Determination of effective blood concentrations of cyclosporine in pediatric severe aplastic anemia based on a time-to-response model
Michael Philippe (1,2), Sylvain Goutelle (2,3), Yves Bertrand (4), Dominique Plantaz (5), Nathalie Bleyzac (1,2), Emilie Hénin (2,6)
(1) Département de Pharmacie, Service d’Hématologie et Oncologie Pédiatrique, IHOP, Lyon, France (2) UMR CNRS 5558 – Equipe Evaluation et Modélisation des Effets Thérapeutiques, Université Claude Bernard Lyon 1, France (3) Département de Pharmacie, Groupement Hospitalier de Gériatrie, Hospices Civils de Lyon, France (4) Unité de Transplantation, Service d’Hématologie et Oncologie Pédiatrique, IHOP, Lyon, France (5) Service d’Hématologie et Oncologie Pédiatrique, CHU Grenoble, France (6) Service de Pharmacologie Clinique et Essais Thérapeutiques, Hospices Civils de Lyon, France
Objectives: Optimal immunosuppressive therapy in acquired severe aplastic anemia (SAA), a rare disease affecting children, remains to be defined. Current recommendations state that cyclosporine (CsA) trough blood concentrations (TBC) should be maintained between 200 and 400 ng/mL, but there is a lack of data supporting this target. Our study aimed at quantifying relationships between exposure to CsA and hematological response, and at determining the effective CsA TBC target range in a cohort of children with SAA.
Methods: Data from 23 pediatric patients with SAA treated with CsA were retrospectively analyzed to develop a population PK/Interface/Time-to-event model, linking CsA doses, TBC, effective concentration and time-to-hematological response (TTR). The effective concentration profile was driven by CsA TBC through an interface compartment1.The input function of the interface compartment was adapted to estimate a lower and an upper bound of effective CsA TBC, thus defining an effective range. A time-to-event model linked effective concentration profile to TTR, defined as two successive neutrophil counts > 0.5x109 cells/L. TTR was prospectively predicted in three additional patients not included in the model building.
Results: Fifteen out of 23 patients (65.2%) had a hematological response with a median TTR of 69 days (min 19- max 182). The median (min-max) age and weight were 8.5 (8-15) years and 34 (9.8-79.3) kg respectively. CsA TBC profiles were adequately described by an allometrically scaled two-compartment model with first-order absorption with a lag-time and a linear elimination. The effective target range of CsA TBC was estimated at 87 - 120 ng/mL (relative standard error < 5%). Simulations showed that the optimal CsA TBC target would be 100 ng/mL resulting in maximal response rate. TBC values above or below the 87-120 ng/mL range would be associated with lower response rate. Moreover, for three new patients, TTR predicted distribution from their TBC values was remarkably consistent with the observed TTR values (57, 41 and 61 days respectively).
Conclusions: This original modeling approach was successful in describing the relationships between CsA TBC and the hematological response in patients with SAA. While further research in a larger population is necessary to confirm our findings, this work suggests that a CsA TBC target of 100 ng/mL, much lower than that currently recommended, would be associated with a better response rate in children with SAA.
 Meille C, Iliadis A, Barbolosi D, Frances N, Freyer G. An interface model for dosage adjustment connects hematotoxicity to pharmacokinetics. J Pharmacokinet Pharmacodyn 2008;35(6):619–33.