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Voluven

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Voluven

CLINICAL PHARMACOLOGY

Mechanism of Action

Voluven® (hydroxyethyl starch in sodium chloride injection) contains hydroxyethyl starch in a colloidal solution which expands plasma volume when administered intravenously. This effect depends on the mean molecular weight (130,000 daltons; range 110,000 - 150,000 daltons), the molar substitution by hydroxyethyl groups (0.4; range 0.38 - 0.45) on glucose units of the starch, the pattern of hydroxyethyl substitution (C2/C6 ratio) of approximately 9:1, and the concentration (6%), as well as the dosage and infusion rate.

Hydroxyethyl starch is a derivative of thin boiling waxy corn starch, which mainly consists of a glucose polymer (amylopectin) predominately composed of α-1-4-connected glucose units with several α-1-6-branches. Substitution of hydroxyethyl groups on the glucose units of the polymer reduces the normal degradation of amylopectin by α-amylase in the body. The low molar substitution (0.4) is the main pharmacological determinant for the beneficial effects of Voluven (hydroxyethyl starch in sodium chloride injection) ®on pharmacokinetics, intravascular volume and hemodilution4). To describe the molecular weight and molar substitution characteristics of the hydroxyethyl starch in Voluven® (hydroxyethyl starch in sodium chloride injection) , the compound is designated as hydroxyethyl starch 130/0.4.

Pharmacodynamics

After isovolemic exchange of blood with 500 mL of Voluven® (hydroxyethyl starch in sodium chloride injection) in healthy volunteers, blood volume is maintained for at least 6 hours.

Pharmacokinetics

The pharmacokinetic profile of hydroxyethyl starch is complex and largely dependent on its molar substitution as well as its molecular weight4). When administered intravenously, molecules smaller than the renal threshold (60,000-70,000 daltons) are readily and rapidly excreted in the urine, while molecules with higher molecular weights are metabolized by plasma α-amylase p rior to excretion via the renal route.

The mean in vivo molecular weight of Voluven® (hydroxyethyl starch in sodium chloride injection) in plasma is 70,000 - 80,000 daltons immediately following infusion and remains above the renal threshold throughout the treatment period.

Following intravenous administration of 500 mL Voluven® (hydroxyethyl starch in sodium chloride injection) to healthy volunteers, plasma levels of Voluven® (hydroxyethyl starch in sodium chloride injection) remain at 75% of peak concentration at 30 minutes post-infusion and decrease to 14% at 6 hours post-infusion. Plasma levels of Voluven® (hydroxyethyl starch in sodium chloride injection) return to baseline levels 24 hours following infusion. Plasma clearance, volume of distribution, and elimination half-life of Voluven® (hydroxyethyl starch in sodium chloride injection) in healthy volunteers following IV administration of 500 mL were 31.4 mL/min, 5.9 liters, and 12 hours, respectively. Approximately 62 % of Voluven® (hydroxyethyl starch in sodium chloride injection) was excreted as hydroxyethyl starch molecules in urine within 72 hours.

The pharmacokinetics of Voluven® (hydroxyethyl starch in sodium chloride injection) are similar following single and multiple dose administration. No significant plasma accumulation occurred after daily administration of 500 mL of a 10% solution containing hydroxyethyl starch 130/0.4 over a period of 10 days. Approximately 70% of Voluven (hydroxyethyl starch in sodium chloride injection) was excreted as hydroxyethyl starch molecules in urine within 72 hours.

Renal Impairment

Following a single intravenous administration of Voluven® (hydroxyethyl starch in sodium chloride injection) (500 mL) in subjects with varying degrees of renal dysfunction, the AUC and clearance of Voluven® (hydroxyethyl starch in sodium chloride injection) increased by 73% and decreased by 42% in patients, respectively, with creatinine clearance < 50 mL/min as compared to patients with creatinine clearance > 50 mL/min. However, terminal half-life and peak hydroxyethyl starch concentration were not affected by renal impairment. Plasma levels of Voluven® (hydroxyethyl starch in sodium chloride injection) returned to baseline levels 24 hours following infusion. Approximately 59 % and 51 % of Voluven® (hydroxyethyl starch in sodium chloride injection) were excreted as hydroxyethyl starch molecules in urine within 72 hours in patients with creatinine clearance ≥ 30 mL/min and < 30 mL/min, respectively.

There are no data available on the use of Voluven® (hydroxyethyl starch in sodium chloride injection) in patients undergoing hemodialysis.

Pharmacokinetic data in patients with hepatic insufficiency or in pediatric or geriatric patients are not available. Effects of gender or race on the pharmacokinetics of Voluven® (hydroxyethyl starch in sodium chloride injection) have not been studied.

Animal Toxicology and Pharmacology

Toxicology

Three-month repeat infusion toxicology studies were conducted in rats and dogs in which three groups of animals were administered daily intravenous infusion over three hours. Dosing volumes of either 60 or 90 mL/kg body weight of hydroxyethyl starch 130/0.4 (10% solution) or 90 mL/kg 0.9% sodium chloride injection were studied. Observed toxicity following repeat infusion of hydroxyethyl starch is consistent with the oncotic properties of the solution resulting in hypervolemia in the animals. There were no apparent gender-related effects on toxicity following repeat administration of hydroxyethyl starch 130/0.4 in rats or dogs.

In reproduction studies in rats and rabbits, hydroxyethyl starch 130/0.4 (10% solution) had no teratogenic properties. Embryolethal effects were observed in rabbits at 5 g/kg body weight/day. In rats, bolus injection of this dose during pregnancy and lactation reduced body weight of offspring and induced developmental delays. Signs of fluid overload were seen in the dams. Hydroxyethyl starch 130/0.4 (10% solution) was observed to have no effect in studies assessing skin sensitization, antigenicity, and blood compatibility.

Pharmacology

The pharmacodynamic effect of Voluven® (hydroxyethyl starch in sodium chloride injection) was examined in a hemorrhagic shock model in conscious rats and a hemodilution model in dogs. In both studies the control group received pentastarch (6% hydroxyethyl starch200/0.5).

Voluven® (hydroxyethyl starch in sodium chloride injection) was as effective as pentastarch in maintaining cardiopulmonary function during isovolemic hemodilution in beagle dogs. In the three-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 Voluven® (hydroxyethyl starch in sodium chloride injection) and pentastarch solutions following induced hemorrhagic shock (67% and 50% blood loss). In the 67% induced bleeding group receiving Voluven® (hydroxyethyl starch in sodium chloride injection) (N=6), the survival rate was 83% which is within the normal range for this type of experiment. In the corresponding pentastarch 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.

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

A study with 10% radiolabeled 14C-hydroxyethyl starch 130/0.4 and 10% 14C- hydroxyethyl starch 200/0.5 solutions was carried out6). In animals treated with hydroxyethyl starch 130/0.4, radioactivity decreased from 4.3% of the total administered dose (2.6 g hydroxyethyl starch 130/0.4 per animal) on day 3 to 0.65% on day 52. In animals treated with hydroxyethyl starch 200/0.5, the 14C-activity decreased from 7.7% of the total administered dose (2.7 g hydroxyethyl starch 200/0.5 per animal) on day 3 to 2.45% on day 52. These results confirm the faster elimination and lower persistence of hydroxyethyl starch 130/0.4 in tissue.

Clinical Studies

Voluven® (hydroxyethyl starch in sodium chloride injection) was studied in controlled clinical trials in adult and pediatric surgical patients and in patients in intensive care units. Clinical studies included patients undergoing various types of surgery (orthopedic, urologic, cardiac) and trauma intensive care for situations in which hypovolemia is treated (pre-, intra-, and postoperative) or prevented (autologous blood donation, acute normovolemic hemodilution, hypervolemic hemodilution before cardiac surgery). The safety and efficacy of Voluven® (hydroxyethyl starch in sodium chloride injection) were compared to other colloidal plasma substitutes [pentastarch (6% hydroxyethyl starch 200/0.5), hetastarch (6% hydroxyethyl starch 450/0.7), gelatin solution or human serum albumin] in studies carried out in common clinical settings of volume replacement therapy. Perioperative fluid administration of Voluven® (hydroxyethyl starch in sodium chloride injection) ranged from 500 to 4500 mL/day in surgical patients, and cumulatively, 6 to 66 L during stays in intensive care units following traumatic brain injury.

A prospective, controlled, randomized, double-blind, multi-center trial of 100 patients undergoing elective orthopedic surgery was conducted in the US evaluating Voluven® (hydroxyethyl starch in sodium chloride injection) (N=49) compared to hetastarch (6% hydroxyethyl starch in 0.9% sodium chloride injection) (N =51) for intraoperative volume replacement therapy7). The primary efficacy variable, total volume of colloid solution required for intraoperative volume replacement therapy, was equivalent for the two treatment groups. Mean volume infused was 1613 ± 778 mL for Voluven® (hydroxyethyl starch in sodium chloride injection) and 1584 ± 958.4 mL for hetastarch. The ratio Voluven® (hydroxyethyl starch in sodium chloride injection) /hetastarch was estimated as 1.024 with a 95% confidence interval (0.84, 1.25), which was included within the equivalence range of (0.55, 1.82) prespecified in the study protocol. This indicated that Voluven® (hydroxyethyl starch in sodium chloride injection) and hetastarch have similar efficacy as intraoperative volume replacement therapy in major orthopedic surgery.

A second objective of the trial was to show superiority for safety between Voluven® (hydroxyethyl starch in sodium chloride injection) and hetastarch. Four safety endpoints were prospectively defined and compared in a sequential manner (in order to preserve the type-1 error rate, i.e., observing a difference where none actually exists). Per protocol, if there was no difference found between treatment arms for the first safety endpoint (EBL), the remaining endpoints were to be considered exploratory analyses requiring additional studies for confirmation.

Overall, no significant differences in serious adverse events were noted between the two treatment arms, but three cases of serious coagulopathy occurred in the hetastarch treatment arm. All three subjects received high doses ( > 3000 mL; labeled ceiling dose = 20 mL/Kg) of the product, which are known to increase the risk of bleeding. Since EBL for the two treatment arms was not statistically different (95% confidence interval includes unity), the difference observed for Factor VIII (see table, below) must be interpreted with caution. An exploratory analysis of total erythrocyte volume transfused (8.0 mL/kg vs. 13.8 mL/kg, Voluven® (hydroxyethyl starch in sodium chloride injection) vs hetastarch, respectively) must also be viewed with caution.

Table: Safety Variables for Study HS-13-30-US

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]
 *Exploratory analyses

There was no statistically significant difference between the two treatment groups with respect to the secondary efficacy endpoints of hemodynamic stability, body temperature, hemodynamic parameters, blood pressure, central venous pressure, heart rate, fibrinogen and platelet count.

In addition to the US trial, three non-US trials were conducted with the primary objective of showing equivalency (based on mean difference rather than mean ratio as in the US study) between Voluven® (hydroxyethyl starch in sodium chloride injection) and pentastarch in maintaining or restoring hemodynamic parameters. The largest of the three trials (N=100) met the prespecified boundary (-500 mL, 500 mL), but the two smaller studies (N=52 and N=59) did not. In exploratory analyses, the effect of Voluven® (hydroxyethyl starch in sodium chloride injection) on coagulation parameters (von Willebrand factor, Factor VIII, and Ristocetin cofactor) was shown to be significantly lower than pentastarch at one or more time points (US and non-US trials). These findings are consistent with the lower molar substitution, lower average molecular weight and narrower molecular weight distribution of Voluven® (hydroxyethyl starch in sodium chloride injection) as compared to pentastarch resulting in a lower in vivo molecular weight and increased elimination from the circulation.

A safety profile of Voluven® (hydroxyethyl starch in sodium chloride injection) at least as favorable as for pentastarch was also demonstrated in studies where Voluven® (hydroxyethyl starch in sodium chloride injection) was administered at doses higher (up to 50 mL/kg or 3 g/kg) than for pentastarch (up to 33 mL/kg or 2 g/kg) in clinical settings where large or repetitive doses are administered. [see ADVERSE REACTIONS]

REFERENCES

4) Jungheinrich C, Neff T. Pharmacokinetics of hydroxyethyl starch. Clin Pharmacokinetik 2005; 44 (7): 681-699

5) Jungheinrich C, Scharpf R, Wargenau M, et al. 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. Anesth Analg 2002; 95 (3): 544 - 51

6) Leuschner J, Opitz J, Winkler A, Scharpf R, Bepperling F. Tissue storage of 14C-labeled hydroxyethyl starch (HES) 130/0.4 and HES 200/0.5 after repeated intravenous administration to rats. Drugs R D 2003; 4 (6): 331-8

7) Gandhi SD, Weiskopf RB, Jungheinrich C et al. Volume replacement therapy during major orthopedic surgery using Voluven® (hydroxyethyl starch in sodium chloride injection) (hydroxyethyl starch 130/0.4) or hetastarch. Anesthesiology 2007; 106:1120-1127

Last reviewed on RxList: 2/1/2008
This monograph has been modified to include the generic and brand name in many instances.

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