Pharmacokinetic and pharmacodynamic bioequivalence study of a pegfilgrastim biosimilar INTP5 in healthy subjects

Singh, Inderjeet; Patel, Akash J.; Patel, Ronak; Jose, Vinu

doi:10.1007/s00280-018-3620-x

Cited by 8 publications

(11 citation statements)

References 17 publications

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“…The absorption of PEG‐rhG‐CSF was slow, with an absorption time of approximately 12‐36 hours in both the test group and the reference group (Table 2). The terminal‐phase half‐life of PEG‐rhG‐CSF estimated after test product administration (38.0 ± 7.41 hours) was shorter than that estimated after administration of the reference product (43.8 ± 18.7 hours), but without clinical and statistical significance, and was consistent with a previous study 17 and peer reports 14–16 . The systemic exposure (AUC 0‐∞ and C max ) to PEG‐rhG‐CSF following administration of the test formulation (3 mg/mL) in Chinese subjects was a little lower than that of the reference formulation (1 mg/mL), which was most likely a result of the large variability (more than 50%) among the individual subjects.…”

Section: Discussionsupporting

confidence: 87%

“…Approximately 4 mL of whole blood was collected via an indwelling cannula (or by venipuncture) into tubes without any anticoagulant for PK analysis. Samples were collected at the following times: predose, 0.5, 2,4,8,12,16,24,36,48,72,96,120,144,168,192,216,240,264,288, and 312 hours after PEG-rhG-CSF administration. After 30 minutes, the blood samples were centrifuged at 2000g for 10 minutes, and the supernatant serum was aliquoted and stored at −80°C for further analysis.…”

Section: Pharmacokinetic Pharmacodynamic and Immunogenicity Assaymentioning

confidence: 99%

“…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.…”

mentioning

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).…”

mentioning

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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Section: Discussionsupporting

confidence: 87%

Section: Pharmacokinetic Pharmacodynamic and Immunogenicity Assaymentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

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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“…With no dose difference between 6 mg nominal doses of the reference and test products, the sample size would need to be ~ 125 to reach 80% power to conclude PK similarity. Recent similarity studies for PG report study sizes of 185 (15) and 172 (16) for a 6 mg dose which should be sufficient according to this analysis given negligible differences in delivered dose content between the products. However, the results of this work suggest that with a mere 2% difference in delivered dose, the number of patients recruited for those trials would not be sufficient to reach 80% power to conclude PK similarity.…”

Section: Discussionmentioning

confidence: 93%

Sensitivity of Pegfilgrastim Pharmacokinetic and Pharmacodynamic Parameters to Product Differences in Similarity Studies

Brekkan

López-Lázaro

Plan³

et al. 2019

AAPS J

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In this work, a previously developed pegfilgrastim (PG) population pharmacokinetic-pharmacodynamic (PKPD) model was used to evaluate potential factors of importance in the assessment of PG PK and PD similarity. Absolute neutrophil count (ANC) was the modelled PD variable. A two-way cross-over study was simulated where a reference PG and a potentially biosimilar test product were administered to healthy volunteers. Differences in delivered dose amounts or potency between the products were simulated. A different baseline absolute neutrophil count (ANC) was also considered. Additionally, the power to conclude PK or PD similarity based on areas under the PG concentration-time curve (AUC) and ANC-time curve (AUEC) were calculated. Delivered dose differences between the products led to a greater than dose proportional differences in AUC but not in AUEC, respectively. A 10% dose difference from a 6 mg dose resulted in 51% and 7% differences in AUC and AUEC, respectively. These differences were more pronounced with low baseline ANC. Potency differences up to 50% were not associated with large differences in either AUCs or AUECs. The power to conclude PK similarity was affected by the simulated dose difference; with a 4% dose difference from 6 mg the power was approximately 29% with 250 subjects. The power to conclude PD similarity was high for all delivered dose differences and sample sizes.

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Meta‐analysis of Pharmacokinetic/Pharmacodynamic Results of 3 Phase 1 Studies with Biosimilar Pegfilgrastim

Gattu

Wang

Bellon

et al. 2021

Clinical Pharm in Drug Dev

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A meta‐analysis using data from 3 phase 1 studies evaluated the pharmacokinetics (PK) and pharmacodynamics (PD) of Sandoz biosimilar versus US‐ and EU‐reference pegfilgrastim. The studies included a single‐dose, double‐blind, 3‐arm, parallel‐group study (study 1); a single‐dose, double‐blind, 2‐way crossover study (study 2); and a single‐dose, double‐blind, 3‐way, 6‐sequence crossover study (study 3). Healthy male and female subjects were randomized to receive the proposed biosimilar (all studies), US‐reference biologic (studies 1 and 3), or EU‐reference biologic (studies 1, 2, and 3). For PK parameters (area under the serum concentration–time curve from time of dosing and extrapolated to infinity, area under the serum concentration–time curve from the time of dosing to the last measurable concentration, and maximum observed serum concentration) and PD parameters (absolute neutrophil count area under the effect curve from the time of dosing to the last measurable concentration and maximum measured absolute neutrophil count) geometric mean ratios and 90% confidence intervals (CIs) for treatment comparisons were calculated using the meta‐analysis approach with a fixed‐effects model. PK/PD biosimilarity was concluded if the 90%CIs were within the equivalence margins of 0.80 to 1.25. The 90%CIs for the geometric mean ratios for the PK/PD parameters were all within the equivalence margins. Safety and tolerability were similar between the proposed biosimilar and the US‐ and EU‐reference pegfilgrastim in healthy subjects. This meta‐analysis of 3 phase 1 studies supports PK/PD similarity of Sandoz biosimilar pegfilgrastim to US‐ and EU‐reference pegfilgrastim. No clinically meaningful differences in safety or tolerability were observed.

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Pharmacokinetic and pharmacodynamic bioequivalence study of a pegfilgrastim biosimilar INTP5 in healthy subjects

Abstract: Pharmacokinetic and pharmacodynamic bioequivalence was established between INTP5 and Neulasta following 3 and 6 mg doses. Safety and immunogenicity profiles were similar between INTP5 and Neulasta.

Cited by 8 publications

References 17 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

Sensitivity of Pegfilgrastim Pharmacokinetic and Pharmacodynamic Parameters to Product Differences in Similarity Studies

Meta‐analysis of Pharmacokinetic/Pharmacodynamic Results of 3 Phase 1 Studies with Biosimilar Pegfilgrastim

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