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Cetuximab Exhibits Sex Differences in Lymphatic Exposure after Intravenous Administration in Rats in the Absence of Differences in Plasma Exposure

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Abstract

Purpose

The aim of this work was to identify whether biochemical and physiological sources of mAb pharmacokinetic sex-effects could be identified in the rat model where target-mediated disposition is avoided.

Methods

Plasma and lymphatic pharmacokinetics of the humanised anti-EGFR antibody cetuximab, along with potential physiological and biochemical drivers of pharmacokinetic sex differences, were examined in male and female rats. Cetuximab was used as a model mAb since plasma clearance is slower in female patients.

Results

When plasma concentrations were normalised to dose, female rats displayed slower plasma clearance than males, but no significant differences were observed in liver and spleen biodistribution. Sex differences in apparent plasma clearance, however, were abolished after normalisation to body weight, surface area or fat-free mass. Significant sex differences were observed in plasma testosterone, endogenous IgG and fat free mass, but did not correlate with apparent clearance. Females did, however, show two-fold higher lymphatic exposure compared to males.

Conclusions

These data suggested that mAbs more efficiently access lymph in females, but this does not affect plasma pharmacokinetics or biodistribution. Further, the data suggest that sex differences observed in humans could be a function of antigen density.

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Abbreviations

EGFR:

Epidermal growth factor receptor

FcRn:

Neonatal Fc receptor

FcγR:

Fc gamma receptor

FFM:

Fat free mass

mAb:

Monoclonal antibody

MPS:

Mononuclear phagocyte system

TMDD:

Target mediated drug disposition

WCC:

Peripheral white blood cell count

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Authors and Affiliations

  1. School of Biomedical Sciences, University of Queensland, St Lucia, QLD, 4072, Australia

    Esther Kuilamu, Christopher Subasic, Rodney F Minchin & Lisa M Kaminskas

  2. National Imaging Facility, Centre for Advanced Imaging, University of Queensland, St Lucia, QLD, 4072, Australia

    Gary J Cowin

  3. Epithelial Pathobiology Group, University of Queensland Diamantina Institute, Translational Research Institute, University of Queensland, Woolloongabba, QLD, Australia

    Fiona Simpson

Authors
  1. Esther Kuilamu
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  2. Christopher Subasic
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  3. Gary J Cowin
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  4. Fiona Simpson
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  5. Rodney F Minchin
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  6. Lisa M Kaminskas
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Correspondence to Rodney F Minchin or Lisa M Kaminskas.

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Kuilamu, E., Subasic, C., Cowin, G.J. et al. Cetuximab Exhibits Sex Differences in Lymphatic Exposure after Intravenous Administration in Rats in the Absence of Differences in Plasma Exposure. Pharm Res 37, 224 (2020). https://doi.org/10.1007/s11095-020-02945-2

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  • DOI: https://doi.org/10.1007/s11095-020-02945-2

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