Hemin mitigates contrast-induced nephropathy by inhibiting ferroptosis via HO-1/Nrf2/GPX4 pathway.

Contrast-induced nephropathy (CIN) is a common complication with adverse outcome after iodinated-contrast injection, yet still lacking effective medication. Heme oxygenase-1 (HO-1) has been reported to play an important role against renal injuries. Hemin, a HO-1 inducer and anti-porphyria medicine, may have a promising effect against CIN. In this study, we aim to investigate the effect of hemin on CIN model and the underlying molecular mechanisms in human proximal tubule epithelial cells (HK-2). To mimic a common condition in percutaneous coronary intervention (PCI) patients, CIN was induced by intravenous iopromide in high-fat fed diabetic rats. We found hemin, given right before iopromide, mitigated CIN with enhanced antioxidative capacity and reduced oxidative stress. HK-2 cells insulted by iopromide demonstrated decreased cell vitality and rising reactive oxygen species (ROS), which could also be inhibited by hemin. The effects of hemin involved a key molecule in ferroptosis, glutathione peroxidase (GPX4), whose down-expression by small interfering RNA (siRNA) reversed the effect of hemin on HK-2 cells. Furthermore, hemin's induction of GPX4 involved HO-1 and nuclear factor erythroid 2-related factor 2 (Nrf2). Either HO-1 or Nrf2 inhibitor prevented hemin's effect on GPX4 to a comparable extent, and over-expression of Nrf2 increased GPX4 expression. Moreover, intervention of ferroptosis inhibitor liproxstatin-1 also alleviated CIN in vivo. Therefore, we showed hemin mitigated CIN, inhibiting oxidative stress and ferroptosis, by upregulation of GPX4 via activation of HO-1/Nrf2. Hemin, as a clinical medicine, has a translational significance in treating CIN, and anti-ferroptosis is a potential therapeutic strategy for CIN.

Comparison of peripheral blood stem cell mobilization with filgrastim versus pegfilgrastim in lymphoma patients - single center experience.

PURPOSE: The purpose of this study was to evaluate mobilization outcomes with biosimilar pegfilgrastim versus filgrastim in association with chemotherapy as a mobilization strategy for lymphoma patients. METHODS: In the current study we included 32 lymphoma patients that received mobilization therapy and PBSC harvesting at the Bone Marrow Transplantation Department of Fundeni Clinical Institute, Bucharest, Romania between January and December 2019. RESULTS: Pegfilgrastim had beneficial effect when compared to filgrastim in reducing grade IV neutropenia both in the univariate and multivariate logistic models. Additionally, similar efficacy, as mobilization rate, after both filgrastim and pegfilgrastim was observed and no differences were noted between the two groups considering the need for platelet or red blood cell support. CONCLUSION: The use of biosimilar pegfilgrastim is a viable alternative to filgrastim in PBSC mobilization for lymphoma patients.

A whole-body circulatory neutrophil model with application to predicting clinical neutropenia from in vitro studies.

A circulatory model of granulopoiesis and its regulation is presented that includes neutrophil trafficking in the lungs, liver, spleen, bone marrow, lymph nodes, and blood. In each organ, neutrophils undergo transendothelial migration from vascular to interstitial space, clearance due to apoptosis, and recycling via the lymphatic flow. The model includes cell cycling of progenitor cells in the bone marrow, granulocyte colony-stimulating factor (G-CSF) kinetics and its neutrophil regulatory action, as well as neutrophil margination in the blood. From previously reported studies, 111 In-labeled neutrophil kinetic data in the blood and sampled organs were used to estimate the organ trafficking parameters in the model. The model was further developed and evaluated using absolute neutrophil count (ANC), band cell, and segmented neutrophil time course data from healthy volunteers following four dose levels of pegfilgrastim (r2  = 0.77-0.99), along with ANC time course responses following filgrastim (r2  = 0.96). The baseline values of various cell types in bone marrow and blood, as well as G-CSF concentration in the blood, predicted by the model are consistent with available literature reports. After incorporating the mechanism of action of both paclitaxel and carboplatin, as determined from an in vitro bone marrow studies, the model reliably predicted the observed ANC time course following paclitaxel plus carboplatin observed in a phase I trial of 46 patients (r2  = 0.70). The circulatory neutrophil model may provide a mechanistic framework for predicting multi-organ neutrophil homeostasis and dynamics in response to therapeutic agents that target neutrophil dynamics and trafficking in different organs.

Carrageenan: Drug Delivery Systems and Other Biomedical Applications.

Marine resources are today a renewable source of various compounds, such as polysaccharides, that are used in the pharmaceutical, medical, cosmetic, and food fields. In recent years, considerable attention has been focused on carrageenan-based biomaterials due to their multifunctional qualities, including biodegradability, biocompatibility, and non-toxicity, in addition to bioactive attributes, such as their antiviral, antibacterial, antihyperlipidemic, anticoagulant, antioxidant, antitumor, and immunomodulating properties. They have been applied in pharmaceutical formulations as both their bioactive and physicochemical properties make them suitable biomaterials for drug delivery, and recently for the development of tissue engineering. This article provides a review of recent research on the various types of carrageenan-based biomedical and pharmaceutical applications.

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®.

Current Overview on Hypercoagulability in COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has brought many unique pathologies, such as coagulopathy, prompting a desperate need for effective management. COVID-19-associated coagulopathy (CAC) can cause various thromboembolic complications, especially in critically ill patients. The pathogenesis is likely due to endothelial injury, immobilization, and an increase in circulating prothrombotic factors. Data on treatment are limited, although prophylactic anticoagulation is advised in all hospitalized patients. Herein, we have comprehensively reviewed the current literature available on CAC and highlight the pathogenesis, clinical features, and management of CAC.

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.

Allogeneic Peripheral Blood Stem Cell Transplant: Correlation of Donor Factors with Yield, Engraftment, Chimerism, and Outcome: Retrospective Review of a Single Institute During a 3-Year Period.

BACKGROUND: Donor factors have a variable correlation with cluster of differentiation (CD)34+ cell dose in allogeneic peripheral blood stem cell (PBSC) harvests. CD34+ cell dose affects the speed of hematopoietic recovery and percentage of donor chimerism in the recipient. METHODS: A total of 25 allogeneic PBSC transplants performed during a 3-year period were included. All donors underwent mobilization with filgrastim. Leukapheresis, flowcytometric CD34+ cell enumeration, and chimerism analysis were performed and correlated with recipient outcome. RESULTS: Besides age, all other donor parameters had a positive correlation with CD34+ cell count. Engraftment kinetics and chimerism had a positive correlation with the CD34+ yield of the PBSC product. Acute graft-vs-host disease (GVHD) was observed in patients with complete chimerism at day 30 after transplantation. CONCLUSION: Adequate CD34+ cell yield happens in healthy donors, independent of donor demographic patterns with G-CSF only. A diverse population of donors can thus be approached for Matched Unrelated Donor (MUD) transplants. An accurate quantitative analysis of early donor chimerism in the recipient (at day 30) is an excellent tool for post-transplant monitoring for acute GvHD.

Promising role of filgrastim and α-tocopherol succinate in amelioration of gastrointestinal acute radiation syndrome (GI-ARS) in mice.

The protective role of α-tocopherol succinate (α-TCS) and the therapeutic efficacy of filgrastim were investigated in gastrointestinal acute radiation syndrome (GI-ARS) induced following 10 Gy whole-body γ-irradiation. Mice were randomly allocated into 5 groups: [1] normal-control, [2] irradiated-control, [3] subcutaneous (s.c.) injection of filgrastim (5 µg/kg/day) for 4 consecutive days given 1 h post-irradiation, [4] s.c. injection with α-TCS (400 mg/kg) 1 day prior to irradiation, [5] s.c. injection with α-TCS (400 mg/kg) 1 day prior to irradiation and filgrastim (5 µg/kg/day) for 4 consecutive days 1 h post-irradiation. Histopathological analysis, serum citrulline level, intestinal interleukin-1ß (IL-1ß), reduced glutathione (GSH), and malondialdehyde (MDA) contents as well as myeloperoxidase (MPO) activity were measured. Intestinal caspase-3, p53, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) immunopositivity were examined. In irradiated-control, MDA increased (249%) and GSH decreased (25%) compared to normal and were unaffected by filgrastim. α-TCS alone significantly reduced MDA (84.5%) and normalized GSH. The combination significantly reduced MDA (59%) and dramatically increased GSH (1573%), pointing to a possible synergistic action. In irradiated-control, MPO and IL-1ß significantly increased (111% and 613%, respectively) compared to normal-control and both were significantly decreased in all treated groups. Compared to normal-control, citrulline significantly declined (68%) in irradiated-control; a significant elevation was achieved by treatments with α-TCS alone or combined with filgrastim (88% and 94%, respectively). The combination therapy significantly decreased the degree of irradiation-induced injury of the epithelium and cellular infiltration and showed the lowest histopathological scoring compared to the other groups (p ≤ 0.05). In irradiated-control, immune-reactive expressions of iNOS, COX-2, caspase-3, and p53 were remarkable (18.62%, 34.27%, 31.19%, and 27.44%, respectively) and after combination therapy were reduced (1.04%, 22.39%, 8.76%, and 4.91%, respectively). The current findings represent a first-hand strategy in dealing with GI-ARS with a potential preference to using a combined therapy of filgrastim and α-TCS.

Research progress in the biological activities of 3,4,5-trimethoxycinnamic acid (TMCA) derivatives.

TMCA (3,4,5-trimethoxycinnamic acid) ester and amide are privileged structural scaffolds in drug discovery which are widely distributed in natural products and consequently produced diverse therapeutically relevant pharmacological functions. Owing to the potential of TMCA ester and amide analogues as therapeutic agents, researches on chemical syntheses and modifications have been carried out to drug-like candidates with broad range of medicinal properties such as antitumor, antiviral, CNS (central nervous system) agents, antimicrobial, anti-inflammatory and hematologic agents for a long time. At the same time, SAR (structure-activity relationship) studies have draw greater attention among medicinal chemists, and many of the lead compounds were derived for various disease targets. However, there is an urgent need for the medicinal chemists to further exploit the precursor in developing chemical entities with promising bioactivity and druggability. This review concisely summarizes the synthesis and biological activity for TMCA ester and amide analogues. It also comprehensively reveals the relationship of significant biological activities along with SAR studies.

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.

Decreased Cytochrome P450 3A activity in palliative patients with haematological diseases: Potential impact on supportive drug therapies.

Cytochrome P450 3A (CYP3A) is the most relevant drug-metabolizing enzyme in human beings involved in the elimination of about 50% of the marketed drugs. Comprehensive in vivo data of CYP3A activity in palliative patients with haematological diseases are missing. Therefore, CYP3A activity was determined under real-life clinical conditions in patients to gain knowledge about dose adjustments for supportive therapies and symptom management in haematology. The single-arm, prospective trial obtained a 4-hours pharmacokinetic profile of midazolam after oral administration of a microdose as marker substance from each enrolled patient. Plasma concentrations of midazolam and its primary metabolite 1'-hydroxy-midazolam were quantified by mass spectrometry techniques. CYP3A activity was calculated as partial metabolic clearance from an established limited sampling area under the curve. All other drugs taken by the participating patients were considered as well as recent laboratory test results and the patients' diagnoses. Partial metabolic clearance of midazolam in patients with haematological diseases was highly variable (36.9 ± 52.7 L/h). In comparison with the CYP3A activity of healthy individuals, this was a highly significant 30% reduction of activity (P < 0.0001). Dosing of major CYP3A substrate drugs needs to be reduced in palliative patients with haematological diseases, otherwise escalation of debilitating symptoms due to drug interactions might occur.

Application of G-CSF in Congestive Heart Failure Treatment.

INTRODUCTION: Congestive Heart Failure (CHF) is a disorder in which the heart is unable to supply enough blood for body tissues. Since heart is an adaptable organ, it overcomes this condition by going under remodeling process. Considering cardiac myocytes are capable of proliferation after MI, stimulation of neovascularization as well as their regeneration might serve as a novel target in cardiac remodeling prevention and CHF treatment. Granulocyte Colony-Stimulating Factor (G-CSF), is a hematopoietic cytokine that promotes proliferation and differentiation of neutrophils and is involved in cardiac repair after MI. So far, this is the first review to focus on GCSF as a novel treatment for heart failure. METHODS: We conducted a search of some databases such as PubMed for articles and reviews published between 2003 and 2017, with different keywords including "G-CSF", "congestive heart failure", "new therapies for CHF", "filgrastim", "in vivo study". RESULTS: GCSF exerts its beneficial effects on cardiac repair through either stem cell mobilization or direct angiogenesis promotion. All of which are capable of promoting cardiac cell repair. CONCLUSION: GCSF is a promising target in CHF-therapy by means of cardiac repair and remodeling prevention through multiple mechanisms, which are effective enough to be used in clinical practice.

Modification of the Myelotoxic and Antitumor Effects of Polychemotherapy by Polysaccharides from Tussilago farfara L.

The experiments on C57Bl/6 mice with Lewis lung carcinoma showed that addition of Tussilago farfara L. polysaccharides to conventional cisplatin/paclitaxel polychemotherapy moderated neutropenia caused by antitumor therapy and increased its efficiency. The stimulating effect of polysaccharides on the granulopoietic lineage cells is comparable with that of recombinant CSF Neupogen.

Influence of Modified Fucoidan and Related Sulfated Oligosaccharides on Hematopoiesis in Cyclophosphamide-Induced Mice.

Immunosuppression derived after cytostatics application in cancer chemotherapy is considered as an adverse side effect that leads to deterioration of quality of life and risk of infectious diseases. A linear sulfated (1→3)-α-l-fucan M-Fuc prepared by chemical modification of a fucoidan isolated from the brown seaweed Chordaria flagelliformis, along with two structurally related synthetic sulfated oligosaccharides, were studied as stimulators of hematopoiesis on a model of cyclophosphamide immunosuppression in mice. Recombinant granulocyte colony-stimulating factor (r G-CSF), which is currently applied in medicine to treat low blood neutrophils, was used as a reference. Polysaccharide M-Fuc and sulfated difucoside DS did not demonstrate significant effect, while sulfated octasaccharide OS showed higher activity than r G-CSF, causing pronounced neutropoiesis stimulation. In addition, production of erythrocytes and platelets was enhanced after the octasaccharide administration. The assessment of populations of cells in blood and bone marrow of mice revealed the difference in mechanisms of action of OS and r G-CSF.

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.

Peripheral Blood Stem Cell Mobilization in Healthy Donors by Granulocyte Colony-Stimulating Factor Causes Preferential Mobilization of Lymphocyte Subsets.

Background: Allogeneic hematopoietic stem cell transplantation is associated with a high risk of immune-mediated post-transplant complications. Graft depletion of immunocompetent cell subsets is regarded as a possible strategy to reduce this risk without reducing antileukemic immune reactivity. Study design and methods: We investigated the effect of hematopoietic stem cell mobilization with granulocyte colony-stimulating factor (G-CSF) on peripheral blood and stem cell graft levels of various T, B, and NK cell subsets in healthy donors. The results from flow cytometric cell quantification were examined by bioinformatics analyses. Results: The G-CSF-induced mobilization of lymphocytes was a non-random process with preferential mobilization of naïve CD4+ and CD8+ T cells together with T cell receptor αß+ T cells, naïve T regulatory cells, type 1 T regulatory cells, mature and memory B cells, and cytokine-producing NK cells. Analysis of circulating lymphoid cell capacity to release various cytokines (IFNγ, IL10, TGFß, IL4, IL9, IL17, and IL22) showed preferential mobilization of IL10 releasing CD4+ T cells and CD3-19- cells. During G-CSF treatment, the healthy donors formed two subsets with generally strong and weaker mobilization of immunocompetent cells, respectively; hence the donors differed in their G-CSF responsiveness with regard to mobilization of immunocompetent cells. The different responsiveness was not reflected in the graft levels of various immunocompetent cell subsets. Furthermore, differences in donor G-CSF responsiveness were associated with time until platelet engraftment. Finally, strong G-CSF-induced mobilization of various T cell subsets seemed to increase the risk of recipient acute graft versus host disease, and this was independent of the graft T cell levels. Conclusion: Healthy donors differ in their G-CSF responsiveness and preferential mobilization of immunocompetent cells. This difference seems to influence post-transplant recipient outcomes.

CXCR4, the master regulator of neutrophil trafficking in homeostasis and disease.

BACKGROUND: Chemokines play a critical role in orchestrating the distribution and trafficking of neutrophils in homeostasis and disease. RESULTS: The CXCR4/CXCL12 chemokine axis has been identified as a central regulator of these processes. CONCLUSION: In this review, we focus on the role of CXCR4/CXCL12 chemokine axis in regulating neutrophil release from the bone marrow and the trafficking of senescent neutrophils back to the bone marrow for clearance under homeostasis and disease. We also discuss the role of CXCR4 in fine-tuning neutrophil responses in the context of inflammation.

Filgrastim use in patients receiving chemotherapy for early-stage breast cancer-a survey of physicians and patients.

PURPOSE: Despite its widespread use as primary febrile neutropenia (FN) prophylaxis during chemotherapy for early-stage breast cancer, the optimal duration of daily filgrastim is unknown. Using the minimum effective duration may improve patient comfort and acceptability while reducing costs. Yet, suboptimal dosing may also negatively impact patient care. A survey was performed to obtain information regarding current practices for granulocyte colony-stimulating factor (G-CSF) use. METHODS: Canadian oncologists involved in the treatment of breast cancer patients, as well as patients who had received neo/adjuvant chemotherapy for breast cancer, were surveyed. Standardized surveys were designed to collect information on perceived reasons for G-CSF use and current practices. RESULTS: The surveys were completed by 38/50 (76%) physicians and 95/97 (98%) patients. For physicians, there was variability in the choice of chemotherapy regimens that required G-CSF support, the dose of filgrastim prescribed and the number of days prescribed. The majority of physicians reported using 5 (31.6%), 7 (47.4%), or 10 (13.2%) days of therapy. Nearly half of the patients (46.3%) recalled having experienced at least one of the chemotherapy-related complications including chemotherapy delays, dose reductions, and FN. While on filgrastim, 66.3% of patients reported myalgia and bone pain. Both physicians and patients expressed interest in participating in clinical trials designed to optimize the duration of filgrastim administration. CONCLUSIONS: Significant variability in practice exists with respect to filgrastim administration. Definitive studies are therefore required to standardize and improve care, as this has the potential to impact treatment outcomes, patient quality of life, and cost savings.

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.