was to test the equivalence of efficacy and compare the safety of the 6% hydroxyethyl starches (HES) Voluven (HES 130/0.4; Fresenius Kabi, Bad Homburg, Germany) and hetastarch (HES 670/0.75 in saline) for intravascular volume replacement therapy during major orthopedic surgery. METHODS: In a prospective, controlled, randomized, double-blind, multicenter trial of patients undergoing major orthopedic surgery, 49 patients were treated with HES 130/0.4 and 51 patients were treated with hetastarch. Infusion of colloids was guided by central venous and arterial blood pressures. The primary efficacy endpoint was the volume of colloid solution infused; the primary safety endpoints were calculated total erythrocyte loss, the nadir factor VIII activity, and the nadir von Willebrand factor concentration within 2 h of completion of surgery. RESULTS: The total volume of colloid solution required for intraoperative volume replacement did not differ between HES 130/0.4 and hetastarch (1,613+/-778 [SD] ml for HES 130/0.4 and 1,584+/-958 ml for hetastarch). The nadir factor VIII activity within 2 h of the end of surgery was lower for hetastarch than for HES 130/0.4 (P=0.0499); for those who received greater than 1,000 ml colloid, the nadir factor VIII activity and von Willebrand factor concentration within 2 h of end of surgery were lower for hetastarch than for HES 130/0.4 (P=0.0487 and P=0.008, respectively). CONCLUSION: Voluven (HES 130/0.4) and hetastarch are equally efficacious plasma volume substitutes; however, HES 130/0.4 has a lesser effect on coagulation.

Hemodilution therapy with hydroxyethyl starch solution (130/0.4) in unilateral idiopathic sudden sensorineural hearing loss: a dose-finding, double-blind, placebo-controlled, international multicenter trial with 210 patients.

OBJECTIVE: Obtain and analyze first data on hydroxyethyl starch (HES 130/0.4) as monotherapy in acute idiopathic sudden sensorineural hearing loss (ISSNHL). DESIGN: Randomized, double-blind, Phase-II, dose-finding study. SETTING: Twenty-five ENT centers in Germany, the Czech Republic, Romania, and Austria. PATIENTS: Two hundred and ten inpatients with first-time ISSNHL of at least 20 dB at two or more frequencies and 95 dB or less at all of the speech frequencies (0.5, 1.0, 2.0, 3.0, and 4.0 kHz) with respect to the other (normal) ear for up to 7 days (d). INTERVENTION: Infusion of 750 mL/d with 45 (Group H), 30 (Group M), or 15 g/d HES (Group L), or glucose 5% (Group G) acting as "placebo" control during 6 days. MAIN ENDPOINT: Gain in average auditory threshold (in dB) from baseline to Day 7. RESULTS (MEDIANS): Average hearing loss at baseline was 24 dB, and infusions started 2 days after ISSNHL onset. No relevant group difference was observed in hearing gain or adverse treatment events, including pruritus. Half of all patients recovered completely by Day 7. SECONDARY ANALYSIS: In patients who started treatment within 2 days after the onset of symptoms and who had systolic blood'pressure (RRsyst) of less than 140 mm Hg, hearing at Day 90 had improved in all 28 cases under glucose 5%; for those who started treatment later and/or had RRsyst of 140 mm Hg or more, the risk for failing to recover under placebo was 29.2% (7/24). Comparing all 118 (51.9%) of 208 patients at such risk, outcome at Day 7 was markedly better in all HES subgroups than in the G'subgroup'(nH:nM:nL:nG = 32:29:32:24, Kruskal-Wallis, p = 0.0221). CONCLUSION: All treatment groups were equivalent, including adverse treatment events. The secondary analysis showed that ISSNHL patients at risk for not improving under placebo (i.e., patients who started treatment more than 48 h after ISSNHL onset and/or with elevated RRsyst) recovered markedly better under infusions of HES 130/0.4.

Volume efficacy and reduced influence on measures of coagulation using hydroxyethyl starch 130/0.4 (6%) with an optimised in vivo molecular weight in orthopaedic surgery : a randomised, double-blind study.

BACKGROUND AND OBJECTIVE: Different types of hydroxyethyl starch (HES) affect blood coagulation differently. We studied the effects of HES 130/0.4 on coagulation in major orthopaedic surgery in relation to the pharmacological parameter in vivo molecular weight. METHODS: 52 patients were randomly allocated to either HES 130/0.4 (6%, mean molecular weight 130 kDa, molar substitution 0.4) or HES 200/0.5 (6%, control) in a double-blind fashion. Colloidal volume requirements for intra- and postoperative haemodynamic stabilisation were compared. Safety analyses of this pharmacological study included a comparison of coagulation factor tests, in vivo molecular weight, and HES plasma concentrations. RESULTS: The colloidal volumes given were similar at the end of surgery (1602 +/- 569 for HES 130/0.4 vs 1635 +/- 567mL for HES 200/0.5), 5h later (1958 +/- 467 vs 1962 +/- 398mL), and up to the first postoperative day (2035 +/- 446 vs 2000 +/- 424mL). HES in vivo molecular weight at the end of surgery was 88,707 +/- 13,938 versus 158,374 +/- 33,933Da (p < 0.001) and 5h later was 86,663 +/- 16,126 versus 136,299 +/- 26,208Da (p < 0.001). In parallel to the lower in vivo molecular weight, factor VIII and von Willebrand factor returned to almost normal in the HES 130/0.4 group up to 5h postoperatively, but not in the control group (p < 0.05). Residual HES plasma concentrations after 24h were low in the HES 130/0.4 group (1.0 mg/mL), but higher in the control group (2.6 mg/mL). CONCLUSION: HES 130/0.4 and HES 200/0.5 were found to be similar with regard to volume efficacy. Sensitive coagulation parameters returned more rapidly to normal in the HES 130/0.4 group. Lower in vivo molecular weight and more rapid excretion of HES 130/0.4 are the likely explanations for the smaller influence on coagulation in this group.

Tissue storage of 14C-labelled hydroxyethyl starch (HES) 130/0.4 and HES 200/0.5 after repeated intravenous administration to rats.

OBJECTIVE: To investigate the effect of the molar substitution of hydroxyethyl starch (HES) solutions on tissue and organ storage in rats after repeated administration. STUDY DESIGN: A controlled, multiple-dose study was performed in 48 rats. Daily bolus injections of 0.7 g/kg of 10% HES 130/0.4 or 10% HES 200/0.5 were administered on 18 consecutive days. In order to examine quantitatively the distribution and excretion of both preparations on HES tissue storage, radiolabelled HES was measured 3, 10, 24 and 52 days after the last administration. Tissue storage was expressed as percentage radioactivity of total administered HES dose in the total body, carcass, liver, kidney, spleen, lymph nodes, plasma and urine. RESULTS: 52 days after the last administration the remaining radioactivity of labelled HES 200/0.5 was nearly 4-fold higher compared with HES 130/0.4 in the total body (2.45% vs 0.65% of the total administered dose). This difference in tissue storage was statistically significant (p < or = 0.01). A comparable difference was observed for the liver and carcass. CONCLUSION: Tissue storage after repeated administration of an HES solution with a low molar substitution (0.4) was significantly lower in the total body as well as in the liver and carcass compared with an HES solution with a medium molar substitution (0.5). However, the potential clinical consequences of these present findings have not yet been determined.

Hydroxyethyl starch (HES) [130/0.4], a new HES specification: pharmacokinetics and safety after multiple infusions of 10% solution in healthy volunteers.

OBJECTIVE: To investigate the pharmacokinetics and safety of a daily infusion of 500 mL of hydroxyethyl starch (HES) [130/0.4] 10% solution on 10 consecutive days. STUDY DESIGN AND PARTICIPANTS: An open, one-way, multiple-dose study was performed in 12 healthy male volunteers. Daily infusions over 30 minutes of 500 mL of HES (130/0.4) 10% solution were performed on 10 consecutive days. Plasma and urine HES concentrations were determined repeatedly during the study until 72 hours after the last infusion. RESULTS: Maximum plasma HES concentrations, assessed with geometric means of 7.7 and 7.4 mg/mL, respectively, as well as the time courses of the plasma concentrations were similar on days 1 and 10 of treatment. Plasma HES concentrations 24 hours after the last infusion were 0.48 mg/mL (mean). Total plasma clearance was calculated as 23.7 and 21.8 mL/min on days 1 and 10, respectively. Urinary recoveries of 69% on day 1 and of 70% on day 10 were in good agreement. CONCLUSION: The results clearly demonstrated that there is no relevant accumulation in plasma after repetitive infusion of the medium-molecular weight HES (130/0.4) solution, which exhibits a high renal excretion rate over 10 days. Local as well as systemic tolerability of 10 repeated doses was good.

Influence of a long-term, high-dose volume therapy with 6% hydroxyethyl starch 130/0.4 or crystalloid solution on hemodynamics, rheology and hemostasis in patients with acute ischemic stroke. Results of a randomized, placebo-controlled, double-blind study.

BACKGROUND: This study was performed to investigate the clinical effects of a 4-day volume therapy with a newly developed, 6% hydroxyethyl starch (HES) 130/0.4 versus crystalloid solution, with particular regard to systemic and cerebral hemodynamics, rheology and safety. METHODS: In a randomized, double-blind study, 40 patients suffering from an acute ischemic stroke received either 6% HES 130/0.4 or crystalloid solution as continuous infusion over 4 days with a total dose of 6.5 liters. Efficacy parameters studied included hemodynamics (cardiac output, blood pressure, flow velocity with transcranial Doppler) and rheology (hematocrit and plasma viscosity). Safety parameters examined included laboratory, hemostaseology (including factor VIII) and an adverse event questionnaire (including pruritus). RESULTS: In both groups, a small, but not significant increase in cardiac output was observed. There were no significant changes regarding the remaining efficacy or safety parameters, except for the well-known increase in serum alpha-amylase through the infusion of HES. CONCLUSION: In our study with patients suffering from acute ischemic stroke, continuous infusion (1 ml/min) of HES 130/0.4 or crystalloid solution did not differ regarding safety or hemodynamic efficacy.

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.

UNLABELLED: 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) > or =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) > or =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 (< or =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.