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A simultaneous analysis of the time-course of leukocytes and neutrophils following docetaxel administration using a semi-mechanistic myelosuppression model

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Summary

Purpose To improve the predictive capacity of a semi-mechanistic myelosuppression model for neutrophils as the model have shown to over-predict the nadir of neutrophils and, secondly, to develop a model describing the time-course of leukocytes and neutrophils simultaneously. Experimental Design The study included 601 cancer patients treated with a 1 h infusion of docetaxel in monotherapy. A total of 3,549 pairwise observations of leukocytes and neutrophils from one treatment cycle were analyzed simultaneously in NONMEM. Results A basic model was developed consisting of a neutrophil and a non-neutrophil model, each with the same structure as the semi-mechanistic myelosuppression model. The leukocytes were modeled as the sum of the predicted neutrophils and non-neutrophils. The model described the time-course of the leukocytes well, but was not able to capture the nadir of the neutrophils. Hence the model was further refined and the included modifications (p < 0.001) in the final model are a sigmoid Emax functions for the drug effect, feedback functions on the cell maturation time in bone-marrow and an optimized number of transit compartments for each of the two cell types. Conclusions A joint semi-mechanistic myelosuppression model describing the time-course of leukocytes and neutrophils following docetaxel administration was developed. The data supported a more complex model compared to the previous model developed by Friberg et al. (2002), and increased the model’s capacity to accurately describe the time-course of neutrophils following docetaxel therapy. The combined model also illustrates the differences between the cell types and allows prediction of neutrophil counts from leukocyte measurements.

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Acknowledgment

We would like to thank Dr Rene Bruno for providing the data. This research was supported by the Swedish Cancer Society. Lena Friberg received a grant from Knut and Alice Wallenberg foundation, Sweden.

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The authors declare no conflicts of interest.

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Authors and Affiliations

  1. The Pharmacometrics Research Group, Department of Pharmaceutical Biosciences, Uppsala University, Box 591, SE-751 24, Uppsala, Sweden

    Angelica Linnea Quartino, Lena E. Friberg & Mats O. Karlsson

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  1. Angelica Linnea Quartino
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  2. Lena E. Friberg
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  3. Mats O. Karlsson
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Correspondence to Angelica Linnea Quartino.

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Quartino, A.L., Friberg, L.E. & Karlsson, M.O. A simultaneous analysis of the time-course of leukocytes and neutrophils following docetaxel administration using a semi-mechanistic myelosuppression model. Invest New Drugs 30, 833–845 (2012). https://doi.org/10.1007/s10637-010-9603-3

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