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

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• 作者：Emilie Hénin (1) (2)
  Benoit Blanchet (3) (4) (5)
  Pascaline Boudou-Rouquette (3) (6) (7)
  Audrey Thomas-Schoemann (3) (4) (5)
  Gilles Freyer (1) (2) (8)
  Michel Vidal (3) (4) (5)
  Fran?ois Goldwasser (3) (6) (7)
  Michel Tod (1) (2)
  
• 关键词：Latent variable ; Toxicity control ; Model ; Utility function
• 刊名：Cancer Chemotherapy and Pharmacology
• 出版年：2014
• 出版时间：February 2014
• 年：2014
• 卷：73
• 期：2
• 页码：287-297
• 全文大小：745 KB
• 作者单位：Emilie Hénin (1) (2)
  Benoit Blanchet (3) (4) (5)
  Pascaline Boudou-Rouquette (3) (6) (7)
  Audrey Thomas-Schoemann (3) (4) (5)
  Gilles Freyer (1) (2) (8)
  Michel Vidal (3) (4) (5)
  Fran?ois Goldwasser (3) (6) (7)
  Michel Tod (1) (2)
  
  1. Université de Lyon, Lyon, France
  2. EMR 3738, Ciblage Thérapeutique en Oncologie, Faculté de Médecine et de Ma?eutique Lyon-Sud, Université Lyon 1, Oullins, France
  3. Centre d’étude et de recours sur les inhibiteurs de l’angiogénèse (CERIA), Paris, France
  4. UMR8638 CNRS, UFR de Pharmacie, PRES Sorbonne Paris Cité, Université Paris Descartes, Paris, France
  5. Unité Fonctionnelle de Pharmacocinétique et Pharmacochimie, Assistance Publique H?pitaux de Paris, H?pital Cochin, Paris, France
  6. Unité de Cancérologie médicale, Assistance Publique H?pitaux de Paris, H?pital Cochin, Paris, France
  7. Sorbonne Paris Cité, Université Paris Descartes, Paris, France
  8. Service d’Oncologie Médicale, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre-Bénite, France
  
• ISSN：1432-0843

文摘

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.