CD34+ cell yield among healthy donors: Large-scale model development and validation.

BACKGROUND: Successful engraftment in hematopoietic stem cell transplantation necessitates the collection of an adequate dose of CD34+ cells. Thus, the precise estimation of CD34+ cells harvested via apheresis is critical. Current CD34+ cell yield prediction models have limited reproducibility. This study aims to develop a more reliable and universally applicable model by utilizing a large dataset, enhancing yield predictions, optimizing the collection process, and improving clinical outcomes. MATERIALS AND METHODS: A secondary analysis was conducted using the Center for International Blood and Marrow Transplant Research database, involving data from over 17 000 healthy donors who underwent filgrastim-mobilized hematopoietic progenitor cell apheresis. Linear regression, gradient boosting regressor, and logistic regression classification models were employed to predict CD34+ cell yield. RESULTS: Key predictors identified include pre-apheresis CD34+ cell count, weight, age, sex, and blood volume processed. The linear regression model achieved a coefficient of determination (R2) value of 0.66 and a correlation coefficient (r) of 0.81. The gradient boosting regressor model demonstrated marginally improved results with an R2 value of 0.67 and an r value of 0.82. The logistic regression classification model achieved a predictive accuracy of 96% at the 200 × 106 CD34+ cell count threshold. At thresholds of 400, 600, 800, and 1000 × 106 CD34+ cell count, the accuracies were 88%, 83%, 83%, and 88%, respectively. The model demonstrated a high area under the receiver operator curve scores ranging from 0.90 to 0.93. CONCLUSION: This study introduces advanced predictive models for estimating CD34+ cell yield, with the logistic regression classification model demonstrating remarkable accuracy and practical utility.

Filgrastim (r-met-hu G-CSF) enhances the efficiency of spermatogenesis in prepubertal Bos indicus bulls.

This study aimed to test the effects of the drug r-met-hu-G-CSF (filgrastim) on spermatogenic efficiency in prepubertal Brahman bulls. Twelve intact, healthy prepubertal bulls were administered 0, 1 (LD = low dose) or 4 (HD = high dose) µg/Kg r-met-hu-G-CSF (daily for 4 days), and haematological analysis was performed. Bulls were castrated (D0 or D60). BW (body weight) and SC (scrotal circumference) were recorded. Testis weight and volume were taken at castration with samples for testis histology and stereology: germ cell types, spermatids count and DSP (daily sperm production per gram)/g of testicular parenchyma. Testicular weight, volume, BW, SC and gonadosomatic index (GSI) were NS (LD-HD; p > .05). At D0 (age 11 months), the most advanced germ cell types (maGCt) ranged from intermediate spermatogonia to pachytene spermatocytes. After 2 months, control animals had round spermatids as maGCt, LD animals 75% round spermatids and 25% elongated spermatids, and HD animals round spermatids. Spermatids/testis were higher in LD (1.23 ± 0.2 millions) than in controls (0.65 ± 0.1 millions, p < .05). Spermatogenic efficiency (DSP/g) was higher in LD (5.4 ± 0.4 million) than in controls (3.2 ± 0.2 million, p < .01). In conclusion, r-met-hu-G-CSF raises spermatogenic efficiency in prepubertal Brahman bulls.

Mobilization characteristics, blood graft composition, and outcome in diffuse large B-cell lymphoma after autologous stem cell transplantation: Results from the prospective multicenter GOA study.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is a common indication for autologous stem cell transplantation (auto-SCT). STUDY DESIGN AND METHODS: This prospective noninterventional study aimed to evaluate the impact of mobilization characteristics and graft cellular content on hematologic recovery and outcome after auto-SCT among 68 patients with DLBCL. RESULTS: Better mobilization capacity as manifested by blood CD34+ cell count >32 × 106 /L and CD34+ cell yield of the first apheresis >2.75 × 106 /kg correlated with faster neutrophil (P = .005 and P = .017) and platelet (P = .002 and P < .001) recovery. A higher number of infused CD34+ cells (> 2.65 × 106 /kg) was associated with better 5-year overall survival (OS; 95% vs 67%, P = .012). The graft CD34+ CD133+ CD38- cell count >0.07 × 106 /kg was predictive of better 5-year OS (87% vs 63%; P = .008) and higher graft CD3+ cell count (>23.1 × 106 /kg) correlated also with better 5-year OS (80% vs 40%, P = .008). In multivariate analysis only disease status of CR I at auto-SCT was associated with better progression-free survival (P = .014) and OS (P = .039). CONCLUSION: The mobilization capacity of CD34+ cells impacted on early hematologic recovery in patients with DLBCL after auto-SCT. Higher graft CD34+ cell count and both CD34+ CD133+ CD38- and CD3+ cells were also associated with better OS. The effect of optimal graft cellular composition on outcome in DLBCL should be evaluated in a randomized study.

Efficacy and safety of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell non-Hodgkin lymphoma (B-NHL): results of the randomized, open-label, non-inferiority AVOID neutropenia study.

BACKGROUND: Lipegfilgrastim has been shown to be non-inferior to pegfilgrastim for reduction of the duration of severe neutropenia (DSN) in breast cancer patients. This open-label, non-inferiority study assessed the efficacy and safety of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell non-Hodgkin lymphoma (NHL) at high risk for chemotherapy-induced neutropenia. PATIENT AND METHODS: One hundred and one patients (median age, 75 years) were randomized to lipegfilgrastim or pegfilgrastim (6 mg/cycle) during six cycles of R-CHOP21. RESULTS: Lipegfilgrastim was non-inferior to pegfilgrastim for the primary efficacy endpoint, reduction of DSN in cycle 1. In the per-protocol population, mean (standard deviation) DSN was 0.8 (0.92) and 0.9 (1.11) days in the two groups, respectively; the adjusted mean difference between groups was - 0.3 days (95% confidence interval, - 0.70 to 0.19). Non-inferiority was also demonstrated in the intent-to-treat population. The incidence of severe neutropenia in cycle 1 was 51% (21/41) in the lipegfilgrastim group and 52% (23/44) in the pegfilgrastim group. Very severe neutropenia (ANC < 0.1 × 109/L) in cycle 1 was reported by 5 (12%) patients in the lipegfilgrastim group and 8 (18%) patients in the pegfilgrastim group. However, over all cycles, febrile neutropenia (strict definition) was reported by only 1 (2%) patient in each treatment group (during cycle 1 in the lipegfilgrastim group and cycle 6 in the pegfilgrastim group). The mean time to absolute neutrophil count recovery (defined as ≥ 2.0 × 109/L) was 8.3 and 9.4 days in the two groups, respectively. Serious adverse events occurred in 46% of patients in each group; none were considered treatment-related. Eight patients died during the study (2 in the lipegfilgrastim group, 5 in the pegfilgrastim group, and 1 who died before starting study treatment). No deaths occurred during the treatment period, and all were considered to be related to the underlying disease. CONCLUSIONS: This study shows lipegfilgrastim to be non-inferior to pegfilgrastim for the reduction of DSN in elderly patients with aggressive B cell NHL receiving myelosuppressive chemotherapy, with a comparable safety profile. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier NCT02044276; EudraCT number 2013-001284-23.

Cost saving, patient centered algorithm for progenitor cell mobilization for autologous hematopoietic cell transplantation.

Administration of plerixafor with granulocyte-colony stimulating factor (G-CSF) mobilizes CD34+ cells much more effectively than G-CSF alone, but cost generally limits plerixafor use to patients at high risk of insufficient CD34+ cell collection based on low peripheral blood (PB) CD34+ counts following 4 days of G-CSF. We analyzed costs associated with administering plerixafor to patients with higher day 4 CD34+ cell counts to decrease apheresis days and explored the use of a fixed split dose of plerixafor instead of weight-based dosing. We analyzed 235 patients with plasma cell disorders or non-Hodgkin's lymphoma who underwent progenitor cell mobilization and autologous hematopoietic cell transplantation (AHCT) between March 2014 and December 2017. Two hundred ten (89%) received G-CSF plus Plerixafor and 25 (11%) received G-CSF alone. Overall, 180 patients (77%) collected in 1 day, 53 (22%) in 2 days and 2 (1%) in 3 days. Based on our data, we present a probabilistic algorithm to identify patients likely to require more than one day of collection using G-CSF alone. CD34+ cell yield, ANC and platelet recovery were not significantly different between fixed and standard dose plerixafor. Plerixafor enabled collection in 1 day and with estimated savings of $5000, compared to patients who did not receive plerixafor and required collection for three days. While collection and processing costs and patient populations vary among institutions, our results suggest re-evaluation of current algorithms.

Evaluation of Structural, Biological, and Functional Similarity of Biosimilar Granulocyte Colony Stimulating Factor to its Reference Product.

PURPOSE: Granulocyte colony stimulating factor (GCSF; also known as filgrastim) is a growth factor used to induce production of granulocytes. As the first locally developed and approved biosimilar medicine of Turkey, Fraven® being a biosimilar of filgrastim has been ab initio manufactured from cell to finished product at two different production facilities. Comprehensive structural, biological and functional characterization studies were performed to compare Fraven® from two different production sites and its reference product Neupogen® sourced from Turkey. METHODS: Primary and higher-order protein structures were analyzed by high performance liquid chromatography electrospray ionization-time of flight mass spectrometry, circular dichroism, and two-dimensional nuclear magnetic resonance spectroscopy. Isoelectric focusing, SDS-Page, size exclusion chromatography, and related proteins analyses were used to compare impurities. In order to assess functional similarity, surface plasmon resonance (SPR) was used. In vitro cell proliferation assay was also performed to show dose related drug response in NFS-60 cell line. RESULTS: Primary, secondary and tertiary structures of biosimilar Fraven® manufactured at both sites were found to be highly similar to the reference Neupogen®. Product related substances and impurities were also highly similar to the reference. Comparability of GCSF receptor binding affinities of each product was shown using the KD values of SPR analysis. In vitro cell proliferation similarity was also evaluated and proven by PLA. CONCLUSION: Based on the similarity assessment, despite being manufactured at two different production sites, biosimilar Fraven® is highly similar to the reference product Turkey originated Neupogen®.

Feasibility and efficacy of low-dose pegfilgrastim for CD34+ cell mobilization in lymphoma.

BACKGROUND: Pegfilgrastim has equivalent efficacy to daily granulocyte colony-stimulating factor (G-CSF) in enhancing neutrophil recovery after chemotherapy, but data on its use for peripheral blood stem cell (PBSC) mobilization are limited. We evaluated the safety and efficacy of CD34+ PBSC mobilization by low-dose (3.6 mg) pegfilgrastim after chemotherapy in patients with malignant lymphoma. STUDY DESIGN AND METHODS: Twenty patients with malignant lymphoma were enrolled in this study. Cytotoxic chemotherapy was started on day 1, and 3.6 mg of pegfilgrastim was subcutaneously administered on day 7. CD34+ cells were counted in the peripheral blood daily from days 11 to 14 using a flow cytometric analysis. RESULTS: In 19 of the 20 patients (95%), the CD34+ cell counts in the peripheral blood exceeded 10 × 106/L, with a mean value of 20.3 on day 11, 38.0 on day 12, 40.3 on day 13, and 40.1 on day 14. Older age was associated with lower maximum CD34+ cell mobilization. The most frequent adverse events associated with pegfilgrastim were back pain, nausea, appetite loss, and lactate dehydrogenase elevation. CONCLUSION: Our data indicated that a single dose of 3.6 mg pegfilgrastim on day 7 after chemotherapy safely and effectively mobilized CD34+ cells.

A physiological model of granulopoiesis to predict clinical drug induced neutropenia from in vitro bone marrow studies: with application to a cell cycle inhibitor.

Neutropenia is one of the most common dose-limiting toxocities associated with anticancer drug therapy. The ability to predict the probability and severity of neutropenia based on in vitro studies of drugs in early drug development will aid in advancing safe and efficacious compounds to human testing. Toward this end, a physiological model of granulopoiesis and its regulation is presented that includes the bone marrow progenitor cell cycle, allowing for a mechanistic representation of the action of relevant anticancer drugs based on in vitro studies. Model development used data from previously reported tracer kinetic studies of granulocyte disposition in healthy humans to characterize the dynamics of neutrophil margination in the presence of endogenous granulocyte-colony stimulating factor (G-CSF). In addition, previously published data from healthy volunteers following pegfilgrastim and filgrastim were used to quantify the regulatory effects of support G-CSF therapies on granulopoiesis. The model was evaluated for the cell cycle inhibitor palbociclib, using an in vitro system of human bone marrow mononuclear cells to quantify the action of palbociclib on proliferating progenitor cells, including its inhibitory effect on G1 to S phase transition. The in vitro results were incorporated into the physiological model of granulopoiesis and used to predict the time course of absolute neutrophil count (ANC) and the incidence of neutropenia observed in three previously reported clinical trials of palbociclib. The model was able to predict grade 3 and 4 neutropenia due to palbociclib treatment with 86% accuracy based on in vitro data.

Quantification and Qualification of Stem Cells From Blood After Mobilization With Filgrastim, and Concentration Using a Platelet-Rich Plasma System.

PURPOSE: To determine the cellular composition of a product created with peripheral blood harvested after systemic mobilization with filgrastim and processed with one point-of-care blood concentrating system, i.e., a platelet-rich plasma (PRP) system. The second purpose was to compare mobilized platelet-rich plasma (M-PRP) with a concentrated bone marrow aspirate (cBMA) and a PRP created from the same subjects with the same PRP system. METHODS: Ten healthy volunteer subjects were recruited for collection and analysis of 3 tissue sources: non-treated peripheral blood, bone marrow aspirate, and filgrastim-mobilized peripheral blood, involving 4 doses of weight-based filgrastim. One point-of-care blood and bone marrow concentrating system was used to create 3 products: PRP, cBMA, and M-PRP. Automated hematologic analysis was performed on all products to quantify total red blood cells, white blood cells (WBCs), monocyte, platelet, and hematopoietic progenitor cell (HPC) concentrations. Flow cytometry was used to determine hematopoietic and mesenchymal progenitor cell populations. Lastly, concentrates were cultured and fibroblast colony-forming units (CFU-F) and morphology of adherent cells were evaluated. RESULTS: M-PRP contained a greater concentration of WBC (mean difference = 53.2 k/µL; P < .0001), monocytes (mean difference = 8.3 k/µL; P = .002), and a trend toward a greater concentration of HPC (mean difference = 200.5 /µL; P = .060) when compared with PRP. M-PRP contained a greater concentration of monocytes (mean difference = 5.5 k/µL; P = .017) and a trend toward a greater concentration of platelets (mean difference = 348 k/µL; P = .051) and HPC (mean difference = 193.4 /µL; P = .068) when compared with cBMA. M-PRP had a similar concentration of platelets to PRP (mean difference = 110 k/µL; P = .051) and PRP had a greater concentration than cBMA (mean difference = 458 k/µL; P = .003). cBMA remained the only product capable of producing CFU-Fs (446 ± 247 /mL) as neither the M-PRP nor PRP produced CFU-Fs. M-PRP produced colonies consistent with WBC. CONCLUSIONS: M-PRP, produced with filgrastim mobilized blood and a proprietary PRP system, contained more total WBCs, monocytes, platelets, and HPCs than cBMA and more WBCs, monocytes, and HPCs than PRP. CLINICAL RELEVANCE: Filgrastim mobilized PRP may be an alternative to cBMA for use as a point-of-care product for orthopaedic treatments.

Hematopoietic effects of Azadirachta indica methanolic extract in cyclophosphamide mediated myelosuppressed albino rat.

Myelosuppression or bone marrow suppression is one of the most common side effects caused by anti-cancer drugs. Certain nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics and viruses like B19 virus can also cause bone marrow suppression resulting in serious consequences like leukopenia, anemia and thrombocytopenia. Currently, it is mainly treated by Filgrastim, use of which is not without side effects. Certain natural drugs can be a safer alternative to treat myelosuppression. Azadirachta indica, commonly known as Neem, is an important medicinal plant of subcontinent. Keeping in view the traditional uses of Neem, present study aims to investigate its potential role in reversing myelosuppression. Albino rats were used to determine hematopoietic activity of Neem leaves after inducing myelosuppression by cyclophosphamide given subcutaneously. Filgrastim was used as reference standard to compare the antimyelosuppressant activity of the drug. The drug was evaluated in three doses i.e. 50mg/kg, 100mg/kg and 200mg/kg body weight, while blood samples were drawn on 0, 1st, 7th, 14th and 21st day. The drug was found to be effective in reversing bone marrow suppression in all three doses based on the hematological parameters (mean WBC, RBC, platelets, Hb, Hct etc.) which improved significantly. The results suggest that the drug can be used as antimyelosuppressant after establishing its safety and identifying its active constituents with their mechanism of action.

RGB-02 (biosimilar pegfilgrastim) in the treatment of chemotherapy-induced neutropenia.

Pegfilgrastim is widely used for the prevention of chemotherapy-induced neutropenia. The development and use of biosimilar agents help to rationalize healthcare expenditure and improve access to modern therapies to all who need them. This review focuses on pegfilgrastims with important role in oncology supportive care. RGB-02 (Gedeon Richter) is a proposed biosimilar to pegylated granulocyte-colony stimulating factor (Neulasta®, Amgen) with sustained release properties. The clinical analyses in three randomized clinical studies provided comparative data between RGB-02 and Neulasta, in a Phase III study patients receiving docetaxel-doxorubicin chemotherapy treatment equivalence was found. No difference was detected in any safety measure including immunogenicity; treatment switch, from the reference product to RGB-02 proved safe. Long-acting pegylated filgrastim RGB-02 has successfully accomplished various steps of biosimilar development.

Filgrastim prophylaxis in elderly cancer patients in the real-life setting: a French multicenter observational study, the TULIP study.

PURPOSE: Few studies are currently available among elderly patients, justifying the need for better understanding of daily medical practices in terms of use of growth factors to prevent chemotherapy (CT)-induced neutropenia. The primary objective of this study was to describe the use of filgrastim in the elderly. METHODS: Cancer patients aged 65 years and above, undergoing CT and initiating a prophylactic treatment with filgrastim, were enrolled. Patients were followed according to routine medical practice from filgrastim initiation until the end of the CT or after a maximum of 6 cycles. RESULTS: One thousand one hundred nineteen evaluable patients were documented in the study (mean age 73.9 ± 6.2 years, 52.1% men). The majority were suffering from solid tumor (73%) with ECOG 0-1 for 80% of them. Approximately two-third had a global risk for FN ≥ 20%, and one third < 20%. Through all CT cycles, no differences were observed between age classes ([65-74], [75-85], or > 85) in dose, duration, and time to first injection from CT start. Most patients (84%) received primary prophylaxis (PP) and 70% were administered during the first CT cycle. The median time from CT start until filgrastim was 4 days. The median duration of filgrastim treatment was 5 days. Dose reductions and CT delays were less frequent in patients receiving PP (4.8% and 7.1% respectively) than secondary prophylaxis (9.2% and 13.3% respectively). CONCLUSIONS: Filgrastim use was consistent with French Market Authorization terms. No difference was shown compared with younger patients. Safety data were consistent with the known safety profile.

Outcomes of chemotherapy-induced (febrile) neutropenia prophylaxis with biosimilar filgrastim (Zarzio®) initiated "same-day" (< 24 h), "per-guidelines" (24-72 h), and "late" (> 72 h): findings from the MONITOR-GCSF study.

PURPOSE: Granulocyte colony-stimulating factors (G-CSFs) are indicated for prophylaxis or management of chemotherapy-induced neutropenia (CIN) and febrile neutropenia (FN). Guidelines recommend G-CSF 24-72 h following chemotherapy; however, some evidence suggests that G-CSF initiated < 24 h may benefit some patients. METHODS: MONITOR-GCSF was a prospective, observational, multicenter, pan-European study of 1447 chemotherapy-treated patients receiving daily biosimilar (standard) filgrastim (Zarzio®/Zarxio®, filgrastim-sndz, Hexal AG, Sandoz Inc.). In this analysis, cycles were classified as same-day, per-guidelines, or late if G-CSF support was initiated < 24 h, 24-72 h, and > 72 h after chemotherapy. Outcomes included occurrence of CIN of any grade (CIN1/4), grade 3 or 4 (CIN3/4), grade 4 (CIN4), or FN: CIN/FN-related hospitalization or CIN/FN-related chemotherapy disturbance. RESULTS: A total of 5930 chemotherapy cycles from 1423 evaluable patients from MONITOR-GCSF had data for day of G-CSF initiation: 795 cycles (13.4%) classified as same-day, 3320 (56.0%) as per-guidelines, and 1815 (30.6%) as late. Groups did not differ as to CIN1/4 and FN episodes, or CIN/FN-related hospitalizations or chemotherapy disturbances. Patients in the same-day and per-guidelines groups had statistically similar odds of not experiencing any outcomes of interest in any given cycle. Patients in the late group had worse odds of experiencing CIN1/4, CIN3/4, and CIN4 episodes in any given cycle. Proportions of patients reporting clinical events of interest were generally similar. CONCLUSIONS: This real-world evidence indicates that CIN/FN prophylaxis initiated with biosimilar filgrastim within 24-72 h post-chemotherapy is effective and safe. Filgrastim administration on the day of chemotherapy may be appropriate in some patients.

Filgrastim following HLA-Identical Allogeneic Bone Marrow Transplantation: Long-Term Outcomes of a Randomized Trial.

Human recombinant granulocyte colony stimulating factor reduces the duration of neutropenia following HLA-identical allogeneic bone marrow transplantation. However, its use remains controversial due to the risk of increasing the incidence of acute graft-versus-host disease (GVHD) and slower platelet recovery. To clarify these risks, we conducted a prospective randomized placebo-controlled trial of filgrastim 5 µg/kg/day i.v. from day 7 post-transplant until neutrophil recovery in 145 consecutive adults undergoing HLA-identical allogeneic bone marrow transplantation, with cyclosporine and methotrexate as GVHD prophylaxis. The primary endpoint was the incidence of acute GVHD; hematological recovery, nonrelapse mortality, and post-transplant complications were secondary endpoints. Filgrastim had no significant effect on the incidence of acute GVHD, platelet recovery, platelet transfusion requirements, chronic GVHD, or survival. Filgrastim accelerated granulocyte recovery significantly (with absolute neutrophil counts >.5 × 109/L achieved after a median of 16 days versus 23 days for placebo; P < .0001), and reduced both early nonrelapse mortality (2.9% versus 10.5%; P = .042) and the duration of i.v. antibiotic therapy (18 days versus 26 days; P = .001) and hospitalization (27 versus 34 days; P = .017). In conclusion, in this setting, filgrastim reduced significantly the duration of neutropenia, i.v. antibiotic therapy, hospitalization, and early nonrelapse mortality, without increasing the risk of acute and chronic GVHD or relapse, or delaying platelet recovery.

Proposed biosimilar pegfilgrastim shows similarity in pharmacokinetics and pharmacodynamics to reference pegfilgrastim in healthy subjects.

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 (AUC0-inf ), or to the last measurable concentration (AUC0-last ), maximum observed serum concentration (Cmax ), absolute neutrophil count (ANC) area under the effect curve from the time of dosing to the last measurable concentration (AUEC0-last ) and ANC maximum effect attributable to the therapy under investigation (Emax ) 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: AUC0-inf (1.0559-1.2244), AUC0-last (1.0607-1.2328), Cmax (1.0312-1.1909) and 95% CIs for PD (ANC): AUEC0-last (0.9948-1.0366), Emax (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.

Pharmacokinetic-pharmacodynamic modelling of neutrophil response to G-CSF in healthy subjects and patients with chemotherapy-induced neutropenia.

AIM: The objective of the present study was to use pharmacokinetic-pharmacodynamic modelling to characterize the effects of chemotherapy on the granulopoietic system and to predict the absolute neutrophil counts (ANCs) for patients with chemotherapy-induced neutropenia treated with filgrastim and pegfilgrastim. METHODS: Data were extracted from 10 phase I-III studies conducted in 110 healthy adults, and 618 adult and 52 paediatric patients on chemotherapy following administration of filgrastim or pegfilgrastim. The structural model accounted for ANC dynamics and the effects of filgrastim and pegfilgrastim, chemotherapy and corticosteroids. The impact of neutrophils on drug disposition was based on a drug receptor-binding model that assumed quasi-equilibrium and stimulation of the production and maturation of neutrophils upon treatment. The chemotherapy and corticosteroid effects were represented by kinetic-pharmacodynamic-type models, where chemotherapy stimulated elimination of neutrophil precursors at the mitotic stage, and corticosteroids stimulated neutrophil production. RESULTS: The systemic half-lives of filgrastim (2.6 h) and pegfilgrastim (10.1 h) were as expected. The effective half-life of chemotherapy was 9.6 h, with a 2-day killing effect. The rate of receptor elimination from mitotic compartments exhibited extreme interindividual variability (% coefficient of variation >200), suggesting marked differences in sensitivity to chemotherapy effects on ANCs. The stimulatory effects of pegfilgrastim were significantly greater than those of filgrastim. Model qualification confirmed the predictive capability of this model. CONCLUSION: This qualified model simulates the time course of ANC in the absence or presence of chemotherapy and predicts nadir, time to nadir and time of recovery from different grades of neutropenia upon treatment with filgrastim and pegfilgrastim.

Quality Comparison of Biosimilar and Copy Filgrastim Products with the Innovator Product.

PURPOSE: Filgrastim, a recombinant human granulocyte-colony stimulating factor, is widely used to treat congenital and acquired neutropenia. Following patent expiration of the innovator filgrastim product, biosimilar filgrastim products have been approved in the EU and shown to be comparable with the innovator with respect to quality, safety and efficacy. In less regulated markets, copy filgrastim products are available but data about their quality are scarce. In the present study, we provide a head-to-head comparative study on the quality of biosimilar and copy filgrastim products. METHODS: Innovator filgrastim product, Neupogen®, two EU-licensed biosimilars, Zarzio® and Tevagrastim®, and two copy filgrastim products, Biocilin® and PDgrastim®, were subjected to peptide mapping, circular dichroism spectroscopy, fluorescence spectroscopy, sodium dodecyl sulfate polyacrylamide gel electrophoresis, high performance size-exclusion chromatography, reversed-phase ultra-performance liquid chromatography, endotoxin test, flow imaging microscopy and in vitro potency assay. RESULTS: Zarzio® and Tevagrastim® have comparable quality to Neupogen®, while Biocilin® showed a significantly lower and PDgrastim® a higher specific activity. Moreover, PDgrastim® showed a higher level of impurities and a lower thermo stability than the other products. CONCLUSIONS: Except for the deviating specific activities of the two copy filgrastim products, we found no substantial differences in product quality between the filgrastim products studied.

A systematic literature review of the efficacy, effectiveness, and safety of filgrastim.

PURPOSE: Filgrastim (NEUPOGEN®) is the originator recombinant human granulocyte colony-stimulating factor widely used for preventing neutropenia-related infections and mobilizing hematopoietic stem cells. This report presents findings of a systematic literature review and meta-analysis of efficacy and safety of originator filgrastim to update previous reports. METHODS: A literature search of electronic databases, congress abstracts, and bibliographies of recent reviews was conducted to identify English-language reports of clinical trials and observational studies evaluating filgrastim in its US-approved indications up to February 2015. Two independent reviewers assessed titles/abstracts and full texts of publications, and extracted data from studies that compared originator filgrastim vs placebo or no treatment. For outcomes with sufficient homogeneous data reported across studies, meta-analysis was performed and relative risk (RR) determined. Data were summarized descriptively for all other evaluated outcomes. RESULTS: A total of 1194 unique articles evaluating originator filgrastim were identified, with 25 meeting eligibility criteria for data extraction: 18 randomized controlled trials, 2 nonrandomized clinical trials, and 5 observational studies. In chemotherapy-induced neutropenia (CIN), filgrastim vs placebo or no treatment significantly reduced febrile neutropenia incidence (RR 0.63, 95% CI 0.53-0.75) and grade 3 or 4 neutropenia incidence (RR 0.50, 95% CI 0.37-0.68). The most commonly reported adverse event (AE) with filgrastim was bone pain (RR 2.61, 95% CI 1.29-5.27 in CIN). Additional efficacy and safety outcomes are described within indications. CONCLUSIONS: This systematic literature review and meta-analysis confirms and updates previous reports on the efficacy and safety of originator filgrastim. Bone pain was the commonly reported AE associated with filgrastim use.

Administration options for pegfilgrastim prophylaxis: patient and physician preferences from a cross-sectional survey.

OBJECTIVE: Although clinical guidelines recommend administration of pegfilgrastim 1-4 days after a myelosuppressive chemotherapy cycle to decrease the incidence of febrile neutropenia (FN), some physicians administer pegfilgrastim on the same day as chemotherapy administration. A novel on-body injector (OBI) that automatically delivers pegfilgrastim the day after chemotherapy is also available. Our objective was to estimate patient and physician preferences among the pegfilgrastim administration options. METHODS: We conducted a cross-sectional survey of patients receiving pegfilgrastim and physicians prescribing pegfilgrastim. Respondents' preferences for pegfilgrastim administration options were elicited using direct elicitation; the relative importance of features associated with the options was estimated in a point-allocation exercise. Physicians considered two hypothetical patient profiles when completing the exercises. RESULTS: The samples included 200 patients and 200 physicians. Patients generally preferred the administration option with which they had experience. Among patients, 48.5% with previous in-clinic injections 24 hours after chemotherapy preferred this option; 56.8% with previous OBI administration preferred this option. For a clinically compromised patient, 37.5% of physicians preferred an in-clinic injection option; 49.5% preferred the OBI. For a less compromised patient, 55.5% preferred an in-clinic injection option; 28.0% preferred the OBI. Avoiding the need to return to the clinic was chosen most often as the most important treatment feature for patients and physicians. CONCLUSIONS: Patients and physicians identified that returning clinic visits for pegfilgrastim administration may be burdensome. A potential solution to mitigate this burden is the OBI, which allows adherence to the labeled use of pegfilgrastim without return visits to the clinic.

A single-center, retrospective analysis to compare the efficacy and safety of filgrastim-sndz to filgrastim for prophylaxis of chemotherapy-induced neutropenia and for neutrophil recovery following autologous stem cell transplantation.

Filgrastim-sndz (Zarxio®) was approved by the FDA in March 2015 as a biosimilar product of its reference product, filgrastim (Neupogen®) for all five indications. The NCCN Clinical Practice Guidelines has incorporated filgrastim-sndz into its recommendations as a category 1 recommendation for use in settings of febrile neutropenia, myelosuppressive chemotherapy administration, and post-hematopoietic stem cell transplant (HSCT). As a cost-saving initiative, our institution switched from filgrastim to filgrastim-sndz for all indications starting in March 2016. The purpose of this study was to assess for any difference in clinical or safety outcomes between filgrastim and filgrastim-sndz. This is an IRB-approved, single institution, 1-year retrospective chart review (September 2015 to August 2016) conducted in hospitalized adults who received either filgrastim or filgrastim-sndz either for prophylaxis of chemotherapy-induced myelosuppression or for neutrophil recovery after autologous HSCT. Our data showed no differences in duration of G-CSF therapy (7.96 vs. 8.5 days, P = 0.36), white blood count (WBC) (8.99 vs. 8.04, P = 0.28), absolute neutrophil count (ANC) (7.62 vs. 6.91 × 109/L, P = 0.36) at the time of granulocyte-colony stimulating factor (G-CSF) discontinuation, or safety of filgrastim and filgrastim-sndz. The efficacy and safety of filgrastim and filgrastim-sndz were similar for prophylaxis of chemotherapy-induced neutropenia and neutrophil recovery post-autologous HSCT.