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Population pharmacokinetics and exposure–response relationship of amatuximab, an anti-mesothelin monoclonal antibody, in patients with malignant pleural mesothelioma and its application in dose selection

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Abstract

Purpose

To characterize amatuximab pharmacokinetics (PK) and the relationship of amatuximab exposure with response in patients with unresectable malignant pleural mesothelioma (MPM) receiving amatuximab with pemetrexed and cisplatin.

Methods

A nonlinear mixed effects PK model was built using data from all of the amatuximab studies conducted to date. Patients received amatuximab alone or in combination with chemotherapy. The influence of demographic, laboratory and disease characteristics on PK parameters was assessed. Exposure–response analyses explored relationships between amatuximab exposure and overall survival (OS), progression-free survival (PFS) and safety. Alternative amatuximab dosing regimens were explored with simulations using population PK and parametric survival models.

Results

Amatuximab PK was best described by a two-compartment model with parallel linear and nonlinear elimination pathways. Body weight and an antidrug antibodies reaction with the titer >64 affected volume of distribution and clearance, respectively. Exposure–response analyses demonstrated that the amatuximab exposure (C min) showed a significant effect on OS (log-rank test, P = 0.0202). For patients with amatuximab C min above the median (38.2 μg/mL), the median OS was 583 days (90 % CI 418 –NE). For patients with C min ≤ 38.2 μg/mL, the median OS was 375 days (90 % CI 325–486). The amatuximab exposure showed similar significant effect on PFS. Exposure–response analysis for adverse events did not reveal any relationship.

Conclusions

In patients with MPM, higher amatuximab exposure in combination with chemotherapy was shown to be associated with longer OS, supporting evaluation of more frequent dosing in future trials to achieve higher exposure and subsequently longer OS.

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Acknowledgments

The study was funded by Morphotek/Eisai.

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Authors and Affiliations

  1. Clinical Pharmacology, Eisai Limited, European Knowledge Centre, Mosquito Way, Hatfield, Hertfordshire, AL10 9SN, UK

    Anubha Gupta & Ziad Hussein

  2. Morphotek, Inc., Exton, PA, USA

    Jason Wustner & Bruce A. Wallin

  3. Thoracic and GI Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

    Raffit Hassan

  4. Former Employee of Morphotek, Inc., Exton, PA, USA

    Julia D. Maltzman

Authors
  1. Anubha Gupta
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  2. Ziad Hussein
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  3. Raffit Hassan
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  4. Jason Wustner
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  5. Julia D. Maltzman
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  6. Bruce A. Wallin
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Corresponding author

Correspondence to Ziad Hussein.

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Conflict of interest

Anubha Gupta is a former employee of Eisai and Ziad Hussein is employed by Eisai. Bruce A. Wallin and Jason Wustner are employed by Morphotek, a subsidiary of Eisai. Julia D. Maltzman is a former employee of Morphotek. Raffit Hassan does not have a potential conflict of interest.

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Gupta, A., Hussein, Z., Hassan, R. et al. Population pharmacokinetics and exposure–response relationship of amatuximab, an anti-mesothelin monoclonal antibody, in patients with malignant pleural mesothelioma and its application in dose selection. Cancer Chemother Pharmacol 77, 733–743 (2016). https://doi.org/10.1007/s00280-016-2984-z

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  • DOI: https://doi.org/10.1007/s00280-016-2984-z

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