Population pharmacokinetic–pharmacodynamic analysis for eribulin mesilate-associated neutropenia

Authors

  • J. G. Coen van Hasselt,

    Corresponding author
    1. Department of Pharmacy & Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Amsterdam, The Netherlands
    • Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
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  • Anubha Gupta,

    1. Eisai Limited, Hatfield, UK
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  • Ziad Hussein,

    1. Eisai Limited, Hatfield, UK
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  • Jos H. Beijnen,

    1. Department of Pharmacy & Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Amsterdam, The Netherlands
    2. Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands
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  • Jan H. M. Schellens,

    1. Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
    2. Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands
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  • Alwin D. R. Huitema

    1. Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
    2. Department of Pharmacy & Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Amsterdam, The Netherlands
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Correspondence

Mr J. G. Coen van Hasselt, Netherlands Cancer Institute/Slotervaart Hospital, Department of Pharmacy and Pharmacology, Louwesweg 6, PO Box 90440, 1006 BK Amsterdam, The Netherlands.

Tel.: +31 20 512 4665

Fax: +31 20 512 2050

E-mail: jgc.vanhasselt@gmail.com

Abstract

Aims

Eribulin mesilate is an inhibitor of microtubule dynamics that is approved for the treatment of late-stage metastatic breast cancer. Neutropenia is one of the major dose-limiting adverse effects of eribulin. The objective of this analysis was to develop a population pharmacokinetic–pharmacodynamic model for eribulin-associated neutropenia.

Methods

A combined data set of 12 phase I, II and III studies for eribulin mesilate was analysed. The population pharmacokinetics of eribulin was described using a previously developed model. The relationship between eribulin pharmacokinetic and neutropenia was described using a semi-physiological lifespan model for haematological toxicity. Patient characteristics predictive of increased sensitivity to develop neutropenia were evaluated using a simulation framework.

Results

Absolute neutrophil counts were available from 1579 patients. In the final covariate model, the baseline neutrophil count (ANC0) was estimated to be 4.03 × 109 neutrophils l−1 [relative standard error (RSE) 1.2%], with interindividual variability (IIV, 37.3 coefficient of variation % [CV%]). The mean transition time was estimated to be 109 h (RSE 1.8%, IIV 13.9CV%), the feedback constant (γ) was estimated to be 0.216 (RSE 1.4%, IIV 12.2CV%), and the linear drug effect coefficient (SLOPE) was estimated to be 0.0451 μg l−1 (RSE 3.2%, IIV 54CV%). Albumin, aspartate transaminase and receival of granulocyte colony-stimulating factor (G-CSF) were identified as significant covariates on SLOPE, and albumin, bilirubin, G-CSF, alkaline phosphatase and lactate dehydrogenase were identified as significant covariates on mean transition time.

Conclusions

The developed model can be applied to investigate optimal treatment strategies quantitatively across different patient groups with respect to neutropenia. Albumin was identified as the most clinically important covariate predictive of interindividual variability in the neutropenia time course.

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