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Comparison of biosimilar filgrastim with a reference product: pharmacokinetics, pharmacodynamics, and safety profiles in healthy volunteers.

ABSTRACT: Purpose:Filgrastim, a granulocyte-colony stimulating factor, is used to treat patients with neutropenia, including neutropenic fever. Leucostim® is a recombinant filgrastim product tested for biosimilarity with its reference product, Neupogen®. We conducted a comparative clinical trial of the 2 products. Patients and methods:A randomized, open-label, 2-way crossover, single-dose Phase I study was conducted for 56 healthy subjects. After a 5 and 10 ?g/kg single subcutaneous administration of test and reference product, pharmacokinetic and pharmacodynamic parameters (absolute neutrophil count and CD34+ cell count) were compared. During the study, safety tests and adverse event monitoring were performed. Results:The test and the reference products had a comparable pharmacokinetic, pharmacodynamic, and safety profile. In both 5 and 10 ?g/kg dosing, the 90% CIs of the test to reference ratio for primary parameters (peak plasma concentration and area under the plasma concentration vs time curve from time 0 extrapolated to the infinite time for plasma filgrastim concentration; maximal effect and area under the time-effect curve from time 0 to time of the last quantifiable effect for absolute neutrophil count) were within the 0.8-1.25 range. In addition, safety profiles between the 2 products were similar without any serious adverse events. Conclusion:This study has provided firm clinical evidence that the test filgrastim product is similar to its reference filgrastim product.

SUBMITTER: Choi C

PROVIDER: S-EPMC6078186 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Three comparative clinical studies assessed the pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity and safety of PF-06881893 (filgrastim-aafi; Nivestym™), a filgrastim biosimilar, versus US-licensed reference product (filgrastim; US-Neupogen®) in healthy volunteers (HVs). METHODS:Two separate open-label, crossover-design PK/PD studies were conducted: a single-dose study (n?=?24) and a multiple-dose study (n?=?60). In each study, HVs were randomized to Nivestym followed by US-Neupogen, or vice versa. Study drug (5 ?g/kg) was administered subcutaneously as a single injection or as five consecutive daily injections. Primary PK and PD endpoints were area under the filgrastim serum concentration-time curve, maximum observed concentration, area under the effect curve (AUEC) for absolute neutrophil count (ANC), maximum observed ANC, AUEC for cluster of differentiation (CD)-34+ count, and maximum observed CD34+ count. In an open-label, parallel-design, non-inferiority, comparative immunogenicity study, HVs were randomized (n?=?128/treatment) to Nivestym or US-Neupogen. The primary endpoint was the proportion of subjects with a negative baseline antidrug antibody (ADA) test result and one or more confirmed post-dose positive ADA result. RESULTS:Overall demographics were as follows: female (n?=?162/340); White (n?=?274/340), Black (n?=?58/340), and other (n?=?8/340); age (18-65 years); and weight (50.8-96.5 kg). All primary PK and PD endpoints met the pre-specified criteria for PK and PD equivalence. The primary endpoint in the comparative immunogenicity study met pre-specified criteria for non-inferiority. CONCLUSIONS:Nivestym demonstrated PK and PD equivalence in single and multiple subcutaneous-dose settings and non-inferiority for immunogenicity to US-Neupogen, with a comparable safety profile, supporting the demonstration of biosimilarity. TRIAL REGISTRATION:ClinicalTrials.gov C1121002 (NCT02766647); C1121003 (NCT02766634); C1121012 (NCT02923791).

Project description:ONS-3010 is being developed by Oncobiologics Inc. (Cranbury, NJ, USA) as a biosimilar of Humira®. This randomized, double blind, single-center phase I study (EudraCT registration # 2013-003551-38) was performed to demonstrate pharmacokinetic (PK) biosimilarity between two reference products (Humira® EU and US) and ONS-3010 in healthy volunteers, and to compare the safety and immunogenicity profiles. In addition, the intended pharmacological activity was assessed and compared by application of a whole blood challenge. Hundred ninety-eight healthy volunteers received a single 40?mg subcutaneous dose of ONS-3010, Humira® EU, or US. The pharmacodynamic effects were assessed by lipopolysaccharide (LPS)/aluminum hydroxide whole blood challenges (n?=?36; n?=?12 per treatment arm; male:female, 1:1). Equivalence was demonstrated on the PK endpoints (AUC0-inf, Cmax, and AUC0-last) based on bounds of 80-125% for the ratio of the geometric means (ONS-3010/Humira®). The immunogenicity profiles were comparable between treatment groups, and there were no indications for differences in routine safety parameters. Administration of adalimumab resulted in the observation of dramatically reduced tumor necrosis factor-? (TNF?) levels upon stimulation with LPS/aluminum hydroxide (>99%), with no differences between the three treatment groups in terms of magnitude or duration. Adalimumab also resulted in a reduction of LPS/aluminum hydroxide-induced interleukin (IL)-8 release (maximally 30%), suggested to have a causal relationship with the anti-TNF? treatment. LPS/aluminum hydroxide-induced release of IL-1? and IL-6 was not inhibited by anti-TNF? treatment. Taken together, these data are promising for the further clinical development of ONS-3010, demonstrate the relevance of the LPS/aluminum challenge to monitor Humira® effects, and emphasize the value of whole blood challenges for monitoring of proximal drug effects in healthy volunteers, and potentially in the target population.

Project description:AimsThis 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.MethodsThe 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).ResultsOverall, 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.ConclusionsPK/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.

Project description:IntroductionPF-06881894 is a proposed biosimilar to pegfilgrastim (Neulasta®). This study evaluated the pharmacodynamic/pharmacokinetic (PD/PK) equivalence, immunogenicity, and safety of PF-06881894 vs pegfilgrastim reference products (US- and EU-Neulasta®) in healthy volunteers.MethodsA phase 1, open-label, randomized, crossover study was conducted to assess the pharmacologic equivalence and safety of a single 6-mg dose of PF-06881894, pegfilgrastim-US, and pegfilgrastim-EU. The primary PD endpoints were area under the effect-versus-time curve for absolute neutrophil count (ANC) from dose administration to 288 h postdose, and maximum observed ANC value among subjects confirmed negative for anti-pegfilgrastim antibodies. Primary PK variables included area under the serum pegfilgrastim-versus-time curve from the time of dose administration to time infinity and maximum observed serum pegfilgrastim concentration. A second phase 1, open-label, randomized (1:1), parallel-group, non-inferiority study was conducted to assess the immunogenicity and safety of multiple 6-mg doses of PF-06881894 versus pegfilgrastim-US. The primary endpoint for the immunogenicity study was the proportion of subjects with both negative baseline and confirmed positive postdose anti-pegfilgrastim antibodies at any time during the study.ResultsAcross the single- and multiple-dose studies (N = 153 and N = 420 treated subjects, respectively), demographics for age (18-65 years), male gender (n = 264/573), and white race (n = 423/573) were similar. Three-way PD/PK equivalence of PF-06881894, pegfilgrastim-US, and pegfilgrastim-EU was demonstrated with the primary PD endpoints and primary PK variables being completely contained within the predefined 90% confidence interval acceptance limits (80-125%). The non-inferiority of PF-06881894 versus pegfilgrastim-US in terms of immunogenicity was established according to the prespecified non-inferiority margin (≤10%). Overall, there were no clinically meaningful differences in safety profiles among or between study groups.ConclusionsSingle-dose PF-06881894 demonstrated PD/PK equivalence and comparable safety with US- and EU-pegfilgrastim reference products. Multiple-dose PF-06881894 demonstrated immunogenicity non-inferiority to pegfilgrastim-US with comparable safety. Both studies contributed to the totality of evidence supporting biosimilarity.Trial registrationClinicalTrials.gov identifiers: NCT02629289; NCT03273842 (C1221005).

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Comparison of biosimilar filgrastim with a reference product: pharmacokinetics, pharmacodynamics, and safety profiles in healthy volunteers.

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