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Recombinant Filgrastim (BK0023) Pharmacodynamics and Pharmacokinetics After Single and Multiple Escalating Doses in an Equivalence Study in Healthy Men

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Abstract

Background and objectives

The new filgrastim formulation, BK0023, whose synthesis method is patented, was tested in a phase I clinical study that was aimed at investigating the pharmacodynamic and pharmacokinetic equivalence and the safety of BK0023 in healthy male subjects.

Methods

Single and multiple escalating doses were administered to healthy male volunteers according to a double-blind, randomised, two-way crossover design. Thirty-two subjects received subcutaneous filgrastim 2.5 µg/kg/day for 7 consecutive days in each period, 36 subjects received 5 µg/kg/day for 7 days in each period, and 22 subjects received 10 µg/kg/day for 5 days. Absolute neutrophil count (ANC) and CD34+ cell count were measured in whole blood as primary and secondary pharmacodynamic parameters. Filgrastim concentrations were measured in serum to calculate the primary pharmacokinetic parameters.

Results

The maximum ANC and the area under the curve of the ANC after the first dose and to the end of treatment satisfied the equivalence criterion (95 % confidence intervals within 85–115 or 85–117 % in case of log-transformation). At all three dose regimens, BK0023 was also bioequivalent to the reference product in terms of pharmacokinetic profile of serum filgrastim. The frequency of the treatment-emergent adverse events did not differ significantly between treatments, with the most frequent untoward effects being back and bone pain.

Conclusions

Equivalence could be established using both the baseline-adjusted values and the original unadjusted values. The tested formulation at all three dose regimens was also bioequivalent to the reference product in terms of pharmacokinetic profile.

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Acknowledgments

The sponsor reviewed and approved the study design, and reviewed and approved the analysis and interpretation of data. Bio-Ker S.r.l. reviewed and approved the manuscript for publication.

Antonio Rusca and Milko M. Radicioni reviewed and approved the study design, were responsible for the clinical activities, and collected the data; Luca Loprete performed the pharmacodynamics and pharmacokinetic analysis; Domenica M. G. Lamparelli was responsible for the bioanalysis of ANC and CD34+ cells; Jutta Michael Hepp was responsible for the bioanalysis of filgrastim; Giancarlo Tonon, Davide Crobu and Rodolfo Schrepfer reviewed and approved the design of the study and the draft manuscript; Gaia Spinetti was involved in the development of the clinical study; and Andrea F. D. Di Stefano managed the study co-ordination, wrote the clinical trial report and drafted the manuscript. All authors read and approved the manuscript.

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Authors and Affiliations

  1. CROSS Research S.A., Via F.A. Giorgioli, 6864, Arzo, Switzerland

    Andrea F. D. Di Stefano, Antonio Rusca, Milko M. Radicioni & Luca Loprete

  2. Laboratory of Diabetological Research, IRCCS MultiMedica, Sesto San Giovanni, Italy

    Gaia Spinetti

  3. Accelera S.r.l., Nerviano, Italy

    Domenica M. G. Lamparelli

  4. Department of Immunoassay, Nuvisan GmbH, Neu-Ulm, Germany

    Jutta Michael Hepp

  5. Bio-ker S.r.l., Sardinia Science and Technology Park, Pula, Italy

    Davide Crobu, Rodolfo Schrepfer & Giancarlo Tonon

Authors
  1. Andrea F. D. Di Stefano
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  2. Gaia Spinetti
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  3. Antonio Rusca
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  4. Milko M. Radicioni
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  5. Luca Loprete
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  6. Domenica M. G. Lamparelli
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  7. Jutta Michael Hepp
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  8. Davide Crobu
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  9. Rodolfo Schrepfer
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  10. Giancarlo Tonon
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Corresponding author

Correspondence to Andrea F. D. Di Stefano.

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Funding

Financial support for this project was received from Bio-Ker S.r.l., Italy. The relationships between the sponsor, Bio-Ker S.r.l. and CROSS Research S.A., Accelera S.r.l., Nuvisan GmbH and IRCCS MultiMedica were regulated by financial agreements.

Conflicts of interest

Antonio Rusca, Milko M. Radicioni, Luca Loprete, Domenica M. G. Lamparelli, Jutta Michael Hepp and Andrea F. D. Di Stefano are employees of CROSS Research S.A., Accelera S.r.l. and Nuvisan GmbH, whose relationships with the sponsor were regulated by financial agreements. Giancarlo Tonon, Davide Crobu and Rodolfo Schrepfer are employees of Bio-ker S.r.l., and Gaia Spinetti is an employee of IRCCS MultiMedica; both companies are owned by MultiMedica Holding.

Ethical approval

The study was conducted in compliance with the Swiss ordinance on clinical trials of therapeutic agents and in accordance with the Declaration of Helsinki and the general principles of ICH Harmonised Tripartite Guidelines for GCP, and after approval by the competent Ethics Committee of Canton Ticino, Switzerland.

Informed consent

Written informed consent was received from all study subjects prior to undergoing any study procedure.

Additional information

Registered at ClinicalTrials.gov on 3 September 2013 (identifier NCT01933971).

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Di Stefano, A.F.D., Spinetti, G., Rusca, A. et al. Recombinant Filgrastim (BK0023) Pharmacodynamics and Pharmacokinetics After Single and Multiple Escalating Doses in an Equivalence Study in Healthy Men. Clin Drug Investig 35, 533–545 (2015). https://doi.org/10.1007/s40261-015-0310-x

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  • DOI: https://doi.org/10.1007/s40261-015-0310-x

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