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Population Pharmacokinetics of MCLA-128, a HER2/HER3 Bispecific Monoclonal Antibody, in Patients with Solid Tumors

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Abstract

Background and Objectives

MCLA-128 is a bispecific monoclonal antibody targeting the HER2 and HER3 receptors and is in development to overcome HER3-mediated resistance to anti-HER2 therapies. The aims of this analysis were to characterize the population pharmacokinetics of MCLA-128 in patients with various solid tumors, to evaluate patient-related factors that affect the disposition of MCLA-128, and to assess whether flat dosing is appropriate.

Methods

MCLA-128 concentration data following intravenous administration were collected in a phase I/II clinical trial. Pharmacokinetic data were analyzed using non-linear mixed-effects modeling. Different compartmental models were evaluated. Various body size parameters including body weight, body surface area, and fat-free mass were evaluated as covariates in addition to age, sex, HER2 status, and tumor burden.

Results

In total, 1115 serum concentration measurements were available from 116 patients. The pharmacokinetics of MCLA-128 was best described by a two-compartment model with linear and non-linear (Michaelis–Menten) clearance. Fat-free mass significantly affected the linear clearance and volume of distribution of the central compartment of MCLA-128, explaining 8.4% and 5.6% of inter-individual variability, respectively. Tumor burden significantly affected the non-linear clearance capacity. Simulations demonstrated that dosing based on body size parameters resulted in similar area under the plasma concentration-time curve for a dosing interval (AUC0–τ), maximum and trough concentrations of MCLA-128, compared to flat dosing.

Conclusions

This analysis demonstrated that the pharmacokinetics of MCLA-128 exhibits similar disposition characteristics to other therapeutic monoclonal antibodies and that a flat dose of MCLA-128 in patients with various solid tumors is appropriate.

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Authors and Affiliations

  1. Department of Pharmacy and Pharmacology, Antoni van Leeuwenhoek Hospital, The Netherlands Cancer Institute and MC Slotervaart, Louwesweg 6, 1066 EC, Amsterdam, The Netherlands

    Aurelia H. M. de Vries Schultink, Thomas P. C. Dorlo, Jos H. Beijnen & Alwin D. R. Huitema

  2. Merus N.V., Utrecht, The Netherlands

    Kees Bol, Robert P. Doornbos, Anastasia Murat & Ernesto Wasserman

  3. Division of Pharmacoepidemiology and Clinical Pharmacology, Department of Pharmaceutical Sciences, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, The Netherlands

    Jan H. M. Schellens & Jos H. Beijnen

  4. Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands

    Alwin D. R. Huitema

Authors
  1. Aurelia H. M. de Vries Schultink
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  2. Kees Bol
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  3. Robert P. Doornbos
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  4. Anastasia Murat
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  5. Ernesto Wasserman
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  6. Thomas P. C. Dorlo
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  7. Jan H. M. Schellens
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  8. Jos H. Beijnen
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  9. Alwin D. R. Huitema
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Corresponding author

Correspondence to Aurelia H. M. de Vries Schultink.

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Conflict of interest

Kees Bol, Robert P. Doornbos, Anastasia Murat, and Ernesto Wasserman are employees of Merus N.V. Aurelia H.M. de Vries Schultink, Thomas P.C. Dorlo, Jan H.M. Schellens, Jos H. Beijnen, and Alwin D.R. Huitema have no conflicts of interest that are directly relevant to the content of this article.

Consent to participate

All patients provided written informed consent before study entry.

Funding

This research was funded by Merus N.V. Thomas P.C. Dorlo is personally supported by NWO/ZonMw through a Veni grant (grant no. 91617140).

Ethics approval

This study was conducted in compliance with the Declaration of Helsinki, International Conference on Harmonization Guidelines for Good Clinical Practice. The protocol was approved by the ethics committees of all participating centers.

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de Vries Schultink, A.H.M., Bol, K., Doornbos, R.P. et al. Population Pharmacokinetics of MCLA-128, a HER2/HER3 Bispecific Monoclonal Antibody, in Patients with Solid Tumors. Clin Pharmacokinet 59, 875–884 (2020). https://doi.org/10.1007/s40262-020-00858-2

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  • DOI: https://doi.org/10.1007/s40262-020-00858-2

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