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British Journal of Clinical Pharmacology Dec 2018This study aimed to demonstrate that the pharmacokinetic (PK) and pharmacodynamic (PD) profile of Sandoz proposed biosimilar pegfilgrastim (LA-EP2006) matches reference... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
This study aimed to demonstrate that the pharmacokinetic (PK) and pharmacodynamic (PD) profile of Sandoz proposed biosimilar pegfilgrastim (LA-EP2006) matches reference pegfilgrastim (Neulasta ) in healthy subjects. Safety and immunogenicity were also assessed.
METHODS
The phase I, randomized, double-blind, two-period crossover study consisted of two treatment periods separated by an 8-week washout period. Healthy subjects aged 18-45 were randomized to either proposed biosimilar/reference pegfilgrastim or reference pegfilgrastim/proposed biosimilar. Proposed biosimilar and reference pegfilgrastim were administered on Day 1 of each treatment period (single 6 mg subcutaneous injection). Blood samples for PK/PD analysis were taken predose and ≤336 h postdose. PK/PD similarity was claimed if 90% (PK) and 95% (PD) confidence intervals (CI) for geometric mean ratios of the area under the serum concentration-time curve (AUC) from time of dosing and extrapolated to infinity (AUC ), or to the last measurable concentration (AUC ), maximum observed serum concentration (C ), absolute neutrophil count (ANC) area under the effect curve from the time of dosing to the last measurable concentration (AUEC ) and ANC maximum effect attributable to the therapy under investigation (E ) were completely contained within the predefined margin (0.8 to 1.25).
RESULTS
Overall, 169 subjects completed the study. PK/PD similarity was demonstrated; 90% CIs of geometric mean ratio of proposed biosimilar/reference for PK: AUC (1.0559-1.2244), AUC (1.0607-1.2328), C (1.0312-1.1909) and 95% CIs for PD (ANC): AUEC (0.9948-1.0366), E (0.9737-1.0169) were completely contained within predefined margin of 0.8 to 1.25. Both biologics had similar safety profiles, were well tolerated and had low incidence of anti-drug antibodies. No neutralizing or clinically relevant antibodies were detected.
CONCLUSIONS
PK/PD similarity of Sandoz proposed biosimilar pegfilgrastim and reference pegfilgrastim was confirmed. No clinically meaningful differences in safety, tolerability and immunogenicity were observed in healthy subjects.
Topics: Adult; Biosimilar Pharmaceuticals; Cross-Over Studies; Double-Blind Method; Female; Filgrastim; Healthy Volunteers; Humans; Male; Polyethylene Glycols
PubMed: 30079636
DOI: 10.1111/bcp.13731 -
Cancer Medicine Oct 2023Pegfilgrastim is indicated to decrease the incidence of chemotherapy-induced febrile neutropenia. It is the first granulocyte-colony stimulating factor approved for...
INTRODUCTION
Pegfilgrastim is indicated to decrease the incidence of chemotherapy-induced febrile neutropenia. It is the first granulocyte-colony stimulating factor approved for prophylactic use regardless of carcinoma type and is marketed in Japan as G-LASTA (Kyowa Kirin Co., Ltd., Tokyo, Japan). MD-110 is a biosimilar of pegfilgrastim. This phase III, multicenter, open-label, single-arm study investigated the efficacy and safety of MD-110 in early-stage breast cancer patients receiving neoadjuvant or adjuvant myelosuppressive chemotherapy.
METHODS
A total of 101 patients received the study drug. Each patient received docetaxel 75 mg/m and cyclophosphamide 600 mg/m (TC) for four cycles on day 1 of each cycle. MD-110 (3.6 mg) was administered subcutaneously on day 2 of each cycle. The primary efficacy endpoint was the duration of severe neutropenia during cycle 1 (days with absolute neutrophil count < 500/mm ). The safety endpoints were adverse events and the presence of antidrug antibodies.
RESULTS
The mean (SD) duration of severe neutropenia for MD-110 was 0.2 (0.4) days. The upper limit of the two-sided 95% confidence interval for the mean duration of severe neutropenia was 0.2 days, below the predefined threshold of 3.0 days. The incidence of febrile neutropenia, the secondary efficacy endpoint, was 6.9% (7/101). Adverse events, occurring in more than 50% of patients, were alopecia, constipation, and malaise, which are common side effects of TC chemotherapy. Antidrug antibodies were negative in all patients.
CONCLUSION
MD-110 was effective against chemotherapy-induced neutropenia. No additional safety concern, compared with the originator, was observed in patients with breast cancer receiving TC chemotherapy.(JapicCTI-205230).
Topics: Female; Humans; Antineoplastic Combined Chemotherapy Protocols; Biosimilar Pharmaceuticals; Breast Neoplasms; Filgrastim; Granulocyte Colony-Stimulating Factor; Neutropenia; Polyethylene Glycols
PubMed: 37824431
DOI: 10.1002/cam4.6519 -
Journal of Oncology Pharmacy Practice :... Sep 2019Guidelines recommend pegfilgrastim for primary prophylaxis of febrile neutropenia after highly myelosuppressive chemotherapy. While deviations from guidelines could...
INTRODUCTION
Guidelines recommend pegfilgrastim for primary prophylaxis of febrile neutropenia after highly myelosuppressive chemotherapy. While deviations from guidelines could result in overuse and increased costs, underuse is also a concern and could compromise quality of care. Our objectives were to evaluate guideline adherence and quantify the extent to which physician heterogeneity may influence pegfilgrastim use.
METHODS
We randomly sampled 550 patients from a retrospective cohort of those who received infusions at an academic cancer center between 1 September 2013 and 1 September 2014. Electronic medical and drug dispensing records provided information on patient characteristics, chemotherapy characteristics, prescribing physician, and pegfilgrastim administration.
RESULTS
We included 154 patients treated by 25 physicians. About half of patients were male and mean age was 61.3 years. Forty (26.1%) patients had no febrile neutropenia risk factors, 62 (40.5%) had one, and 51 (33.3%) had two or more. Thirty patients (19.5%) received pegfilgrastim, of which 12 (40%) received palliative chemotherapy. Nine (60%) of 15 patients on a regimen with a febrile neutropenia risk ≥ 20% received pegfilgrastim. Pegfilgrastim use significantly varied by cancer type (p < 0.01), chemotherapy regimen (p < 0.001), and regimen febrile neutropenia risk (p < 0.001). Multivariable analysis reaffirmed the association between chemotherapy regimen febrile neutropenia risk ≥ 20% and pegfilgrastim use (odds ratio (OR) = 10.1, 95% confidence interval (CI): 1.6-62.7) and suggested that 31% (95% CI: 8%-71%) of the variation in use was attributable to physician characteristics.
CONCLUSION
Pegfilgrastim was potentially overused for palliative chemotherapy and underused for chemotherapy regimens with febrile neutropenia risk ≥ 20%. Successful interventions to modify prescribing practices likely require an understanding of the relationship between specific physician characteristics and pegfilgrastim use.
Topics: Aged; Antineoplastic Agents; Febrile Neutropenia; Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Guideline Adherence; Humans; Male; Middle Aged; Neoplasms; Polyethylene Glycols; Practice Guidelines as Topic; Practice Patterns, Physicians'; Prescription Drug Overuse; Retrospective Studies; Risk Factors
PubMed: 30124123
DOI: 10.1177/1078155218792698 -
Expert Opinion on Biological Therapy Apr 2015Despite significant scientific advances toward the development of a safe, nontoxic and effective radiation countermeasure for acute radiation syndrome (ARS) over the...
Despite significant scientific advances toward the development of a safe, nontoxic and effective radiation countermeasure for acute radiation syndrome (ARS) over the past six decades, no drug has been approved by the US FDA. Several biologics are currently under development as radiation countermeasures for ARS, of which three have received FDA Investigational New Drug (IND) status for clinical investigation. Presently, two of these agents, entolimod (CBLB502) and HemaMax (recombinant human IL-12) are progressing with large animal studies and clinical trials. Neupogen (G-CSF, filgrastim) has recently been recommended for approval by an FDA Advisory Committee. Filgrastim, GM-CSF (Leukine, sargramostim), and PEGylated G-CSF (Neulasta) have high potential and well-documented therapeutic effects in countering myelosuppression and may receive full licensing approval by the FDA in the future. The former two biologics are available in the US Strategic National Stockpile (SNS) for use in the event of nuclear or radiological emergency. The Emergency Use Authorization (EAU) application for entolimod may be filed soon with the FDA. Biologics are attractive agents that are progressing along the path for FDA approval, to fill the unmet need for ARS countermeasures.
Topics: Acute Radiation Syndrome; Animals; Biological Products; Drug Approval; Filgrastim; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Peptides; Polyethylene Glycols; Radiation-Protective Agents; Recombinant Proteins
PubMed: 25416452
DOI: 10.1517/14712598.2015.986453 -
Advances in Therapy Mar 2022Biologic therapeutics can trigger immune responses in patients. As part of the totality of evidence that is required for regulatory approval of biosimilars,... (Randomized Controlled Trial)
Randomized Controlled Trial
INTRODUCTION
Biologic therapeutics can trigger immune responses in patients. As part of the totality of evidence that is required for regulatory approval of biosimilars, immunogenicity similarity must be assessed in the clinical programs. Pegfilgrastim-cbqv (UDENYCA) is a pegfilgrastim biosimilar approved in the USA and European Union. This article demonstrates the similar immunogenicity of pegfilgrastim-cbqv compared with its reference product, pegfilgrastim (Neulasta).
METHODS
The immunogenicity of pegfilgrastim-cbqv was assessed in three clinical studies in healthy subjects (one specifically designed to evaluate immunogenicity similarity and two studies to assess pharmacokinetics and pharmacodynamics bioequivalence) using a tiered approach, in which plasma samples were tested for the presence of antidrug antibodies (ADAs) as well as ADA binding-specificity, titer and neutralizing activity. To assess the clinical impact of ADAs, pharmacokinetics, pharmacodynamics and safety profiles were compared between ADA-positive and -negative subjects.
RESULTS
These studies demonstrated similar immunogenicity of pegfilgrastim-cbqv and pegfilgrastim. The small differences in ADA incidence between treatment groups observed in the immunogenicity study were driven by non-neutralizing, low-titer, polyethylene glycol (PEG)-reactive ADAs, which are commonly present in healthy subjects. No treatment-emergent neutralizing antibodies (NAbs) were detected in either treatment group, and there was no apparent impact of ADAs on pharmacokinetics, pharmacodynamics or safety.
CONCLUSION
Pegfilgrastim-cbqv has similar immunogenicity to pegfilgrastim. The presented immunogenicity, pharmacokinetics, pharmacodynamics and safety data support the overall demonstration of no clinically meaningful differences between pegfilgrastim-cbqv and pegfilgrastim.
CLINICAL TRIAL REGISTRATION
NCT02418104 (CHS-1701-04, April 2015), NCT02650973 (CHS-1701-05, February 2016) and NCT02385851 (CHS-1701-03, March 2015).
Topics: Biosimilar Pharmaceuticals; Case-Control Studies; Filgrastim; Healthy Volunteers; Humans; Polyethylene Glycols
PubMed: 35034311
DOI: 10.1007/s12325-021-02024-x -
International Journal of Radiation... 2023A mass casualty disaster involving radiological or nuclear agents continues to be a public health concern which requires consideration of both acute and late tissue...
PURPOSE
A mass casualty disaster involving radiological or nuclear agents continues to be a public health concern which requires consideration of both acute and late tissue toxicities in exposed victims. With the advent of advanced treatment options for the mitigation of hematological injuries, there are likely to be survivors of total body irradiation (TBI) exposures as high as 8-10 Gy. These survivors are at risk for a range of delayed multi-organ morbidities including progressive renal failure.
MATERIAL AND METHODS
Here, we established the WAG/RijCmcr rat as an effective model for the evaluation of medical countermeasures (MCM) for acute hematologic radiation syndrome (H-ARS). The LD dose for adult and pediatric WAG/RijCmcr rats was determined for both sexes. We then confirmed the FDA-approved MCM pegfilgrastim (peg-GCSF, Neulasta®) mitigates H-ARS in adult male and female rats. Finally, we evaluated survival and renal dysfunction up to 300 d post-TBI in male and female adult rats.
RESULTS
In the WAG/RijCmcr rat model, 87.5% and 100% of adult rats succumb to lethal hematopoietic acute radiation syndrome (H-ARS) at TBI doses of 8 and 8.5 Gy, respectively. A single dose of the hematopoietic growth factor peg-GCSF administered at 24 h post-TBI improved survival during H-ARS. Peg-GCSF treatment improved 30 d survival from 12.5% to 83% at 8 Gy and from 0% to 63% at 8.5 Gy. We then followed survivors of H-ARS through day 300. Rats exposed to TBI doses greater than 8 Gy had a 26% reduction in survival over days 30-300 compared to rats exposed to 7.75 Gy TBI. Concurrent with the reduction in long-term survival, a dose-dependent impairment of renal function as assessed by blood urea nitrogen (BUN) and urine protein to urine creatinine ratio (UP:UC) was observed.
CONCLUSION
Together, these data show survivors of H-ARS are at risk for the development of delayed renal toxicity and emphasize the need for the development of medical countermeasures for delayed renal injury.
Topics: Male; Rats; Female; Animals; Humans; Dose-Response Relationship, Radiation; Acute Radiation Syndrome; Disease Models, Animal; Kidney; Survivors; Whole-Body Irradiation
PubMed: 36688956
DOI: 10.1080/09553002.2023.2170491 -
Supportive Care in Cancer : Official... Nov 2017Chemotherapy-induced febrile neutropenia (FN) causes treatment delays and interruptions and can have fatal consequences. Current guidelines provide recommendations on... (Review)
Review
PURPOSE
Chemotherapy-induced febrile neutropenia (FN) causes treatment delays and interruptions and can have fatal consequences. Current guidelines provide recommendations on granulocyte colony-stimulating factors (G-CSF) for prevention of FN, but guidance is unclear regarding use of short- vs long-acting G-CSF (e.g., filgrastim vs pegfilgrastim/lipegfilgrastim, respectively). An international panel of experts convened to develop guidance on appropriate use of pegfilgrastim for prevention of chemotherapy-induced FN.
METHODS
Guidance recommendations were developed following a literature review, survey, evaluation of current practice, and an expert meeting. Consensus was established using an anonymous Delphi-based approach.
RESULTS
Guidance recommendations for prevention of treatment-associated FN were as follows: for treatment with curative intent, maintenance of dose intensity using G-CSF to prevent dose delays/reduction should be standard of care; for treatment-associated FN risk ≥ 20%, short-acting G-CSF/pegfilgrastim should be given from cycle 1 onwards; and for treatment-associated FN risk < 20%, short-acting G-CSF/pegfilgrastim should be given if factors suggest overall risk (including treatment-related and patient-related risk factors) is ≥ 20%. It was agreed that pegfilgrastim and 11 days' filgrastim have similar efficacy and safety and that pegfilgrastim is preferred to < 11 days' filgrastim (and may be preferred to ≥ 11 days' filgrastim based on adherence and convenience); pegfilgrastim is not appropriate in weekly chemotherapy; in split-dose chemotherapy, pegfilgrastim is recommended 24 h after last chemotherapy dose; and during palliative chemotherapy, patient adherence and convenience may favor pegfilgrastim.
CONCLUSION
In this era of targeted therapies, additional trials with G-CSF are still required. These recommendations should be used with existing guidelines to optimize pegfilgrastim use in clinical practice.
Topics: Chemotherapy-Induced Febrile Neutropenia; Consensus; Female; Filgrastim; Humans; Male; Polyethylene Glycols
PubMed: 28842778
DOI: 10.1007/s00520-017-3842-1 -
Acta Reumatologica Portuguesa 2021Granulocyte colony-stimulating factor (G-CSF) is increasingly being used to prevent febrile neutropenia associated with chemotherapy. Large-vessel vasculitis (LVV) has...
Granulocyte colony-stimulating factor (G-CSF) is increasingly being used to prevent febrile neutropenia associated with chemotherapy. Large-vessel vasculitis (LVV) has been recognized as a rare side effect of G-CSF treatment. We report a case of G-CSF associated LVV in a patient with breast cancer. While clear pathogenic mechanisms remain unknown, G-CSF may cause vasculitis due to inflammatory cytokines production. This adverse reaction should be recognized in patients with suggestive symptoms following the administration of pegfilgrastim. A 56-year-old woman with luminal B breast cancer who had undergone surgery and adjuvant chemotherapy, initially with paclitaxel, was started on a doxorubicin plus cyclophosphamide protocol, followed by supportive use of long-acting G-CSF pegfilgrastim. Following the administration of pegfilgrastim, the patient developed intermittent fever and was given empiric antibiotics in the outpatient setting with no improvement. There were no signs of cancer progression, and the contrast-enhanced CT scan highlighted wall thickening of the aortic arch and the proximal segment of the subclavian artery, which was not present in previous imaging studies. The patient was diagnosed with LVV, and a differential diagnosis was performed to rule out paraneoplastic setting, immune-mediated diseases, infection or other drug-induced vasculitis. Treatment with steroids was initiated and tapered with significant improvement and resolution of the radiological signs of aortitis.
Topics: Female; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Middle Aged; Polyethylene Glycols; Vasculitis
PubMed: 34962243
DOI: No ID Found -
Scientific Reports Feb 2020PEGylated recombinant human granulocyte colony stimulating factor (pegfilgrastim) is used clinically to accelerate immune reconstitution following chemotherapy and is...
PEGylated recombinant human granulocyte colony stimulating factor (pegfilgrastim) is used clinically to accelerate immune reconstitution following chemotherapy and is being pursued for biosimilar development. One challenge to overcome in pegfilgrastim biosimilar development is establishing pharmacokinetic (PK) similarity, which is partly due to the degree of PK variability. We herein report that commercially available G-CSF and PEG ELISA detection kits have different capacities to detect pegfilgrastim aggregates that rapidly form in vitro in physiological conditions. These aggregates can be observed using SDS-PAGE, size-exclusion chromatography, dynamic light scattering, and real-time NMR analysis and are associated with decreased bioactivity as reflected by reduced drug-induced cellular proliferation and STAT3 phosphorylation. Furthermore, individual variability in the stability and detectability of pegfilgrastim in human sera is also observed. Pegfilgrastim levels display marked subject variability in sera from healthy donors incubated at 37 °C. The stability patterns of pegfilgrastim closely match the stability patterns of filgrastim, consistent with a key role for pegfilgrastim's G-CSF moiety in driving formation of inactive aggregates. Taken together, our results indicate that individual variability and ELISA specificity for inactive aggregates are key factors to consider when designing and interpreting studies involving the measurement of serum pegfilgrastim concentrations.
Topics: Animals; Biological Variation, Individual; Cell Line, Tumor; Cell Proliferation; Enzyme-Linked Immunosorbent Assay; Filgrastim; Humans; Mice; Polyethylene Glycols; STAT3 Transcription Factor
PubMed: 32051479
DOI: 10.1038/s41598-020-59346-z -
Journal of Medical Economics 2021Therapeutic guidelines recommend prophylaxis against chemotherapy-induced (febrile) neutropenia (CIN/FN). Pegfilgrastim (Neulasta), biosimilar pegfilgrastim-jmdb...
AIMS
Therapeutic guidelines recommend prophylaxis against chemotherapy-induced (febrile) neutropenia (CIN/FN). Pegfilgrastim (Neulasta), biosimilar pegfilgrastim-jmdb (Fulphila), and pegfilgrastim with on-body injector (OBI; Neulasta Onpro) are options for CIN/FN prophylaxis. We aimed to simulate the cost-savings and budget-neutral expanded access to CIN/FN prophylaxis or anticancer treatment achieved through conversion from pegfilgrastim-OBI to pegfilgrastim-jmdb and to evaluate the economic impact of FN-related hospitalization costs due to pegfilgrastim-OBI failure.
METHODS
Cost-savings from conversion from pegfilgrastim-OBI to biosimilar pegfilgrastim-jmdb were simulated in a panel of 15,000 patients with cancer from the US payer perspective. The primary analyses included conversion rates of 10% to 100%. Adjusted analyses also considered OBI device failure rates of 1% to 7% and associated costs of FN-related hospitalization. Simulations of budget-neutral expanded access to prophylaxis with pegfilgrastim-jmdb or to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for diffuse large B-cell lymphoma (DLBCL) were also performed.
RESULTS
In a 15,000-patient panel, conversion from pegfilgrastim-OBI to pegfilgrastim-jmdb resulted in cost-savings ranging from $481,259 (10% conversion) to $4,812,585 (100% conversion) in a single cycle. Over 6 cycles at 100% conversion, savings were $28,857,510 and could provide 9,191 additional doses of pegfilgrastim-jmdb or 4,463 cycles of R-CHOP to patients with DLBCL. Adjusted for OBI failure, cost-savings over 6 cycles ranged from $2,935,565 (10% conversion; pegfilgrastim-OBI failure rate of 1%) to $32,236,499 (100% conversion; 7% failure). These cost-savings could provide 943 doses of pegfilgrastim-jmdb or 454 doses of R-CHOP (10% conversion; 1% pegfilgrastim-OBI failure) or provide 10,261 doses of pegfilgrastim-jmdb or 4,982 cycles of R-CHOP (100% conversion; 7% failure).
CONCLUSION
Conversion from pegfilgrastim to pegfilgrastim-jmdb is associated with significant cost-savings which increase markedly when also accounting for pegfilgrastim-OBI failure and associated FN-related hospitalizations. These general and failure-related cost-savings could be allocated on a budget-neutral basis to provide more patients with additional CIN/FN prophylaxis or antineoplastic treatment.
Topics: Antineoplastic Combined Chemotherapy Protocols; Cost-Benefit Analysis; Filgrastim; Granulocyte Colony-Stimulating Factor; Humans; Polyethylene Glycols; Recombinant Proteins
PubMed: 33866947
DOI: 10.1080/13696998.2021.1916863