In preclinical trials in rats, radiolabeled Neumega 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 in urine was low, indicating that the molecule was metabolized before excretion. In a clinical study, a single dose of Neumega was administered to subjects with severely impaired renal function (creatinine clearance <30 mL/min). The mean ± S.D. values for C_max 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 C_max 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 mg/kg subcutaneous and intravenous doses were administered in a randomized fashion. As the degree of renal impairment increased, the Neumega AUC increased, although half-life remained unchanged. In the six patients with severe impairment, the mean ± S.D. C_max 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.

The pharmacokinetic studies suggest that overall exposure to oprelvekin increases as renal function decreases, indicating that a 50% dose reduction of Neumega 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 was administered to non-myelosuppressed cancer patients, daily subcutaneous dosing for 14 days with Neumega 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. 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 treatment.

In a randomized, double-blind, placebo-controlled study in normal volunteers, subjects receiving Neumega had a mean increase in plasma volume of >20%, and all subjects receiving Neumega had at least a 10% increase in plasma volume. Red blood cell volume decreased similarly (due to repeated phlebotomy) in the Neumega and placebo groups. As a result, whole blood volume increased approximately 10% and hemoglobin concentration decreased approximately 10% in subjects receiving Neumega compared with subjects receiving placebo. Mean 24 hour sodium excretion decreased, and potassium excretion did not increase, in subjects receiving Neumega compared with subjects receiving placebo.

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