Volume 5 Supplement 1
Pharmacokinetics and tolerability of intravenous infusion of the new hydroxyethyl starch 130/0.4 (6%) in 19 subjects with mild to severe renal impairment: terminal half life and peak concentration (Cmax)remain unaffected
© The Author(s) 2001
Received: 15 January 2001
Published: 2 March 2001
Hydroxyethyl starches are almost exclusively excreted renally, for the larger molecules only after hydrolysis by amylase to smaller fragments which can be filtered glomerularly. A new specification, HES 130/0.4 (Voluven®), was developed in order to improve pharmacokinetics by more rapid metabolism while preserving efficacy of volume effect compared to HES 200/0.5 (6%). In this study, the dependency of pharmacokinetics of HES 130/0.4 on renal function was studied according to GCP after fully informed consent.
Patients and methods
Prospectively 19 volunteers (m, f) with different degrees of stable, non-anuric renal dysfunction, ranging from almost normal creatinine clearance CLcr (80 to < 120), mild (50 to < 80), moderate (30 to < 50), to severe (15 to < 30) renal impairment (mean: 50.6 ml/min/1.73 m2), were given a single infusion of 500 ml 6% HES 130/0.4 over 30 min. HES serum levels were measured at 0, 5, 10, 30, 60, 120, 240, 360, 480 min, 24 h, 48 h, and 72 h after start of infusion as well as urinary excretion until 72–96 h. CLcr using urine collections had been obtained at least twice before and twice after dosing. Standard pharmacokinetic calculations and regression analysis were performed (primary parameters: area under the curve AUC0-inf, Cmax).
AUC0-inf clearly depended on renal function comparing subjects with CLcr below to ≥ 50 (ratio 1.73; 95% confidence interval: 1.44, 2.07). This means that a more than doubled AUC could be excluded. Half-life for drug elimination from the central (= blood) compartment in a two-compartment model increased from 2.6 h at CLcr ≥ 50 to 4.9 h in subjects with CLcr < 50. Cmax (mean: 4.34 mg/ml) as well as terminal half-life from the model independent approach (mean: 16.1, range 14.1–18.9 h) were not affected by renal impairment. At CLcr ≥ 30, 59% of the drug could be retreived in urine, vs 51% at CLcr 15 to < 30. The mean molecular weight of HES in serum was 62,704 D at 30 min, with a tendency to lower values with increased renal impairment. Also, higher pre-dose amylase levels correlated with lower baseline CLcr. No serious AE or deterioration in CLcr occurred.
500 ml of HES 130/0.4 (6%) can be safely administered to patients even with severe renal impairment as long as urine flow is preserved. Pharmacokinetics of HES 130/0.4 (6%) in subjects with moderate to severe renal impairment (CLcr 15 to < 50 ml/min/1.73 m2) resembles that of HES 200/0.5 (6%) in healthy volunteers.