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Pharmacokinetics, immunogenicity, and safety of weekly dosing of brentuximab vedotin in pediatric patients with Hodgkin lymphoma

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Abstract

Purpose

Because of the observed success of phase I/II trials, the novel anti-CD30 agent brentuximab vedotin is now being evaluated as a frontline agent in the high-risk pediatric Hodgkin lymphoma trial HLHR13. The objectives of this study were to evaluate the pharmacokinetic variability during weekly dosing of 1.2 mg/kg of brentuximab vedotin, determine factors that may explain this variability, compare our drug exposure with published data, and evaluate toxicity of brentuximab vedotin in the pediatric population.

Methods

Brentuximab vedotin, MMAE and anti-therapeutic antibody levels were measured in the serum samples of 16 pediatric patients with Hodgkin lymphoma. A compartmental pharmacokinetic model was fit to the data by using nonlinear mixed-effects modeling.

Results

Clearance and volume of brentuximab vedotin were significantly correlated with weight (p < .001), which was responsible for over 60% of the parameters inter-individual variability. Clearance and volume were higher in boys compared to girls (p = 0.08 and p = 0.03, respectively). Brentuximab vedotin’s AUC and C max were lower in our pediatric study than those reported in adult studies (25 and 11%, respectively). Toxicity was comparable to that of the standard-of-care backbone using vincristine instead of brentuximab vedotin. The sera of all 16 patients remained negative for anti-therapeutic antibodies during and at the end of therapy.

Conclusions

As in previous studies, weight continues to be the most significant factor explaining brentuximab vedotin’s pharmacokinetic variability in pediatric patients. Exposure to weekly dosing appears to be safe and tolerable in pediatric patients.

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Acknowledgements

This study was supported in part by the NIH Cancer Center Support Grant CA21765 and the American Lebanese Syrian Associated Charities (ALSAC).

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Authors and Affiliations

  1. Department of Oncology, St. Jude Children’s Research Hospital, The University of Tennessee Health Science Center, 262 Danny Thomas Pl, Mailstop 260, Memphis, TN, 38105, USA

    Jamie E. Flerlage & Monika L. Metzger

  2. Department of Biostatistics, St. Jude Children’s Research Hospital, The University of Tennessee Health Science Center, Memphis, TN, USA

    Jianrong Wu

  3. Pharmaceutical Sciences, St. Jude Children’s Research Hospital, The University of Tennessee Health Science Center, Memphis, TN, USA

    John C. Panetta

Authors
  1. Jamie E. Flerlage
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  2. Monika L. Metzger
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  3. Jianrong Wu
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Correspondence to Jamie E. Flerlage.

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The authors declare that they have no conflict of interest.

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Flerlage, J.E., Metzger, M.L., Wu, J. et al. Pharmacokinetics, immunogenicity, and safety of weekly dosing of brentuximab vedotin in pediatric patients with Hodgkin lymphoma. Cancer Chemother Pharmacol 78, 1217–1223 (2016). https://doi.org/10.1007/s00280-016-3180-x

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  • DOI: https://doi.org/10.1007/s00280-016-3180-x

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