In rats treated at doses of 1150 mcg/kg/day for 4 weeks (5 of 32 animals) and for 13 weeks at doses of 100 mcg/kg/day (4 of 32 animals) and 500 mcg/kg/day (6 of 32 animals)‚ articular swelling of the hind legs was observed. Some degree of hind leg dysfunction was also observed; however‚ symptoms reversed following cessation of dosing. In rats‚ osteoclasis and osteoanagenesis were found in the femur‚ humerus‚ coccyx‚ and hind legs (where they were accompanied by synovitis) after IV treatment for 4 weeks (115 to 1150 mcg/kg/day)‚ and in the sternum after IV treatment for 13 weeks (115 to 575 mcg/kg/day). These effects reversed to normal within 4 to 5 weeks following cessation of treatment.

In the 52-week chronic‚ repeated-dose studies performed in rats (IP injection up to 57.5 mcg/kg/day)‚ and cynomolgus monkeys (IV injection of up to 115 mcg/kg/day)‚ changes observed were similar to those noted in the subacute studies. Expected pharmacological actions of Filgrastim included dose-dependent increases in white cell counts‚ increased circulating segmented neutrophils and alkaline phosphatase levels‚ and increased myeloid:erythroid ratios in the bone marrow. Decreases in platelet counts were also noted in primates. In no animals tested were hemorrhagic complications observed. Rats displayed dose-related swelling of the hind limb‚ accompanied by some degree of hind limb dysfunction; osteopathy was noted microscopically. Enlarged spleens (both species) and livers (monkeys)‚ reflective of ongoing extramedullary granulopoiesis‚ as well as myeloid hyperplasia of the bone marrow‚ were observed in a dose-dependent manner.

Pharmacologic Effects of NEUPOGEN®

In phase 1 studies involving 96 patients with various nonmyeloid malignancies‚ NEUPOGEN® administration resulted in a dose-dependent increase in circulating neutrophil counts over the dose range of 1 to 70 mcg/kg/day.^9-11 This increase in neutrophil counts was observed whether NEUPOGEN® was administered IV (1 to 70 mcg/kg twice daily)‚⁹ SC (1 to 3 mcg/kg once daily)‚¹¹ or by continuous SC infusion (3 to 11 mcg/kg/day).¹⁰ With discontinuation of NEUPOGEN® therapy‚ neutrophil counts returned to baseline‚ in most cases within 4 days. Isolated neutrophils displayed normal phagocytic (measured by zymosan-stimulated chemoluminescence) and chemotactic (measured by migration under agarose using N-formyl-methionyl-leucyl-phenylalanine [fMLP] as the chemotaxin) activity in vitro.

The absolute monocyte count was reported to increase in a dose-dependent manner in most patients receiving NEUPOGEN®; however‚ the percentage of monocytes in the differential count remained within the normal range. In all studies to date‚ absolute counts of both eosinophils and basophils did not change and were within the normal range following administration of NEUPOGEN®. Increases in lymphocyte counts following NEUPOGEN® administration have been reported in some normal subjects and cancer patients.

White blood cell (WBC) differentials obtained during clinical trials have demonstrated a shift towards earlier granulocyte progenitor cells (left shift)‚ including the appearance of promyelocytes and myeloblasts‚ usually during neutrophil recovery following the chemotherapy-induced nadir. In addition‚ Dohle bodies‚ increased granulocyte granulation‚ and hypersegmented neutrophils have been observed. Such changes were transient and were not associated with clinical sequelae, nor were they necessarily associated with infection.

Pharmacokinetics

Absorption and clearance of NEUPOGEN® follows first-order pharmacokinetic modeling without apparent concentration dependence. A positive linear correlation occurred between the parenteral dose and both the serum concentration and area under the concentration-time curves. Continuous IV infusion of 20 mcg/kg of NEUPOGEN® over 24 hours resulted in mean and median serum concentrations of approximately 48 and 56 ng/mL‚ respectively. Subcutaneous administration of 3.45 mcg/kg and 11.5 mcg/kg resulted in maximum serum concentrations of 4 and 49 ng/mL‚ respectively‚ within 2 to 8 hours. The volume of distribution averaged 150 mL/kg in both normal subjects and cancer patients. The elimination half-life‚ in both normal subjects and cancer patients‚ was approximately 3.5 hours. Clearance rates of NEUPOGEN® were approximately 0.5 to 0.7 mL/minute/kg. Single parenteral doses or daily IV doses‚ over a 14-day period‚ resulted in comparable half-lives. The half-lives were similar for IV administration (231 minutes‚ following doses of 34.5 mcg/kg) and for SC administration (210 minutes‚ following NEUPOGEN® doses of 3.45 mcg/kg). Continuous 24-hour IV infusions of 20 mcg/kg over an 11- to 20-day period produced steady-state serum concentrations of NEUPOGEN® with no evidence of drug accumulation over the time period investigated.

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