Voluven - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology
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Voluven - Scientific Information

Manufacture: Fresenius Kabi USA, LLC
Country: Canada
Condition: Low Blood Sugar (Hypoglycemia)
Class: Plasma expanders
Form: Liquid solution, Intravenous (IV)
Ingredients: Poly (O-2-hydroxyethyl) starch, sodium chloride, sodium hydroxide, hydrochloric acid, water for injection, Na +, Cl-

Pharmaceutical Information

Drug Substance

Description of Drug Substance Hydroxyethyl starch is a derivative of amylopectin, which is a highly branched compound of starch. In humans and animals amylopectin is rapidly hydrolyzed by amylase. In order to reduce the metabolic degradation, glucose residues of the amylopectin are reacted with ethylene oxide. The hydroxyethyl groups can be introduced at three positions (C2,C3,C6) of the glucose residues. The degree of substitution and the substitution pattern, expressed by the C2/C6 ratio, determine the enzymatic degradation of HES. HES 130/0.4 contained in Voluven is characterized by its molar substitution, molecular weight and the C2/C6 ratio.
Proper or common name Hydroxyethyl Starch (HES) (130/0.4)
Chemical name Poly (O-2 hydroxyethyl) starch
Structural formula



Molecular weight (Mw) The molecular weight indicates the weight average. The Mw of HES 130/0.4 lies between 110,000 and 150,000 Dalton, which corresponds approximately to 609 to 830 partially hydroxyethylated glucose units.
Molar substitution (MS) The ratio of hydroxyethyl groups to glucose units is called the molar substitution (MS). The MS for this substance is 0.4 (0.38 - 0.45), tetrastarch, and determines the molar ratio of hydroxyethyl ether groups to glucose units.
C2/C6 ratio This parameter gives information about the preferred position of hydroxyethylation and reflects the different intrinsic reactivity of the secondary and the primary alcohol functionality at the respective positions of the glucose ring. The value of the C2/C6 ratio should be higher than 8 for HES 130/0.4.
Product Characteristics Hydroxyethyl starch (6% HES 130/0.4, a tetrastarch) in isotonic sodium chloride solution is colorless and clear.

Clinical Trials

A prospective, controlled, randomised, double-blind, multi-center trial of 100 patients was conducted that evaluated Voluven (6% hydroxyethyl starch 130/0.4), compared to US approved 6% hetastarch 450/0.7 containing 0.9% saline, for intraoperative volume substitution during major orthopedic surgery. The primary efficacy parameter was the total volume of colloidal solution required.

The primary efficacy variable total volume of colloid solution required for intraoperative volume substitution was equivalent for the two treatment groups. Mean volume was 1613 ± 778 mL for Voluven and 1584 ± 958.4 mL for hetastarch. The ratio Voluven/hetastarch was estimated as 1.024 with a 95% confidence interval [0.84;1.25].

The results for the four primary safety variables are shown in the following table:

Variable Mean Ratio Voluven/Hetastarch
Voluven
N=49
Hetastarch
N=51
Estimate 95% Cl
Calculated red
blood cell loss [L]
1.17 1.31 0.910 [0.720;1.141]
Factor VIII [%] 100.5 81.4 1.244 [1.000;1.563]
von Willebrand
factor [%]
97.7 88.7 1.128 [0.991;1.285]
Fresh frozen plasma
(mL)
72 144 0.723 [0.000;2.437]

A significant difference between treatment groups in fluid input was found for the sum of erythrocyte volumes from packed RBC + salvaged blood + other blood in mL/kg body weight (8.0 mL/kg vs. 13.8 mL/kg).

There were no significant differences noted between the two groups in serious adverse events. Three cases of serious coagulopathies occurred in the hetastarch group only. However, all three cases had also received high doses (>3000 mL) which are known to increase the risk for effects of the drug on the coagulation system.

With respect to the secondary efficacy endpoints of hemodynamic stability, body temperature, hemodynamic parameters, BP, central venous pressure, heart rate, fibrinogen and platelets there was no statistically significant difference between the two treatment groups.

Detailed Pharmacology

The pharmacodynamic effect of 6% HES 130/0.4 was examined in a shock model in conscious rats and an exchange model in dogs. In both studies the control group received 6% HES 200/0.5 (pentastarch).

Six percent HES 130/0.4 solution was as effective as 6% HES 200/0.5 solution in maintaining cardio-pulmonary functions during isovolemic hemodilution in Beagle dogs. In the 3-hour follow-up period no additional administration of colloid was necessary.

There were no differences in long-term survival of rats after a single administration of 6% HES 130/0.4 and 6% HES 200/0.5 solution following an induced hemorrhagic shock (67% and 50% blood loss). In the 6% HES 130/0.4 group bled at 67%, the survival rate was 83% since one animal died. However, non-survival of one animal lies within the normal range for this type of experiment. In the corresponding 6% HES 200/0.5 group survival was 100%. Infusion of Ringer's lactate resulted in a 50% survival rate after a 50% blood loss and a 0% survival after a 67% blood loss. In conclusion, 6% HES 130/0.4 had a life saving effect equivalent to 6% HES 200/0.5 in this rat model.

After multiple I.V. administration of 0.7 g per kg BW per day of 10% HES 130/0.4 or 10% HES 200/0.5 solution during 18 consecutive days, the plasma HES concentration in rats treated with 10% HES 130/0.4 was lower compared to rats treated with 10% HES 200/0.5. Ten percent HES 130/0.4 was eliminated faster than 10% HES 200/0.5. In both groups, clear signs of HES tissue storage were detected in lymph nodes and spleen. Numerous empty vacuoles in macrophages were observed. Only a minimal cellular vacuolization was found in the liver and kidney. Histochemical differences between the groups were not observed.

Therefore, a study with radiolabelled 10% 14C-HES 130/0.4 and 10% 14C-HES 200/0.5 solution was carried out. In animals treated with HES 130 radioactivity decreased from 4.3% of the total administered dose (2.6 g HES 130/animal) on day 3 to 0.6% on day 52. In animals treated with HES 200/0.5 the 14C-activity decreased from 7.7% of the total administered dose (2.7 g HES 200/animal) on day 3 to 2.45% on day 52. These results confirm the faster elimination and lower persistence of HES 130/0.4 in tissue.

Microbiology

Not applicable.

Toxicology

Repeated-Dose Toxicity

The intravenous infusion of 90 mL of 10% HES 130/0.4 per kg BW/day infused over 3 hours each day in rats and dogs for 3 months resulted in no signs of overt toxicity, except for an increased workload on the kidney and the liver, uptake and metabolism of hydroxyethyl starch in the reticulo-endothelial system, hepatic parenchyma, and other tissues associated with the animals ́ unphysiological state during the test period.

Reproductive Toxicity

HES 130/0.4 had no teratogenic properties in rats or rabbits. Embryolethal effects were observed in rabbits at 50 mL/kg BW/day of 10% HES 130/0.4. In rats, bolus injection of this dose during pregnancy and lactation reduced body weight of offspring and induced developmental delays. However, embryo-fetotoxicity in rats and rabbits was only observed at maternal-toxic dose levels. Signs of fluid overloading were seen in the dams. Fertility studies on directly exposed animals have not been conducted.

Mutagenicity study

No mutagenic effects were observed with HES 130/0.4 10% solution according to the following tests on mutagenic activity: Salmonella typhimuriumreverse mutation assay (in vitro), mammalian cells in the in vitro gene mutation assay (HPRT), assessment of the clastogenic activity in cultured human peripheral lymphocytes (in vitro), bone marrow cytogenetic test in Sprague-Dawley rats.

Sensitization study

In a skin sensitization study, 30 male Dunkin-Hartley guinea pigs were treated intracutaneously and topically with undiluted HES 130/0.4 10% to examine the local irritation. Animals of the control group were treated with isotonic NaCl solution (negative control). The positive control group was treated with potassium dichromate.

No skin irritation after application of HES 130/0.4 10% solution was observed. HES 130/0.4 10% has no sensitizing properties.

Non-antigenicity study

A study in 5 female Dunkin-Hartley guinea pigs was done to demonstrate non-antigenicity of HES 130/0.4 10% in sensitized guinea pigs. After the 48-day sensitization period the animals received 3 mL of HES 130/0.4 10% intravenously.

No sensitizing properties of HES 130/0.4 10% were observed in this animal model.

Blood compatibility study

A study to examine the hemolytic properties of HES 130/0.4 10% solution on human red blood cells was performed. Undiluted HES 130/0.4 10% solution was shown to have no hemolytic effect on human red blood cells.

In an in vitro study, Voluven and 6% HES 130/0.4 in an isotonic electrolyte solution did not cause hemolysis in human whole blood.

Local tolerance

In a local tolerance study in 12 Himalayan rabbits (6 males and 6 females) were administered a single intravenous infusion (300 mL 10% HES 130/0.4 / 3 hours / animal), intra-arterially (300 mL 10% HES 130/0.4 / 3 hours / animal), paravenously (0.5 mL 10% HES 130/0.4 / animal), and subcutaneously (1 mL 10% HES 130/0.4 / animal). Isotonic saline (NaCl 0.9%) served as a negative control.

Under these test conditions 10% HES 130/0.4 showed good local tolerance in rabbits after intravenous infusion at a dose level that corresponded to 4-5 fold the level used in man. Microscopic investigations did not show any substance-related local changes.

In a further local tolerance test in New Zealand White rabbits, Voluven and 6% HES 130/0.4 in an isotonic electrolyte solution were administered in intended intravenous administration site as well as in unintended injection sites (intraarterial, paravenous, subcutaneous and intramuscular). Both Voluven and 6% HES 130/0.4 in an isotonic electrolyte solution showed good local tolerance in rabbits after intravenous infusion and also indicating no difference between both HES solutions.