"The U.S. Food and Drug Administration today approved a new use for Jakafi (ruxolitinib) to treat patients with polycythemia vera, a chronic type of bone marrow disease. Jakafi is the first drug approved by the FDA for this condition.
Mechanism Of Action
Voluven® 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) predominantly 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® on pharmacokinetics, intravascular volume and hemodilution4. To describe the molecular weight and molar substitution characteristics of the hydroxyethyl starch in Voluven®, the compound is designated as hydroxyethyl starch 130/0.4.
After isovolemic exchange of blood with 500 mL of Voluven® in healthy volunteers, blood volume is maintained for at least 6 hours.
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 prior to excretion via the renal route.
The mean in vivo molecular weight of Voluven® 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® to healthy volunteers, plasma levels of Voluven® remain at 75% of peak concentration at 30 minutes post-infusion and decrease to 14% at 6 hours post-infusion. Plasma levels of Voluven® return to baseline levels 24 hours following infusion. Plasma clearance, volume of distribution, and elimination half-life of Voluven® 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® was excreted as hydroxyethyl starch molecules in urine within 72 hours.
The pharmacokinetics of Voluven® 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® was excreted as hydroxyethyl starch molecules in urine within 72 hours.
Following a single intravenous administration of Voluven® (500 mL) in subjects with varying degrees of renal dysfunction, the AUC and clearance of Voluven® increased by 73% and decreased by 42% in subjects, respectively, with creatinine clearance <50 mL/min as compared to subjects 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® returned to baseline levels 24 hours following infusion. Approximately 59 % and 51 % of Voluven® were excreted as hydroxyethyl starch molecules in urine within 72 hours in subjects with creatinine clearance ≥30 mL/min and <30 mL/min, respectively5.
There are no data available on the use of Voluven® in subjects 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® have not been studied.
Animal Pharmacology And/Or 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 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) had no effect in studies assessing skin sensitization, antigenicity, and blood compatibility.
The pharmacodynamic effect of Voluven® 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 starch 200/0.5).
Voluven® 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® and pentastarch solutions following induced hemorrhagic shock (67% and 50% blood loss). In the 67% induced bleeding group receiving Voluven® (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.
Voluven® was studied in controlled clinical trials among adult and pediatric subjects undergoing various types of surgery (orthopedic, urologic, cardiac) in which hypovolemia is treated (pre-, intra-, and postoperative) or prevented (autologous blood donation, acute normovolemic hemodilution, hypervolemic hemodilution before cardiac surgery). Adult subjects in intensive care units also were studied. The safety and efficacy of Voluven® 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]. Perioperative fluid administration of Voluven® ranged from 500 to 4500 mL/day in surgical subjects, and cumulatively, from 6 to 66 L in intensive care subjects following traumatic brain injury.
Orthopedic Surgery Trial
A prospective, controlled, randomized, double-blind, multi-center trial of 100 subjects undergoing elective orthopedic surgery was conducted in the US evaluating Voluven® (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® 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), which was included within the equivalence range of (0.55, 1.82) prespecified in the study protocol. This indicated that Voluven® 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® 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. [see ADVERSE REACTIONS in Clinical Trials]
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® 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® 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® as compared to pentastarch resulting in a lower in vivo molecular weight and increased elimination from the circulation.
Severe Sepsis Trial
A randomized, double-blind, multicenter study of subjects with severe sepsis ≥ 18 years old compared Voluven® (n=100) vs. normal saline (n=96) infused over a maximum of 4 days for the treatment of hypovolemia9. The primary endpoint was volume of study drug (mL) required to achieve initial hemodynamic stabilization (HDS), defined as MAP ≥ 65 mmHg, CVP 8-12 mmHg, urine output ≥ 2 mL/kg over 4 h, and central venous oxygen saturation ≥ 70% maintained for four hours with no increase in the infusion rate of vasopressors or inotropic support and ≤ 1 L of additional study drug administration. Safety parameters included the incidence of acute renal failure, prospectively defined as need for renal replacement therapy (RRT) or doubling of baseline serum creatinine at some point during the 90-day observation period. AKIN and RIFLE criteria also were evaluated.
Baseline characteristics for the two treatment arms were 24.0% vs. 18.8% for intra-abdominal sepsis, 53.0% vs. 60.4% for pulmonary sepsis, and 8.0% vs. 14.6% for urogenital sepsis, Voluven® vs. normal saline, respectively.
Subjects achieving HDS (N=88 vs. 86) required less Voluven® compared to control: 1379 mL ± 886 (Voluven®) vs. 1709 ± 1164 mL (normal saline), representing a mean difference of 331 mL (95% confidence interval: -640 mL to -21 mL). Less time was needed from start of study drug to achievement of HDS in the Voluven® group compared to the normal saline group (11.8 hours ± 10.1 hours vs. 14.3 hours ± 11.1 hours; mean ± SD).
A post hoc sensitivity analysis was performed to determine the number of subjects not achieving HDS as a result of a change made to the protocol definition of HDS after enrollment had commenced, i.e., from requiring all four hemodynamic criteria to requiring normalization of MAP and two of the three remaining hemodynamic criteria. Approach 1 used the original definition of HDS for subjects enrolled prior to the protocol change and the revised definition of HDS for subjects enrolled subsequently; Approach 2 used the revised definition of HDS for all enrolled subjects. More Voluven® subjects than control subjects were declared to have achieved HDS, although not all the requirements for HDS had been fulfilled (see Table 2).
Table 2: Post Hoc Sensitivity Analysis
|Number of subjects without declaration of HDS||12
|Number of subjects without declaration of HDS plus
number of subjects with HDS declared by Approach 1
|Number of subjects without declaration of HDS plus
number of subjects with HDS declared by Approach 2
The number of treatment emergent serious adverse events (SAEs) and number of treatment emergent SAEs leading to death in the Voluven® and normal saline treatment arms during the 90-day observation period were 53 vs. 44 and 38 vs. 32, respectively.
Acute kidney injury scores (AKIN and RIFLE classifications) were comparable between groups (see Table 3, below). The number of subjects undergoing RRT was 21 vs. 11 for the 90-day observation period and 17 vs. 8 for the first 7 days of treatment. Mean duration of RRT was 9.1 days in the Voluven® arm vs. 4.3 days in the normal saline arm.
Kaplan-Meier curves for time to RRT (Figure 1, below) showed a trend against Voluven® (p=0.06, logrank test) [see ADVERSE REACTIONS].
Table 3: Evaluation of Subjects According to the AKIN Classification
|Worst AKIN Stage||m||n (%)||m||n (%)|
|None||100||52 (52.0)||96||52 (54.2)|
|AKIN Stage 1||100||21 (21.0)||96||21 (21.9)|
|AKIN Stage 2||100||5 (5.0)||96||6 (6.3)|
|AKIN Stage 3||100||22 (22.0)||96||17 (17.7)|
|p-value of test for trend||0.5857|
AKIN classification was based on serum creatinine values and renal replacement therapy. Urine output criteria were ignored. Percentages are based on the number of evaluable subjects (m), i.e., the number of subjects for whom an AKIN score could be determined.
Figure 1: Kaplan-Meier Curves for time to RRT
In a randomized, controlled trial among a heterogeneous adult ICU population (N=7000) that included subjects with sepsis as well as trauma subjects and postoperative elective surgery subjects, Voluven® was compared against 0.9% NaCl for volume replacement therapy10. The primary endpoint was death within 90 days. Secondary endpoints included renal risk (RIFLE-R), injury (RIFLE-I) and failure (RIFLE-F) until day 7 of product exposure, and use of RRT within 90 days. Mortality was not significantly different overall [597 of 3315 (18%) Voluven® subjects vs. 566 of 3336 (17%) control subjects; p=0.26] or in six pre-defined subgroups including patients with sepsis. RIFLE-R occurred in 54% (Voluven®) and 57.3% (0.9% NaCl, p=0.007), RIFLE-I occurred in 34.6% and 38.0% of subjects (p=0.005) and RIFLE-F occurred in 10.4% and 9.2% of subjects (p=0.12), respectively. RRT was used in 235 (7.0%) Voluven® subjects compared to 196 (5.8%) normal saline subjects (relative risk, 1.21; 95% CI, 1.00 to 1.45; p=0.04; p=0.05 after adjustment for baseline). No loss of renal function or end stage renal disease (RIFLE-L and RIFLE-E) was reported. [see ADVERSE REACTIONS in Clinical Trials]
In another RCT performed in 804 severe sepsis patients using a different HES type, HES 130/0.42 in Ringer’s acetate injection (not approved in the U.S.), mortality rate in patients with severe sepsis treated with HES 130/0.42 was higher (relative risk, 1.17; 95% CI, 1.01 to 1.36; p=0.03), and the frequency of patients who received RRT was also higher (relative risk, 1.35; 95% CI, 1.01 to 1.80; p=0.04) compared to those who received modified acetated Ringer’s solution8. [see ADVERSE REACTIONS in Clinical Trials]
Last reviewed on RxList: 7/13/2016
This monograph has been modified to include the generic and brand name in many instances.
Additional Voluven Information
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