title: Model-Based Determination of Effective Blood Concentrations of Cyclosporine for Neutrophil Response in the Treatment of Severe Aplastic Anemia in Children.
abstract: 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.
authors.affiliation: Institut d'Hématologie et d'Oncologie Pédiatrique, 1 place Joseph Renaut, 69008, Lyon, France, michael.philippe@chu-lyon.fr.
authors.forename: Michaël
authors.initials: M
authors.lastname: Philippe
authors.forename: Emilie
authors.initials: E
authors.lastname: Hénin
authors.forename: Yves
authors.initials: Y
authors.lastname: Bertrand
authors.forename: Dominique
authors.initials: D
authors.lastname: Plantaz
authors.forename: Sylvain
authors.initials: S
authors.lastname: Goutelle
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bleyzac
mesh_terms: D000293:Adolescent; D000741:Anemia, Aplastic / Q000188:drug therapy*; D002648:Child; D002675:Child, Preschool; D016572:Cyclosporine / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D007223:Infant; D008297:Male; D008954:Models, Biological; D009504:Neutrophils / Q000378:metabolism; D017711:Nonlinear Dynamics; D012189:Retrospective Studies; D012720:Severity of Illness Index; D013997:Time Factors
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine