Pharmacology Update
Tbo-filgrastim Injection
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationships relevant to this field of study.
A modified recombinant human granulocyte colony-stimulating factor (G-CSF) has been approved by the FDA. The new tbo-filgrastim differs from filgrastim by the addition of a N-terminal methionine residue and lack of glycosylation at residue 133 (r-metHuG-GCSF). The drug was approved by way of a full biologic license application, although it fits the definition of a biosimilar molecule. The product is approved in Europe as a biosimilar to filgrastim (Neupogen®). Tbo-filgrastim is manufactured by Sicor Biotech and marketed by Teva.
Indication
Tbo-filgrastim is indicated for the reduction in the duration of severe neutropenia in patients with nonmyeloid malignances receiving myelosuppressive anti-cancer therapy with a clinically significant risk of febrile neutropenia.1
Dosage
The recommended dose is 5 mcg/kg/day given subcutaneously. Administration should be started no earlier than 24 hours following myelosuppressive therapy.
Tbo-filgrastim is available as 300 mcg/0.5 mL and 480 mcg/0.8 mL in single-use prefilled syringes.
Potential Advantages
Tbo-filgrastim provides an alternative to filgrastim and is expected to be priced competitively to filgrastim.
Potential Disadvantages
The immunogenicity and the potential of tbo-filgrastim to prolong QTc interval have not been adequately assessed.1 These are to be evaluated as part of the post-marketing requirements.2
Comments
The approval of tbo-filgrastim was based on a Phase 3, multicenter, randomized, controlled study in chemotherapy-naïve patients with high-risk stage II or stage IV breast cancer receiving doxorubicin (60 mg/m2) and docetaxel (75 mg/m2).1,2 Subjects (n = 348) were randomized to placebo, tbo-filgrastim, and a non-U.S.-approved filgrastim. The primary endpoint was the duration of severe neutropenia. The mean duration of severe neutropenia in cycle 1 was 1.1 days vs 3.8 days for placebo. The FDA did not consider the non-U.S.-approved filgrastim comparator relevant to the demonstration of efficacy and safety.2 The most common adverse event was bone pain, which was observed in 24% of patients.2 Tbo-filgrastim has been shown to be bioequivalent to filgrastim in terms of pharmacokinetic parameters and pharmacodynamic parameters (absolute neutrophil count).3,4 A meta-analysis of three clinical trials conducted with tbo-filgrastim and filgrastim in patients for the prophylaxis of febrile neutropenia during the first cycle in patients being treated with myelosuppressive chemotherapy for breast, lung cancer, and non-Hodgkin’s lymphoma suggests non-inferiority for tbo-filgrastim.5 Two studies conducted in Europe reported similar efficacy and safety in patients with lung cancer receiving platinum-based chemotherapy (n = 240) and chemotherapy for non-Hodgkin’s lymphoma (n = 92).6,7 Subjects received either tbo-filgrastim or filgrastim (5 mcg/kg/day) daily for 5-14 days for the first cycle. Efficacy endpoint was duration of severe neutropenia or incidence of neutropenia in the first cycle.
Clinical Implications
Tbo-filgrastim has been available in Europe for several years as an approved biosimilar. It was recently approved in the United States after a full Biologic License Application, as the biosimilar pathway was not available at the time of submission. Due to a patent litigation settlement between Amgen and Teva, tbo-filgrastim will not be available until November 2013.
References
1. Tbo-filgrastim Prescribing Information. North Wales, PA: teva Pharmaceuticals; August 2012.
2. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/125294Orig1s000SumR.pdf. Accessed november 19, 2012.
3. Lubenau H, et al. Bioequivalence of two recombinant granulocyte colony-stimulating factor products after subcutaneous injection in healthy volunteers. Int J Clin Pharmacol Ther 2009;47: 275-282.
4. Lubenau H, et al. Pharmacokinetic and pharmacodynamic profile of new biosimilar filgrastim XM02 equivalent to marketed filgrastim neupogen: single-blind, randomized, crossover trial. BioDrugs 2009;23:43-51.
5. Engert A, et al. Incidence of febrile neutropenia and myelotoxicity of chemotherapy: A meta-analysis of biosimilar G-CSF studies in breast cancer, lung cancer, and non-Hodgkin’s lymphoma. Onkologie 2009;32:599-604.
6. Gatzemeier U, et al. XM02, the first biosimilar G-csF, is safe and effective in reducing the duration of severe neutropenia and incidence of febrile neutropenia in patients with small cell or non-small cell lung cancer receiving platinum-based chemotherapy. J Thorac Oncol 2009;4:736-740.
7. Engert A, et al. XM02, the first granulocyte colony-stimulating factor biosimilar, is safe and effective in reducing the duration of severe neutropenia and incidence of febrile neutropenia in patients with non-Hodgkin lymphoma receiving chemotherapy. Leuk Lymphoma 2009;60:374-379.
A modified recombinant human granulocyte colony-stimulating factor (G-CSF) has been approved by the FDA.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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