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Population Pharmacokinetic Modelling of Filgrastim in Healthy Adults following Intravenous and Subcutaneous Administrations

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Abstract

Background and Objective: Filgrastim is a human granulocyte-colony stimulating factor (G-CSF). The biological activity of filgrastim is identical to that of endogenous G-CSF. It controls neutrophil production within the bone marrow by stimulating the proliferation, differentiation and survival of myeloid progenitor cells and some end-cell function activation. The purpose of this work is to propose a target-mediated drug disposition pharmacokinetic model of filgrastim.

Methods: A mechanism-based population pharmacokinetic model was developed to account for receptormediated endocytosis as a mechanism for nonlinear disposition of G-CSF. Time profiles of serum filgrastim concentrations following subcutaneous doses of 2.5, 5 and 10 μg/kg and intravenous infusion of 5 μg/kg over 0.5 hour were studied. The pharmacokinetic model included first-order elimination from the serum, receptor binding, turnover of free receptors and internalization of drug-receptor complexes. The proposed targetmediated drug disposition models served as a tool to study drug absorption and the impact of receptor binding on filgrastim clearance.

Results: Filgrastim was found to exhibit parallel absorption with first- and zero-order kinetics and bioavailability of 69.1%. The majority of the drug (58.6%) was absorbed by zero-order processes, presumably through the lymphatic system. The equilibrium dissociation constant (Kd) was estimated as 16.38 pM.

Conclusion: The proposed model predicts that clearance is initially mostly governed by the binding of filgrastim to G-CSF receptors. Subsequently, the clearance slows down because of the saturation of binding sites, and occurs mostly via the linear (renal) pathway. Finally, for G-CSF concentrations lower than the Kd, target-mediated clearance dominates. The presented receptor-mediated model adequately describes filgrastim serum concentrations and quantifies the role of receptor binding in G-CSF clearance.

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Acknowledgements

This study was sponsored by Novartis Pharmaceuticals AG (Basel, Switzerland). Etienne Pigeolet and Philip Lowe are employees of Novartis. Philip Lowe owns shares in Novartis. Wojciech Krzyzanski has received grants from Novartis. Paweł Wiczling, Frank Lüdicke and Sigrid Balser have no conflicts of interest that are directly relevant to the contents of this study.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, University at Buffalo, 547 Cooke Hall, Buffalo, New York, 14260, USA

    Pawel Wiczling &  Wojciech Krzyzanski

  2. Department of Biopharmaceutics and Pharmacodynamics, Medical University of Gdańsk, Gdańsk, Poland

    Pawel Wiczling

  3. Modeling & Simulation, Novartis Pharmaceuticals AG, Basel, Switzerland

    Philip Lowe & Etienne Pigeolet

  4. Sandoz Biopharmaceutical Development, Holzkirchen, Germany

    Frank Lüdicke & Sigrid Balser

Authors
  1. Pawel Wiczling
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  2. Philip Lowe
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  3. Etienne Pigeolet
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  4. Frank Lüdicke
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  5. Sigrid Balser
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  6. Wojciech Krzyzanski
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Corresponding author

Correspondence to Wojciech Krzyzanski.

Appendix

Appendix

The target-mediated disposition model of G-CSF was initially written in molar concentrations as follows (equations 15–17):

$${{{\rm{d}}[{{\rm{C}}_{\rm{s}}}]} \over {{\rm{dt}}}} = {{{\rm{Input}}} \over {{{\rm{M}}_{{\rm{G}} - {\rm{CSF}}}} \times {{\rm{V}}_{\rm{d}}}}} + {{{{\rm{k}}_{{\rm{G}} - {\rm{CSF}}}}} \over {{{\rm{M}}_{{\rm{G}} - {\rm{CSF}}}} \times {{\rm{V}}_{\rm{d}}}}} - {{\rm{k}}_{\rm{e}}}[{{\rm{C}}_{\rm{s}}}] - {{\rm{k'}}_{{\rm{on}}}}[{\rm{R}}][{{\rm{C}}_{\rm{s}}}] + {{\rm{k}}_{{\rm{off}}}}[{\rm{RC}}]$$
((Eq. 15))
$${{{\rm{d}}[{\rm{R}}]} \over {{\rm{dt}}}} = {{\rm{k}}_{{\rm{syn}}}} - {{\rm{k}}_{{\rm{deg}}}}[{\rm{R}}] - {{\rm{k'}}_{{\rm{on}}}}[{\rm{R}}][{{\rm{C}}_{\rm{s}}}] + {{\rm{k}}_{{\rm{off}}}}[{\rm{RC}}]$$
((Eq. 16))
$${{{\rm{d}}[{\rm{RC}}]} \over {{\rm{dt}}}} = {{\rm{k'}}_{{\rm{on}}}}[{\rm{R}}][{{\rm{C}}_{\rm{s}}}] - {{\rm{k}}_{{\rm{off}}}}[{\rm{RC}}] - {{\rm{k}}_{{\rm{int}}}}[{\rm{RC}}]$$
((Eq. 17))

where the square brackets denote molar concentrations and MG-CSF is the molar mass of G-CSF. Multiplying the above equations by MG-CSF and Vd led to equations 18–20:

$${{{\rm{d}}{{\rm{A}}_{\rm{s}}}} \over {{\rm{dt}}}} = {\rm{Input}} + {{\rm{k}}_{{\rm{G}} - {\rm{CSF}}}} - {{\rm{k}}_{\rm{e}}} \times {{\rm{A}}_{\rm{s}}} - {{\rm{k}}_{{\rm{on}}}}/{{\rm{V}}_{\rm{d}}} \times {\rm{R}} \times {{\rm{A}}_{\rm{s}}} + {{\rm{k}}_{{\rm{off}}}} \times {\rm{ARC}}$$
((Eq. 18))
$${{{\rm{dAR}}} \over {{\rm{dt}}}} = {{\rm{k}}_{{\rm{syn}}}} - {{\rm{k}}_{{\rm{deg}}}} \times {\rm{AR}} - {{\rm{k}}_{{\rm{on}}}}/{{\rm{V}}_{\rm{d}}} \times {\rm{AR}} \times {{\rm{A}}_{\rm{s}}} + {{\rm{k}}_{{\rm{off}}}} \times {\rm{ARC}}$$
((Eq. 19))
$${{{\rm{dARC}}} \over {{\rm{dt}}}} = {{\rm{k}}_{{\rm{on}}}}/{{\rm{V}}_{\rm{d}}} \times {\rm{AR}} \times {{\rm{A}}_{\rm{s}}} - {{\rm{k}}_{{\rm{off}}}} \times {\rm{ARC}} - {{\rm{k}}_{{\mathop{\rm int}} }} \times {\rm{ARC}}$$
((Eq. 20))

where As, AR and ARC denoted the amounts of G-CSF, its receptor and drug-receptor complex in MG-CSF units, and kon = k′on on=MG–CSF

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Wiczling, P., Lowe, P., Pigeolet, E. et al. Population Pharmacokinetic Modelling of Filgrastim in Healthy Adults following Intravenous and Subcutaneous Administrations. Clin Pharmacokinet 48, 817–826 (2009). https://doi.org/10.2165/11318090-000000000-00000

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