"Sabahaddin Akman, owner of the Istanbul, Turkey, firm Ozay Pharmaceuticals, has pleaded guilty to charges of smuggling misbranded and adulterated cancer treatment drugs into the United States.
Akman pleaded guilty in the U.S. District Court"...
The primary hematopoietic activity of Neumega (oprelvekin) is stimulation of megakaryocytopoiesis and thrombopoiesis. Neumega (oprelvekin) has shown potent thrombopoietic activity in animal models of compromised hematopoiesis, including moderately to severely myelosuppressed mice and nonhuman primates. In these models, Neumega (oprelvekin) improved platelet nadirs and accelerated platelet recoveries compared to controls.
Preclinical trials have shown that mature megakaryocytes which develop during in vivo treatment with Neumega (oprelvekin) are ultrastructurally normal. Platelets produced in response to Neumega (oprelvekin) were morphologically and functionally normal and possessed a normal life span.
IL-11 has also been shown to have non-hematopoietic activities in animals including the regulation of intestinal epithelium growth (enhanced healing of gastrointestinal lesions), the inhibition of adipogenesis, the induction of acute phase protein synthesis, inhibition of proinflammatory cytokine production by macrophages, and the stimulation of osteoclastogenesis and neurogenesis. Non-hematopoietic pathologic changes observed in animals include fibrosis of tendons and joint capsules, periosteal thickening, papilledema, and embryotoxicity (see PRECAUTIONS, Pediatric Use and PRECAUTIONS, Pregnancy Category C).
IL-11 is produced by bone marrow stromal cells and is part of the cytokine family that shares the gp130 signal transducer. Primary osteoblasts and mature osteoclasts express mRNAs for both IL- 11 receptor (IL-11R alpha) and gp130. Both bone-forming and bone-resorbing cells are potential targets of IL-11. (1)
The pharmacokinetics of Neumega (oprelvekin) have been evaluated in studies of healthy, adult subjects and cancer patients receiving chemotherapy. In a study in which a single 50 µg/kg subcutaneous dose was administered to eighteen healthy men, the peak serum concentration (Cmax) of 17.4 ± 5.4 ng/mL (mean ± S.D.) was reached at 3.2 ± 2.4 hrs (Tmax) following dosing. The terminal half-life was 6.9 ± 1.7 hrs. In a second study in which single 75 µg/kg subcutaneous and intravenous doses were administered to twenty-four healthy subjects, the pharmacokinetic profiles were similar between men and women. The absolute bioavailability of Neumega (oprelvekin) was > 80%. In a study in which multiple, subcutaneous doses of both 25 and 50 µg/kg were administered to cancer patients receiving chemotherapy, Neumega (oprelvekin) did not accumulate and clearance of Neumega (oprelvekin) was not impaired following multiple doses.
In a dose escalation Phase 1 study, Neumega (oprelvekin) was also administered to 43 pediatric patients (ages 8 months to 18 years) and 1 adult patient receiving ICE (ifosfamide, carboplatin, etoposide) chemotherapy. Administered doses ranged from 25 to 125 µg/kg. Analysis of data from 40 pediatric patients showed that Cmax, Tmax, and terminal half-life were comparable to that in adults. The mean area under the concentration-time curve (AUC) for pediatric patients (8 months to 18 years), receiving 50 µg/kg was approximately half that achieved in healthy adults receiving 50 µg/kg. Available data suggest that clearance of oprelvekin decreases with increasing age.
In preclinical trials in rats, radiolabeled Neumega (oprelvekin) was rapidly cleared from the serum and distributed to highly perfused organs. The kidney was the primary route of elimination. The amount of intact Neumega (oprelvekin) in urine was low, indicating that the molecule was metabolized before excretion. In a clinical study, a single dose of Neumega (oprelvekin) was administered to subjects with severely impaired renal function (creatinine clearance < 30 mL/min). The mean ± S.D. values for Cmax and AUC were 30.8 ± 8.6 ng/mL and 373 ± 106 ng*hr/mL, respectively. When compared with control subjects in this study with normal renal function, the mean Cmax was 2.2 fold higher and the mean AUC was 2.6 fold (95% confidence interval, 1.7%-3.8%) higher in the subjects with severe renal impairment. In the subjects with severe renal impairment, clearance was approximately 40% of the value seen in subjects with normal renal function. The average terminal half-life was similar in subjects with severe renal impairment and those with normal renal function.
A second clinical study of 24 subjects with varying degrees of renal function was also performed and confirmed the results observed in the first study. Single 50 µg/kg subcutaneous and intravenous doses were administered in a randomized fashion. As the degree of renal impairment increased, the Neumega (oprelvekin) AUC increased, although half-life remained unchanged. In the six patients with severe impairment, the mean ± S.D. Cmax and AUC were 23.6 ± 6.7 ng/mL and 373 ± 55.2 ng*hr/mL, respectively, compared with 13.1 ± 3.8 ng/mL and 195 ± 49.3 ng*hr/mL, respectively, in the six subjects with normal renal function. A comparable increase in exposure was observed after intravenous administration of Neumega (oprelvekin) .
The pharmacokinetic studies suggest that overall exposure to oprelvekin increases as renal function decreases, indicating that a 50% dose reduction of Neumega (oprelvekin) is warranted for patients with severe renal impairment (see PRECAUTIONS, Use in Patients with Renal Impairment and DOSAGE AND ADMINISTRATION). No dosage reduction is required for smaller changes in renal function.
In a study in which Neumega (oprelvekin) was administered to non-myelosuppressed cancer patients, daily subcutaneous dosing for 14 days with Neumega (oprelvekin) increased the platelet count in a dose-dependent manner. Platelet counts began to increase relative to baseline between five and nine days after the start of dosing with Neumega (oprelvekin) . After cessation of treatment, platelet counts continued to increase for up to seven days then returned toward baseline within 14 days. No change in platelet reactivity as measured by platelet activation in response to ADP, and platelet aggregation in response to ADP, epinephrine, collagen, ristocetin and arachidonic acid has been observed in association with Neumega (oprelvekin) treatment.
In a randomized, double-blind, placebo-controlled study in normal volunteers, subjects receiving Neumega (oprelvekin) had a mean increase in plasma volume of > 20%, and all subjects receiving Neumega (oprelvekin) had at least a 10% increase in plasma volume. Red blood cell volume decreased similarly (due to repeated phlebotomy) in the Neumega (oprelvekin) and placebo groups. As a result, whole blood volume increased approximately 10% and hemoglobin concentration decreased approximately 10% in subjects receiving Neumega (oprelvekin) compared with subjects receiving placebo. Mean 24 hour sodium excretion decreased, and potassium excretion did not increase, in subjects receiving Neumega (oprelvekin) compared with subjects receiving placebo.
Two randomized, double-blind, placebo-controlled trials in adults studied Neumega (oprelvekin) for the prevention of severe thrombocytopenia following single or repeated sequential cycles of various myelosuppressive chemotherapy regimens.
Study in Patients with Prior Chemotherapy-Induced Thrombocytopenia
One study evaluated the effectiveness of Neumega (oprelvekin) in eliminating the need for platelet transfusions in patients who had recovered from an episode of severe chemotherapy-induced thrombocytopenia (defined as a platelet count ≥ 20,000/µL), and were to receive one additional cycle of the same chemotherapy without dose reduction. Patients had various underlying nonmyeloid malignancies, and were undergoing dose-intensive chemotherapy with a variety of regimens. Patients were randomized to receive Neumega (oprelvekin) at a dose of 25 µg/kg or 50 µg/kg, or placebo. The primary endpoint was whether the patient required one or more platelet transfusions in the subsequent chemotherapy cycle. Ninety-three patients were randomized. Five patients withdrew from the study prior to receiving the study drug. As a result, eighty-eight patients were included in a modified intent-to-treat analysis. The results for the Neumega (oprelvekin) 50 µg/kg and placebo groups are summarized in Table 1. The placebo group includes one patient who underwent chemotherapy dose reduction and who avoided platelet transfusions.
TABLE 1: STUDY RESULTS
|Neumega 50 µg/kg
|Number (%) of patients avoiding platelet transfusion||2 (7%)||8 (28%)|
|Number (%) of patients requiring platelet transfusion||28 (93%)||21 (72%)|
|Median (mean) number of platelet transfusion events||2.5 (3.3)||1 (2.2)|
In the primary efficacy analysis, more patients avoided platelet transfusion in the Neumega (oprelvekin) 50 µg/kg arm than in the placebo arm (p = 0.04, Fisher's Exact test, 2-tailed). The difference in the proportion of patients avoiding platelet transfusions in the Neumega (oprelvekin) 50 µg/kg and placebo groups was 21% (95% confidence interval, 2%-40%). The results observed in patients receiving 25 µg/kg of Neumega (oprelvekin) were intermediate between those of the placebo and the 50 µg/kg groups.
Study in Patients Receiving Dose-Intensive Chemotherapy
A second study evaluated the effectiveness of Neumega (oprelvekin) in eliminating platelet transfusions over two dose-intensive chemotherapy cycles in breast cancer patients who had not previously experienced severe chemotherapy-induced thrombocytopenia. All patients received the same chemotherapy regimen (cyclophosphamide 3,200 mg/m2 and doxorubicin 75 mg/m2). All patients received concomitant filgrastim (G-CSF) in all cycles. The patients were stratified by whether or not they had received prior chemotherapy, and randomized to receive Neumega (oprelvekin) 50 µg/kg or placebo. The primary endpoint was whether or not a patient required one or more platelet transfusions in the two study cycles. Seventy-seven patients were randomized. Thirteen patients failed to complete both study cycles - eight of these had insufficient data to be evaluated for the primary endpoint. The results of this trial are summarized in Table 2.
TABLE 2: STUDY RESULTS
|No Prior Chemotherapy
|Number (%) of patients avoiding platelet transfusion||15
|Number (%) of patients requiring platelet transfusion||16 |
|Number (%) of patients not evaluable||6
This study showed a trend in favor of Neumega (oprelvekin) , particularly in the subgroup of patients with prior chemotherapy. Open-label treatment with Neumega (oprelvekin) has been continued for up to four consecutive chemotherapy cycles without evidence of any adverse effect on the rate of neutrophil recovery or red blood cell transfusion requirements. Some patients continued to maintain platelet nadirs > 20,000/µL for at least four sequential cycles of chemotherapy without the need for transfusions, chemotherapy dose reduction, or changes in treatment schedules.
Platelet activation studies done on a limited number of patients showed no evidence of abnormal spontaneous platelet activation, or an abnormal response to ADP. In an unblinded, retrospective analysis of the two placebo-controlled studies, 19 of 69 patients (28%) receiving Neumega (oprelvekin) 50 µg/kg and 34 of 67 patients (51%) receiving placebo reported at least one hemorrhagic adverse event which involved bleeding.
Study in Patients Following Myeloablative Chemotherapy
In a randomized, double-blind, placebo-controlled, Phase 2 study conducted in 80 women with high-risk breast cancer who received 0 (n=26), 25 µg/kg (n=28), or 50 µg/kg (n=26) Neumega (oprelvekin) following myeloablative chemotherapy and autologous bone marrow transplantation, the incidence of platelet transfusions and time to neutrophil and platelet engraftment were similar in the Neumega (oprelvekin) and placebo-treated arms. The study showed a statistically significant increased incidence in edema, conjunctival bleeding, hypotension, and tachycardia in patients receiving Neumega (oprelvekin) as compared to placebo.
In long term follow-up of patients, the distribution of survival and progression-free survival times was similar between patients randomized to Neumega (oprelvekin) therapy and those randomized to receive placebo.
(1) Du, X. and Williams, D., Interleukin 11: review of molecular, cell biology and clinical use. Blood. 1997;89(11):3897-3908.
Last reviewed on RxList: 10/21/2008
This monograph has been modified to include the generic and brand name in many instances.
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