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01.02.2014 | Original Article

Fractionation of daily dose increases the predicted risk of severe sorafenib-induced hand–foot syndrome (HFS)

verfasst von: Emilie Hénin, Benoit Blanchet, Pascaline Boudou-Rouquette, Audrey Thomas-Schoemann, Gilles Freyer, Michel Vidal, François Goldwasser, Michel Tod

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 2/2014

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Abstract

Objectives

The objective was to quantify the risk dynamics for the sorafenib-induced hand–foot syndrome (HFS) and to explore by simulations the dose–toxicity relationships according to different dosing regimens.

Patients and methods

Eighty-nine patients treated with sorafenib were considered: Treatment duration and regimen, and number and frequency of HFS observations were highly variable. A nonlinear mixed-effect model was built to link sorafenib administrations to the risk of each HFS score, through a latent variable model. Model evaluation was driven by goodness-of-fit and simulation-based diagnostics. Impact of sorafenib regimen on HFS dynamics was evaluated by simulations. A surrogate measure of benefit-to-risk ratio was calculated by using the concept of utility function, accounting for efficacy on tumor growth inhibition and severe HFS risk.

Results and discussion

An original pharmacokinetic–pharmacodynamic model for sorafenib-induced HFS, including the kinetics of a latent variable model, relating sorafenib administrations, per se its exposure, to HFS dynamics is proposed. From the model simulations, it appears that the more the daily dose is fractioned, the more the patients are at risk of HFS. Interestingly, the number of daily occasions was found more influential than the dose itself. Taking into account tumor growth inhibition in the utility function, the twice-daily administration schedule is favored for daily doses >600 mg. This approach illustrates how understanding the dynamic relationship between drug administrations and a limiting adverse event may help to control toxicity and adequately adjust treatment modalities.

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Titel: Fractionation of daily dose increases the predicted risk of severe sorafenib-induced hand–foot syndrome (HFS)
verfasst von: Emilie Hénin
Benoit Blanchet
Pascaline Boudou-Rouquette
Audrey Thomas-Schoemann
Gilles Freyer
Michel Vidal
François Goldwasser
Michel Tod
Publikationsdatum: 01.02.2014
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 2/2014
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-013-2352-1

Springer Medizin

Fractionation of daily dose increases the predicted risk of severe sorafenib-induced hand–foot syndrome (HFS)