Pharmacology Update
Pegfilgrastim (NeulastaTM)—A Pegylated Form of Filgrastim
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
The FDA has approved a pegylated form of filgrastim (Neupogen). Filgrastim is a recombinant granulocyte colony-stimulating factor (CSF) that stimulates the production and maturation of neutrophils and enhances the function of mature neutrophils. Pegylation (combining a drug with PolyEthylene Glycol) is a novel approach to modifying a parenteral drug’s pharmacokinetics and, in turn, its pharmacodynamics.1 In this case, combining filgrastim with monomethoxypolyethylene glycol permits one dose per chemotherapy cycle compared to daily dosing with filgrastim. It will be marketed by Amgen as Neulasta.
Indications
Pegfilgrastim is indicated to decrease the incidence of infection (ie, febrile neutropenia) in patients with non-myeloid malignancies receiving myelosuppressive chemotherapeutic agents with significant potential for febrile neutropenia.2 Pegfilgrastim has not been studied in patients administered drugs with delayed myelosuppression (eg, nitrosoureas, mitomycin C). It should be used with caution in patients with sickle cell disease as it may precipitate a severe sickle cell crisis. Pegfilgrastim should not be used for peripheral blood progenitor cells (PBPC) mobilization as rare cases of splenic rupture have been reported with filgrastim.2
Dosage
Pegfilgrastim is administered as a single subcutaneous injection of 6 mg per chemotherapy cycle. It should not be given 14 days before and 24 hours after chemotherapy.2 The recommended injection sites are outer areas of the upper arms, front of the middle thighs, upper outer areas of the buttocks, and the abdomen (except for the 2-inch area around the navel).
Pegfilgrastim is available as a 6-mg single-dose syringe.
Potential Advantages
Pegfilgrastim is administered once per chemotherapy cycle compared to daily injections for filgrastim. This amounts to 1 injection of pegfilgrastim compared to 11 injections of filgrastim. The clearance of pegfilgrastim is directly related to the number of neutrophils as clearance increases (concentration decreases) with neutrophil recovery.2
Potential Disadvantages
Medullary bone pain is the most common side effect and has been reported in 26% of patients. The incidence appears to be comparable to that of filgrastim.3,4 Non-aspirin analgesics such as acetaminophen are recommended to relieve bone pain. Other side effects include redness, swelling, or itching at the injection site. Adult respiratory distress syndrome (ARDS) has been reported in patients with sepsis who received filgrastim. Therefore, pegfilgrastim should be discontinued or withheld if ARDS occurs.2 Pegfilgrastim is administered as a single-dose per cycle and does not permit titration to desired absolute neutrophil counts (ANC). Lithium may potentiate the release of neutrophils. There is a theoretical possibility that pegfilgrastim may stimulate the growth of certain tumors.2
Comments
Pegfilgrastim and filgrastim were compared in 2 multicenter, randomized, double-blind, active-control studies in patients with metastatic breast cancer who received 4 cycles of doxorubicin 60 mg/m2 and docetaxel 75 mg/m2. A weight-based dose of a single injection of pegfilgrastim (100 µg/kg every 21 days; n = 310) and a fixed-dose of 6 mg (n = 157) were compared to daily doses of filgrastim (5 µg/kg/d).2,3 There was no difference in the primary end point of mean days of severe neutropenia. (1.7-1.8 days for pegfilgrastim and 1.6 days for filgrastim). In the weight-based dose study, the mean duration of severe neutropenia for cycles 2, 3, and 4 favor pegfilgrastim over filgrastim. They were 0.7, 0.6, and 0.9 days for pegfilgrastim and 1.1, 1.2, and 1.3 days, respectively, for filgrastim. Differences for cycles 2 and 3 were statistically significant at P < 0.05 level. A lower overall rate of febrile neutropenia was also reported (9% vs 18%; P = 0.029).3 Pegfilgrastim may also be less likely to cause overshoot of neutrophils. There were no differences in adverse events such as bone pain and elevated laboratory values, although the frequency of elevated LDH (19% vs 29%) and alkaline phosphatase (9% vs 16%) were numerically lower with pegfilgrastim.2
Pegfilgrastim costs about $2400 per injection compared to $1700 for 11 doses of filgrastim.
Clinical Implications
Neutropenia is the most serious side effect of myelosuppressive chemotherapy in cancer patients, potentially leading to increased risk of infections and may delay the time until next doses of chemotherapy. A recent meta-analysis concluded that prophylaxis with recombinant granulocyte CSFs have been associated with a reduced risk of febrile neutropenia (odds ratio [OR] 0.38; 95% CI, 0.29-0.49; P = 0.001), documented infection (OR 0.51; 95% CI, 0.36-0.73; P = 0.001), and a trend toward reduced infection-related mortality (OR 0.60; 95% CI, 0.30-1.22; P = 0.16). Patients who received CSF were also less likely to have a dose reduction or treatment delay (OR 0.32; 95% CI, 0.21-0.47; P = 0.001).4 Pegfilgrastim offers a much more convenient, but expensive, alternative to filgrastim.
Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Assistant Clinical Professor of Medicine, University of California-San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Both are Associate Editors of Internal Medicine Alert.
References
1. Harris JM, et al. Clin Pharmacokinet. 2001;40(7): 539-551.
2. Neulasta Product Information. Amgen Inc. January 2002.
3. Holmes FA, et al. J Clin Oncol. 2002;20:727-731.
4. Lyman GH, et al. Am J Med. 2002;112(5):406-411.
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