Relationship Between Absolute Neutrophil Count Profiles and Pharmacokinetics of DA-3031, a Pegylated Granulocyte Colony-Stimulating Factor (Pegylated-G-CSF): A Dose Block-Randomized, Double-Blind, Dose-Escalation Study in Healthy Subjects

Ahn, Li Young; Shin, Kye Chul; Lim, Kyoung Soo; Kim, Tae Eun; Jeon, Hyewon; Yoon, Seo Hyun; Cho, Joo Youn; Shin, Sang Goo; Jang, In Jin; Yu, Kyung‐Sang

doi:10.1007/s40261-013-0130-9

Cited by 8 publications

(20 citation statements)

References 18 publications

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“…Neulasta (pegfilgrastim) has been approved and marketed in the European Union and in the United States since 2002, and its efficacy and safety have been demonstrated in a variety of tumor types and settings 8–11 . Globally, several pegfilgrastim biosimilars have been developed 12–16 . and approved by the US Food and Drug Administration, European Medicines Agency, and other regulators.…”

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confidence: 99%

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Pharmacokinetics and Pharmacodynamics of Two Formulations of Pegylated Recombinant Human Granulocyte Colony‐Stimulating Factor in Healthy Chinese Subjects: An Open‐Label, Randomized, Parallel‐Design Bioavailability Study

et al. 2020

Clinical Pharm in Drug Dev

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Pegylated recombinant human granulocyte colony‐stimulating factor (PEG‐rhG‐CSF, pegfilgrastim) is a long‐acting derivative of recombinant human granulocyte colony‐stimulating factor with limited renal clearance and a longer half‐life. It is used for the prevention of febrile neutropenia, owing to its capacity to promote neutrophil recovery. In this study, the pharmacokinetics, pharmacodynamics, safety, and immunogenicity of 2 formulations of PEG‐rhG‐CSF were evaluated in healthy Chinese subjects. Twenty‐four male subjects who received a single dose of subcutaneous PEG‐rhG‐CSF 100 µg/kg were randomized to either treatment A (3 mg/mL) or treatment B (1 mg/mL). Noncompartmental pharmacokinetic parameters of PEG‐rhG‐CSF were derived from serum concentration‐time data. In addition, absolute neutrophil count (ANC) as a pharmacodynamic maker, immunogenicity through antidrug antibody testing, and safety were evaluated. The mean area under the concentration‐time curve from time zero to the last quantifiable concentration (AUC0‐t) and the mean maximum concentration (Cmax) of PEG‐rhG‐CSF after treatment A were 5070 ng·h/mL and 125 ng/mL, respectively; these values were comparable to those measured after treatment B (5340 ng·h/mL and 123 ng/mL, respectively). The mean value of area under the △ANC (baseline‐adjusted ANC)‐time curve and the maximum △ANC values were 4380 × 109 h/L and 33.1 × 109/L, respectively, in the treatment A group, and 5170 × 109 h/L and 38.6 × 109/L, respectively, in the treatment B group. The pharmacokinetic and pharmacodynamic profiles were similar for the 2 PEG‐rhG‐CSF formulations following a single dose of 100 µg/kg. The safety and immunogenicity profiles were also similar, with no significant differences. The dose adjustment of PEG‐rhG‐CSF was not considered necessary for formulation transformation.

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confidence: 99%

“…[8][9][10][11] Globally, several pegfilgrastim biosimilars have been developed. [12][13][14][15][16] and approved by the US Food and Drug Administration, European Medicines Agency, and other regulators. However, Neulasta was not marketed in China until 2012, and only 2 biosimilars have been approved by Chinese National Medical Products Administration (NMPA).…”

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confidence: 99%

Pharmacokinetics and Pharmacodynamics of Two Formulations of Pegylated Recombinant Human Granulocyte Colony‐Stimulating Factor in Healthy Chinese Subjects: An Open‐Label, Randomized, Parallel‐Design Bioavailability Study

et al. 2020

Clinical Pharm in Drug Dev

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“…It is measured daily and different metrics are derived from it, including the DSN. These ANC‐derived metrics, including the area under the effect curve (AUEC) of ANC, depth and time of ANC nadir, and time to ANC recovery, are also used as secondary efficacy endpoints …”

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confidence: 99%

Quantitative Relationship Between AUEC of Absolute Neutrophil Count and Duration of Severe Neutropenia for G‐CSF in Breast Cancer Patients

Schrieber

et al. 2018

Clin Pharma and Therapeutics

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The aim of the study was to evaluate the quantitative relationship between duration of severe neutropenia (DSN, the efficacy endpoint) and area under effect curve of absolute neutrophil counts (ANC-AUEC, the pharmacodynamic endpoint), based on data from filgrastim products, a human granulocyte colony-stimulating factor (G-CSF). Clinical data from filgrastim product comparator and test arms of two randomized, parallel-group, phase III studies in breast cancer patients treated with myelosuppressive chemotherapy were utilized. A zero-inflated Poisson regression model best described the negative correlation between DSN and ANC-AUEC. The models predicted that with 10 × 10 day/L of increase in ANC-AUEC, the mean DSN would decrease from 1.1 days to 0.93 day in Trial 1 and from 1.2 days to 1.0 day in Trial 2. The findings of the analysis provide useful information regarding the relationship between ANC and DSN that can be used for dose selection and optimization of clinical trial design for G-CSF.

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“…During the past decade or so, great efforts have been directed at finding a more stable and thus more effective G-CSF, given the instability of the wildtype G-CSF in vivo. Amino acid locus mutation as well as chemical modifications of G-CSF have been reported [12][13][14][15], and PEG-rhG-CSF injection has already been marketed [16,17]. Our previous studies showed that G-CSFa is more potent in stimulating proliferation and differentiation of myeloid cells of the granulocytic lineage than the wild-type counterpart, both in vitro and in vivo [6].…”

Section: Discussionmentioning

confidence: 99%

A Novel Recombinant Human Granulocyte Colony-Stimulating Factor (G-CSFa) Enhances Peripheral Platelet Recovery in Mice Exposed to adiotherapy and Has No Immunogenicity in Rats

Jie¹

2014

J Carcinog Mutagen

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Using site-direct mutagenesis and recombinant DNA technology, we had previously obtained a structurally modified derivative of human G-CSF termed G-CSFa. G-CSFa contains alanine 17 (instead of cysteine 17 as in wildtype G-CSF) as well as four additional amino acids (methionine, arginine, glycine and serine) at the amino terminus. Previous studies showed that G-CSFa is more potent than the wild-type counterpart in stimulating proliferation and differentiation of myeloid cells of the granulocytic lineage, both in vitro and in vivo. Here, we show that G-CSFa can significantly accelerate peripheral platelet recovery in C57BL/6 mice exposed to radiotherapy. We further demonstrate that G-CSFa is not immunogenic in rats, by confirming the absence of any binding antibodies, analyzed using ELISA, or neutralizing antibodies, determined using the NFS-60 cell proliferation bioassay, to G-CSFa in the sera of Sprague-Dawley rats following repeated G-CSFa administration. Taken together, these findings further support the benefits of G-CSFa for clinical therapy.

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Relationship Between Absolute Neutrophil Count Profiles and Pharmacokinetics of DA-3031, a Pegylated Granulocyte Colony-Stimulating Factor (Pegylated-G-CSF): A Dose Block-Randomized, Double-Blind, Dose-Escalation Study in Healthy Subjects

Abstract: DA-3031 showed non-linear pharmacodynamic and pharmacokinetic profiles and an extended duration of action compared with non-modified filgrastim, without unexpected toxicities in healthy subjects.

Cited by 8 publications

References 18 publications

Pharmacokinetics and Pharmacodynamics of Two Formulations of Pegylated Recombinant Human Granulocyte Colony‐Stimulating Factor in Healthy Chinese Subjects: An Open‐Label, Randomized, Parallel‐Design Bioavailability Study

Pharmacokinetics and Pharmacodynamics of Two Formulations of Pegylated Recombinant Human Granulocyte Colony‐Stimulating Factor in Healthy Chinese Subjects: An Open‐Label, Randomized, Parallel‐Design Bioavailability Study

Quantitative Relationship Between AUEC of Absolute Neutrophil Count and Duration of Severe Neutropenia for G‐CSF in Breast Cancer Patients

A Novel Recombinant Human Granulocyte Colony-Stimulating Factor (G-CSFa) Enhances Peripheral Platelet Recovery in Mice Exposed to adiotherapy and Has No Immunogenicity in Rats

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