Pharmacokinetics of Hydroxyethyl Starch

Abstract

Hydroxyethyl starch has recently become the subject of renewed interest because of the introduction of a new specification, hydroxyethyl starch 130/0.4, as well as the clinical availability of a solution using a previous hydroxyethyl starch type (hydroxyethyl starch 670/0.75) with a carrier other than 0.9% saline. Various types of hydroxyethyl starch show different pharmacokinetic behaviour. Since hydroxyethyl starch is a polydisperse solution acting as a colloid, pharmacodynamic action depends on the number of oncotically active molecules, not on the plasma concentration alone; therefore, solutions with a lower in vivo molecular weight contain more molecules at similar plasma concentrations. On the other hand, high plasma concentrations as well as high in vivo molecular weight can affect blood coagulation, especially factor VIII and von Willebrand factor. Hydroxyethyl starch types with a molar substitution >0.4 accumulate in plasma after repetitive administration, most pronounced with hetastarch (hydroxyethyl starch 670/0.75). Correspondingly, tissue storage as measured by (14)C tracer studies in animals showed significantly higher values for hydroxyethyl starch 200/0.5 compared with hydroxyethyl starch 130/0.4 (about 4-fold at the latest timepoint after the last administration), and considerably higher values for hetastarch compared with both hydroxyethyl starch 130/0.4 and 200/0.5. Hydroxyethyl starch 130/0.4 does not accumulate in plasma after single- and multiple-dose administration in contrast to all other available hydroxyethyl starch specifications. Plasma clearance of hydroxyethyl starch 130/0.4 is at least 20-fold higher than that for hetastarch, and considerably higher than for pentastarch. In patients with renal insufficiency, pharmacokinetic data are only available for hydroxyethyl starch 130/0.4. Cumulative urinary excretion, even in the presence of severe non-anuric renal failure, is higher for hydroxyethyl starch 130/0.4 than values published for older hydroxyethyl starch specifications. Hydroxyethyl starch 130/0.4 may be given to patients with severe renal impairment as long as urine flow is preserved. The pharmacodynamics with respect to the volume effect does not directly mirror pharmacokinetics in the case of hydroxyethyl starch solutions. Equivalent volume efficacy has been proven for hydroxyethyl starch 130/0.4 compared with 200/0.5. Prolonged persistence of hydroxyethyl starch in plasma and tissues can be avoided by using rapidly metabolisable hydroxyethyl starch types with molar substitution <0.5. Influence on coagulation is minimal with hydroxyethyl starch 130/0.4, and no adverse effects on kidney function have been observed even with large repetitive doses when used according to the product information.

Cardiovascular, Colloid Osmotic Pressure, and Hemostatic Effects of 2 Formulations of Hydroxyethyl Starch in Healthy Horses

“…According to the package insert, at least 80% of the HES polymers in a bag of 6% HS are within a MW range of 20–2,600 kD 24. The smaller MW molecules are excreted rapidly (the renal threshold for excretion is 60 kD or less) whereas the medium size molecules are broken down by α‐amylase and excreted over a 12–24 hour period after a bolus, the larger molecular weight molecules can remain in circulation or bound in body tissues for days after the initial bolus 17. The lower MW TS has an average MW of 130 kD and a range from 110 to 150 kD,25 and has a clearance that is 26‐ to 31‐fold faster than HS,17 with a terminal half‐life after a single bolus of about 12 hours.…”

“…The smaller MW molecules are excreted rapidly (the renal threshold for excretion is 60 kD or less) whereas the medium size molecules are broken down by α‐amylase and excreted over a 12–24 hour period after a bolus, the larger molecular weight molecules can remain in circulation or bound in body tissues for days after the initial bolus 17. The lower MW TS has an average MW of 130 kD and a range from 110 to 150 kD,25 and has a clearance that is 26‐ to 31‐fold faster than HS,17 with a terminal half‐life after a single bolus of about 12 hours. The persistence of the prolonged CT for up to 24 hours might also have been seen because the larger HES molecules are more likely to impair platelet function 20.…”

“…It is possible that accumulation of HES might occur when administered as a constant rate infusion resulting in more pronounced adverse effects. Based on the pharmacokinetics from human studies, it might be expected that constant rate infusion of the TS product would result in less long‐term accumulation than HS 17. Third, this study focused on the potential adverse effects of HES solutions on coagulation and primarily on platelet function with minimal assessment of secondary coagulation.…”

“…Plasma clearance is higher with lower molecular weight and lower molar substitution formulations. While this property decreases the risk for tissue accumulation, it also shortens the duration of effect 17. Formulations with increased molecular weight and higher molar substitution ratios are more likely to interfere with coagulation 4, 18, 19, 20…”

Post‐operative volume therapy in cardiac surgery: effects on hemostatic and circulatory variables

“…Because of this, the repeated administration of HES was regarded as contraindicated in patients with renal or liver failure. The prolonged persistence of HES in plasma and tissues can be avoided by use of rapidly degradable HES solutions with degree of substitution <0.5 (tetrastarches) (Jungheinrich and Neff 2005). Waitzinger and coworkers (2003) showed that even the use of repeated doses of HES 130/0.4 caused no accumulation in the plasma of human volunteers.…”