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Pharmacokinetic and pharmacodynamic analysis of neutropenia following nab-paclitaxel administration in Japanese patients with metastatic solid cancer

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Abstract

Purpose

To develop a pharmacokinetic (PK) and pharmacodynamic (PD) model for neutropenia following nab-paclitaxel administration and identify factors associated with drug disposition and changes in neutrophil counts in patients with solid cancer.

Methods

PK/PD analysis by nonlinear mixed effects approach was performed using the data from 27 patients who participated in phase I studies of nab-paclitaxel monotherapy conducted in Japan. The patients were treated with either weekly (80, 100, or 125 mg/m2) or every 3 weeks (200, 260, or 300 mg/m2). The observed paclitaxel concentrations in whole blood and neutrophil counts in the first cycle were used for PK/PD analysis. Covariate analysis was performed to identify factors affecting PK and the decrease in neutrophil counts.

Results

The developed 3-compartment, non-linear PK model described relationships of body surface area with total body clearance and volume of distribution for the peripheral compartment. Covariate factors affecting neutrophil counts were age and serum albumin level. Simulation based on the developed PK/PD model showed a substantial impact of age and serum albumin level on the time course of neutrophil counts after nab-paclitaxel administration. Advanced age was related to greater decrease in neutrophil counts, and serum albumin level, inversely related to change in neutrophil counts.

Conclusion

We have developed a novel PK/PD model for nab-paclitaxel in which age and serum albumin level were considered clinically important covariate factors. This model needs to be further validated using a larger patient population.

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Acknowledgements

The authors acknowledge Taiho Pharmaceutical Co., Ltd. for their support providing the anonymous clinical data. We also thank Enago for the professional English editing of this manuscript.

Funding

No financial support was received for the present study.

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Authors and Affiliations

  1. Department of Clinical Pharmacokinetics and Pharmacodynamics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Takahiro Tsushima, Hidefumi Kasai & Yusuke Tanigawara

  2. Division of Gastrointestinal Oncology, Shizuoka Cancer Centre, 1007 Shimonagakubo, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8777, Japan

    Takahiro Tsushima

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  1. Takahiro Tsushima
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Correspondence to Yusuke Tanigawara.

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Tsushima, T., Kasai, H. & Tanigawara, Y. Pharmacokinetic and pharmacodynamic analysis of neutropenia following nab-paclitaxel administration in Japanese patients with metastatic solid cancer. Cancer Chemother Pharmacol 86, 487–495 (2020). https://doi.org/10.1007/s00280-020-04140-x

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