Filgrastim (r-metHuG-CSF) in the 21st Century: SD/01

Morstyn, George; Foote, MaryAnn; Walker, Timothy D.; Molineux, Graham

doi:10.1159/000046557

Cited by 36 publications

(21 citation statements)

References 6 publications

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“…Although we observed some changes in other blood cell counts in both the normal dog and the gray collie dog, the changes were minor compared with the changes in blood neutrophils, a finding consistent with the natural role of G-CSF in regulating neutrophil production (Morstyn et al, 2001). Some of the observed changes in hematocrit and lymphocyte counts may have been age related, because both dogs entered the study at a very young age.…”

Section: Discussionsupporting

confidence: 75%

“…In these dogs recurrent severe neutropenia leads to bacterial infections and shortened life expectancy (Lothrop et al, 1988;Hammond et al, 1990). Current treatment includes antibiotics for infections and daily administration of recombinant human granulocyte colony-stimulating factor (G-CSF) to prevent neutropenia and infections (Morstyn et al, 2001;Lyman, 2005). In humans, the disease is usually caused by mutations in ELANE, the gene for neutrophil elastase, and daily subcutaneous administration of recombinant human G-CSF reduces the severity of the recurrent neutropenia and thereby greatly ameliorates the disease (Morstyn et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

“…Current treatment includes antibiotics for infections and daily administration of recombinant human granulocyte colony-stimulating factor (G-CSF) to prevent neutropenia and infections (Morstyn et al, 2001;Lyman, 2005). In humans, the disease is usually caused by mutations in ELANE, the gene for neutrophil elastase, and daily subcutaneous administration of recombinant human G-CSF reduces the severity of the recurrent neutropenia and thereby greatly ameliorates the disease (Morstyn et al, 2001). G-CSF delivery by gene therapy using lentiviral vectors is an alternative approach to the treatment of cyclic neutropenia and other diseases causing severe chronic neutropenia.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Repeated Lentivirus-Mediated Granulocyte Colony-Stimulating Factor Administration to Treat Canine Cyclic Neutropenia

2012

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Section: Discussionsupporting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Repeated Lentivirus-Mediated Granulocyte Colony-Stimulating Factor Administration to Treat Canine Cyclic Neutropenia

2012

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“…Pegfilgrastim (Peg-G) comprises the protein filgrastim, to which a polyethylene glycol (Peg) molecule is bound covalently to the N-terminal methionine residue (19,20). It was first approved in the United States in 2002, and approved for use in Japan in November 2014.…”

Section: Resultsmentioning

confidence: 99%

Chemotherapy continuity and incidence of febrile neutropenia with CHOP therapy in an outpatient setting

Usami

Kimura

Iwai

et al. 2016

Molecular and Clinical Oncology

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Abstract. The cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) regimen is considered to be a standard treatment for non-Hodgkin's lymphoma (NHL). Patients receiving CHOP chemotherapy often experience febrile neutropenia (FN) due to myelotoxicity. The proper management of FN is essential to guarantee a positive outcome of the NHL treatment. Therefore, the present study retrospectively examined chemotherapy continuity and the incidence of FN during CHOP therapy in an outpatient setting. The subjects were 136 patients who received CHOP chemotherapy between January 2012 and December 2014. A total of 31 patients unable to be treated in an outpatient setting were excluded from the study. Of the remaining 105 patients, 73 patients who did not require hospitalization during the chemotherapy treatment were included in the non-hospitalized group, and 32 patients who required hospitalization during chemotherapy treatment were included in the re-hospitalization group. The numbers of patients from these two groups who completed the planned treatment were 71 and 24, respectively (P<0.01). In addition, the duration of granulocyte-colony stimulating factor (G-CSF) treatment was 5.3±1.22 and 6.1±1.46 days, respectively (P<0.01). The numbers of patients experiencing FN in an outpatient setting were 14 and 19, respectively (P<0.01). During administration of primary prophylaxis with G-CSF, the incidence of FN was 21.0% (22/105) in cycle 1. In conclusion, the present study has revealed a requirement to educate patients about infection prevention prior to the first cycle of chemotherapy. Patients who require the administration of long-term G-CSF are at risk of unplanned re-hospitalization, and treating them with polyethylene glycol G-CSF to reduce the number of required injections should be considered as an option. Therefore, proper supportive therapy and management of infection are important to safely treat patients with CHOP in an outpatient setting.

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“…The PEG modification effectively eliminates renal clearance of the drug (Johnston et al, 2000); therefore, depletion is essentially mediated by neutrophil uptake and degradation. The experimentally measured lifetime of SD/01 is dose-dependent, but is approximately 4 to 5 days in rats (Morstyn et al, 2001).…”

Section: Effects Of Nonspecific Clearance ()mentioning

confidence: 95%

Cell-Level Pharmacokinetic Model of Granulocyte Colony-Stimulating Factor: Implications for Ligand Lifetime and Potency in Vivo

Sarkar

Lauffenburger

2003

Molecular Pharmacology

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The cytokine granulocyte colony-stimulating factor (GCSF) is of great clinical importance, with primary application to rapidly elevate the peripheral neutrophil levels of chemotherapy patients through accelerated granulopoiesis. However, these mature bloodstream neutrophils express the GCSF receptor (GCSFR), presenting a significant and specific clearance mechanism of circulating GCSF that increases with time. Here, we formulate a mathematical model that describes these cell-level GCSF/GCSFR dynamics and correlate the effect of these endocytic trafficking processes to ligand depletion in an in vitro culture. We further incorporate this cell-level model into an existing pharmacokinetic/pharmacodynamic (PK/PD) model, to gain insight into the effects that specific molecular and cellular parameters may have on overall PK/PD effects in vivo. Our cell-level model suggests that ligand depletion may be reduced in vitro by decreasing the endosomal affinity of endocytosed GCSF/GCSFR complexes, matching experimental findings. Additionally, our modified PK/PD model suggests that a GCSF analog with a modification that effectively eliminates renal clearance should have a significantly longer half-life in vivo and should therefore improve peripheral neutrophil counts. This is consistent with clinical studies on a polyethylene glycol chemical conjugate of GCSF termed SD/01. The model predicts that a GCSF analog that eliminates renal clearance and has reduced endosomal binding affinity may result in an even longer ligand half-life and increased neutrophil counts at a lower dose than either wild-type GCSF or SD/01. More generally, this type of hierarchical model provides a correlation between the molecular and pharmacological properties of a drug and may elucidate design goals for such protein therapeutics.Currently, the design and development of a therapeutic drug takes, on the average, 12 years and costs more than $800 million. Of this total cost, approximately one third is spent on drugs and experiments that fail. In addition, once a candidate drug makes it into clinical trials, the success rate is still less than 20%. One of the major problems in the development of a successful drug is the inability to correlate the effects of a molecular perturbation in the drug to the resulting effects in efficacy and half-life in vivo. This correlation can be particularly nonintuitive for protein therapeutics, such as hematopoietic cytokines, that act as agonists for cell-surface receptors.The pharmacodynamic properties of such agonists depend not only on receptor binding affinity but also on subsequent intracellular signaling cascades and endocytic trafficking of the cell-surface cytokine/receptor complexes. Endocytic trafficking often serves to attenuate the generated signals, resulting in ligand depletion and receptor down-regulation, which in turn reduces the pharmacodynamic potency of the drug over time. Furthermore, the pharmacokinetic profile of such a cytokine is often determined not only by nonspecific renal and hepatic cl...

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Filgrastim (r-metHuG-CSF) in the 21st Century: SD/01

Cited by 36 publications

References 6 publications

Repeated Lentivirus-Mediated Granulocyte Colony-Stimulating Factor Administration to Treat Canine Cyclic Neutropenia

Repeated Lentivirus-Mediated Granulocyte Colony-Stimulating Factor Administration to Treat Canine Cyclic Neutropenia

Chemotherapy continuity and incidence of febrile neutropenia with CHOP therapy in an outpatient setting

Cell-Level Pharmacokinetic Model of Granulocyte Colony-Stimulating Factor: Implications for Ligand Lifetime and Potency in Vivo

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