Model-Based Determination of Effective Blood Concentrations of Cyclosporine for Neutrophil Response in the Treatment of Severe Aplastic Anemia in Children

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• 作者：Micha?l Philippe ; Emilie Hénin ; Yves Bertrand ; Dominique Plantaz…
• 关键词：aplastic anemia ; cyclosporine ; modeling ; pharmacokinetics ; regulatory T lymphocytes
• 刊名：The AAPS Journal
• 出版年：2015
• 出版时间：September 2015
• 年：2015
• 卷：17
• 期：5
• 页码：1157-1167
• 全文大小：1,038 KB
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• 作者单位：Micha?l Philippe (1) (2)
  Emilie Hénin (2) (3)
  Yves Bertrand (1)
  Dominique Plantaz (4)
  Sylvain Goutelle (2) (5) (6)
  Nathalie Bleyzac (1) (2)
  
  1. Institut d’Hématologie et d’Oncologie Pédiatrique, 1 place Joseph Renaut, 69008, Lyon, France
  2. Laboratoire de Biométrie et Biologie Evolutive, UMR CNRS 5558, Université Lyon 1, 43 bd du 11 novembre 1918, 69622, Villeurbanne, France
  3. Service de Pharmacologie et Essais Thérapeutiques, Faculté de Médecine Laennec, Hospices Civils de Lyon, Rue Guillaume Paradin, 69376, Lyon Cedex 08, France
  4. Unité d’onco-hématologie pédiatrique, H?pital La tronche, Université de Grenoble, Avenue du Maquis du Grésivaudan, 38700, Grenoble, France
  5. Faculté de Pharmacie de Lyon, ISPB, Université Lyon 1, 8 avenue Rockefeller, 69373, Lyon, France
  6. Service Pharmaceutique, Groupement Hospitalier de Gériatrie, Hospices Civils de Lyon, 136 Rue Commandant Charcot, 69005, Lyon, France
  
• 刊物主题：Pharmacology/Toxicology; Biochemistry, general; Biotechnology; Pharmacy;
• 出版者：Springer US
• ISSN：1550-7416

文摘

Optimal immunosuppressive therapy in acquired severe aplastic anemia (SAA) remains to be refined, especially cyclosporine (CsA) use. Current recommendations state that CsA trough blood concentrations (TBC) should be maintained between 200 and 400?ng/mL despite the lack of supporting data. This study aimed at quantifying relationships between CsA exposure and neutrophil response and determining an effective range for CsA TBC. Twenty-three SAA patients treated with CsA were retrospectively analyzed. Nonlinear mixed effect modeling approaches were used to develop a pharmacokinetic-pharmacodynamic model. The pharmacokinetic model described the relationships between CsA doses and TBC. The pharmacodynamic model allowed to estimate boundaries for optimal CsA effects, neutrophils being used as biomarker of response. A time-to-event model linked effective concentration to time-to-therapeutic success. CsA TBC were adequately described by a two-compartment model with first-order absorption, a lag time, and a linear elimination. The efficient range of CsA TBC was estimated between 87 and 120?ng/mL. Model-based simulations and external validation in three additional patients confirmed these results. This original modeling approach was successful in describing the relationship between CsA TBC and neutrophil response in SAA patients. Although further evaluation of the model is necessary, this work suggests that an optimal CsA TBC target of 100?ng/mL would be associated with a better neutrophil response in children with SAA.